WO2014010990A1 - 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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- WO2014010990A1 WO2014010990A1 PCT/KR2013/006269 KR2013006269W WO2014010990A1 WO 2014010990 A1 WO2014010990 A1 WO 2014010990A1 KR 2013006269 W KR2013006269 W KR 2013006269W WO 2014010990 A1 WO2014010990 A1 WO 2014010990A1
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- 0 CCC(c1ncccc1S*)=O Chemical compound CCC(c1ncccc1S*)=O 0.000 description 7
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
- A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
- A01N47/36—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the group >N—CO—N< directly attached to at least one heterocyclic ring; Thio analogues thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/61—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
- C07D213/71—Sulfur atoms to which a second hetero atom is attached
Definitions
- Y represents fluorine, chlorine or bromine.
- the compound of formula 2b wherein Y is chlorine or bromine can be converted into the compound of formula 2a wherein Y is fluorine by reacting with the compound of formula 6 in the presence of a phase-transfer catalyst in a solvent, as shown in the above reaction scheme 1.
- reaction step can be carried out at a temperature ranging from -40 to -90°C, preferably at a temperature of -50 to -80°C, more preferably at a temperature of -60 to -78°C.
- A represents C 3 -C 5 -alkyl or C 3 -C 6 -cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C 1 -C 2 -alkyl and C 1 -C 2 -alkoxy,
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
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.
The following compound of formula 1 is known as flucetosulfuron which has superior herbicidal activity (WO 2002/030921). According to JP Patent Laid-open Publication No. 2003-335758, the compound of formula 1 is prepared by using an intermediate compound of the following formula 2:
[Formula 1]
[Formula 2]
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy; and
Y represents fluorine, chlorine or bromine.
In order to introduce a key radical fluorine into the compound of formula 1, a compound of formula 2a in which Y is fluorine is required. The compound of formula 2a is obtained by reacting the compound of formula 4 with the Cu (II) salt of formula 5 in a solvent to produce the compound of formula 2b, which is subsequently reacted with the compound of formula 6 optionally in the presence of a phase-transfer catalyst, as shown in the following reaction scheme 1.
[Reaction Scheme 1]
wherein A is the same as defined above, Y’ represents chlorine or bromine, and M represents alkaline metal such as sodium, potassium and cesium.
As shown in the above reaction, two-step reactions are required in order to simply introduce fluorine into the compound of formula 4 of which the base structure is the same as the compound of formula 2a. Furthermore, it is difficult to completely remove a Cu by-product inevitably produced from the reaction and such a by-product affects the subsequent fluorination reaction, which lowers the yield thereof. The pyridyl ketone derivatives of formula 4 are disclosed in US 5,354,749 A1, Kevin A. Memoli, Tetrahedron Lett. 1996, 37, 3617 or DE 4,304,007 A1, or they can be obtained by a similar method disclosed therein, which consists disadvantageously of four-step reactions.
Considering the above problems, the present inventors have intensively studied the method of preparing conveniently the key intermediate compound of formula 2 for producing flucetosulfuron of formula 1 to conceive successfully the process to introduce C(=O)CHYCH3 (Y represents fluorine, chlorine or bromine) radical into the C-2 position of pyridine by a one-step reaction. Using the process, the present inventors have developed the method of preparing the objective compound of formula 2 starting from commercial material by only two-step reactions to complete the present invention.
The object of the present invention is to provide a novel method for the preparation of a key intermediate compound for producing flucetosulfuron showing superior herbicidal activity.
Another object of the present invention is to provide novel pyridine derivatives used in the preparation of the intermediate compound and a method for the preparation thereof.
Therefore, the present invention provides pyridine derivatives of the following formula 3 for the preparation of flucetosulfuron.
[Formula 3]
wherein,
D represents fluorine or chlorine, or represents S-A,
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy,
E represents bromine or C(=O)CHYCH3, and
Y represents fluorine, chlorine or bromine.
Preferable compounds of the above pyridine derivatives are pyridyl ketone derivatives of the following formula 3a and 2-bromopyridine derivatives of the following formula 3b.
[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 represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy.
Examples of preferable compounds of formula 3a are 1-(3-fluoropyridin-2-yl)-2-fluoropropan-1-one, 1-(3-chloropyridin-2-yl)-2-fluoropropan-1-one, 1-(3-chloropyridin-2-yl)-2-chloropropan-1-one and 1-(3-chloropyridin-2-yl)-2-bromopropan-1-one.
Examples of preferable compounds of formula 3b are 2-bromo-3-isopropylthiopyridine, 2-bromo-3-benzylthiopyridine, 2-bromo-3-(4-methoxybenzyl) thiopyridine, 2-bromo-3-(t-butylthio)pyridine and 2-bromo-3-cyclohexylthiopyridine.
The compounds of formula 3a according to the present invention are prepared by reacting the compound of the following formula 7 with n-butyllithium and N,N-dimethylaminoethanol (DMAE) and then with the compound of the following formula 8.
[Formula 7]
[Formula 8]
wherein,
D represents fluorine or chlorine,
Y represents fluorine, chlorine or bromine, and
W represents C1-C4-alkoxy, C1-C4-dialkylamine or morpholine.
The compounds of formula 3b according to the present invention are prepared by reacting the compound of formula 10 with a strong base of lithium amides of formula 11 and then with the electrophile compound of formula 12.
[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 represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy, and
X represents chlorine or S-A.
Especially, when X is S-A, the compound of formula 12 is disulfide compound having the symmetrical structure of the following formula 12a.
[Formula 12a]
A-S-S-A
The method of preparing the intermediate compound of formula 2 for the preparation of flucetosulfuron according to the present invention is characterized in that the compound of formula 3a is reacted with the compound of formula 9 in the presence of a Cu catalyst, a ligand, a base and a 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 represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy.
Another method of preparing the intermediate compound of formula 2 for the preparation of flucetosulfuron according to the present invention is characterized in that the compound of formula 3b is reacted with n-butyllithium, and then with the electrophile compound of formula 8.
[Formula 3b]
[Formula 8]
[Formula 2]
wherein,
W represents C1-C4-alkoxy, C1-C4-dialkylamine or morpholine,
Y represents fluorine, chlorine or bromine, and
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy.
Hereinafter, the present invention is described in more detail.
According to the present invention, two methods, method A and method B are provided for preparing the intermediate compound of formula 2 for the preparation of flucetosulfuron, depending on the order of introducing C(=O)CHYCH3 radical and S-A radical into the C-2 position and the C-3 position of pyridine, respectively.
[Method A]
In the first method for preparing the compound of formula 2, the C(=O)CHYCH3 radical is first introduced into the C-2 position of pyridine, and then the S-A radical is introduced into the C-3 position of pyridine. As a starting material, the easily obtainable compound of formula 7 is reacted with n-butyllithium and N,N-dimethylaminoethanol (DMAE) to introduce lithium selectively into the C-2 position of pyridine, and then reacted with the compound of formula 8 to produce the novel compound of formula 3a by forming a C-C bond. Afterward, the object compound of formula 2 can be prepared through a short process of reacting the compound of formula 3a with the compound of formula 9 in the presence of a Cu catalyst, ligand, base and solvent. The compound of formula 2b wherein Y is chlorine or bromine can be converted into the compound of formula 2a wherein Y is fluorine by reacting with the compound of formula 6 in the presence of a phase-transfer catalyst in a solvent, as shown in the above reaction scheme 1.
The above reactions and detailed reaction conditions are described as the following reaction scheme.
[Reaction Scheme 2]
wherein,
D represents fluorine or chlorine,
Y represents fluorine, chlorine or bromine,
W represents C1-C4-alkoxy, C1-C4-dialkylamine or morpholine, and
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy.
The substituents mentioned herein have the following meanings.
C3-C5-alkyl means propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, pentyl, sec-pentyl and t-amyl;
C3-C6-cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
C1-C2-alkyl means methyl and ethyl; and
C1-C2-alkoxy means methoxy and ethoxy.
Fort et al. disclose a method of removing hydrogen in the C-2 position of the compound of formula 7 selectively and introducing lithium ion therein (Eur. J. Org. Chem. 2001, 603; Lett. Org. Chem. 2009, 6, 50). In the first step of reaction scheme 2, the compound of formula 7 is reacted with a mixture of n-butyllithium and N,N-dimethylaminoethanol to remove the hydrogen in the C-2 position selectively and introduce lithium ion, by using the Fort method. Once an intermediate of lithium ion state is formed, it can be reacted with the electrophile compound of formula 8 directly in the same reaction vessel to prepare the novel intermediate compound of formula 3a. A conventional solvent which does not participate in the reaction can be used in this step. It is preferable to use one or more solvents selected from alkanes such as hexane and heptane, and ethers such as dimethyl ether, diethyl ether, methyl t-butyl ether, dimethoxyethane, tetrahydrofuran and dioxane. The reaction step can be carried out at a temperature ranging from 0 to -90℃, preferably at a temperature of -20 to -90℃, more preferably at a temperature of -40 to -78℃. The compound of formula 8 can be commercially obtained or can be prepared by using a conventional ester synthesis or amide synthesis from a corresponding organic acid. The electrophile compound of formula 8 is used in an amount of 0.9 to 1.5 equivalents, preferably 1.0 to 1.1 equivalents based on the starting compound of formula 7.
In the second step, the novel intermediate compound of formula 3a is reacted with the compound of formula 9 in the presence of a base, solvent, ligand and Cu catalyst to prepare the object compound of formula 2 by forming a C-S bond. The base includes inorganic base such as cesium carbonate, potassium carbonate, sodium bicarbonate, or organic base such as triethylamine, pyridine and diazabicycloundecene (DBU). Preferable bases are cesium carbonate, potassium carbonate and triethylamine, and more preferable bases are cesium carbonate and potassium carbonate. As a Cu catalyst, copper oxide (Cu2O), copper iodide (CuI), copper chloride (CuCl) and copper bromide (CuBr) can be used. Preferable catalysts are copper oxide (Cu2O) or copper iodide (CuI). The Cu catalyst is used in an amount of 0.01 to 0.5 equivalent, preferably in an amount of 0.05 to 0.2 equivalent. As a solvent, nonprotic polar solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAC), N-methylpyrrolidine (NMP) or aromatic solvents such as benzene, toluene and xylene can be used. Preferable solvents are dimethylsulfoxide, dimethylformamide, N-methylpyrrolidine or toluene, and more preferable ones are dimethylsulfoxide or dimethylformamide. The reaction step can be carried out at a temperature ranging from 0 to 60℃ and preferably at a temperature of 15 to 25℃. 2-(ethoxycarbonyl)cyclohexanone, 1,2-cyclohexanediamine or N,N-diethylamine can be used as a ligand.
[Method B]
The second method for preparing the compound of formula 2 is that the S-A radical is first introduced into the C-3 position of pyridine, and then the C(=O)CHYCH3 radical is introduced into the C-2 position of pyridine. As a starting material, the easily obtainable compound of formula 10 is reacted with strong base of lithium amides of the compound of formula 11 in a suitable solvent at -40 to -90℃ to introduce lithium into the C-3 position of pyridine, and it is then reacted with the electrophile compound of formula 12 to produce the novel compound of formula 3b. Afterward, the object compound of formula 2 can be prepared through a short process of introducing lithium into the C-2 position of the compound of formula 3b through bromine-lithium exchange reaction and then reacting with the electrophile compound of formula 8.
The above reactions and detailed reaction conditions are described as the following reaction scheme.
[Reaction Scheme 3]
wherein,
n represents 0 or 3,
X represents chlorine or S-A, especially, when X is S-A, the compound of formula 12 is disulfide compound having a symmetrical structure,
Y represents fluorine, chlorine or bromine,
W represents C1-C4-alkoxy, C1-C4-dialkylamine or morpholine, and
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy.
In the first step of reaction scheme 3, the compound of formula 10 is reacted with strong base of lithium amides of the compound of formula 11 to introduce lithium into the C-3 position of pyridine. In this reaction step, lithium diisopropylamide (n=0) or lithium 2,2,6,6-tetramethylpiperazide (n=3) can be used as the strong base compound of formula 11. A conventional solvent which does not participate in the reaction can be used in this step. It is preferable to use one or more solvents selected from alkanes such as hexane and heptane, and ethers such as dimethyl ether, diethyl ether, methyl t-butyl ether, dimethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane. The reaction step can be carried out at a temperature ranging from -40 to -90℃, preferably at a temperature of -60 to -90℃, more preferably at a temperature of -78 to -90℃. Once an intermediate of lithium ion state is formed, it can be reacted with the electrophile compound of formula 12 directly in the same reaction vessel to prepare the novel intermediate compound of formula 3b. The disulfide or sulfenyl chloride compound of formula 12 can be commercially obtained or can be prepared by using a conventional synthetic process (Gillis, H.M., Greene, L., Thompson, A. Synlett, 2009, 112; Leino, R., Lonngvist, J.-E. Tetrahedron Lett. 2004, 8489). The electrophile compound of formula 12 is used in an amount of 0.9 to 1.5 equivalent, preferably 1.0 to 1.1 equivalent based on the starting compound of formula 10. The solvent which is used in the first step can be used in the next step without change.
In the second step, the object compound of formula 2 can be prepared through a short process of reacting the novel compound of formula 3b with n-butyllithium in a suitable solvent to introduce lithium into the C-2 position of the compound of formula 3b through a bromine-lithium exchange reaction and then reacting with the electrophile compound of formula 8. A conventional solvent which does not participate in the reaction can be used in this step. It is preferable to use one or more solvents selected from alkanes such as hexane and heptane, and ethers such as dimethyl ether, diethyl ether, methyl t-butyl ether, dimethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane, and aromatic carbohydrates such as toluene and xylene. The reaction step can be carried out at a temperature ranging from -40 to -90℃, preferably at a temperature of -50 to -80℃, more preferably at a temperature of -60 to -78℃. Once lithium is introduced into the C-2 position, the reaction with the electrophile compound of formula 8 is carried out in the same solvent at the same temperature. The electrophile compound of formula 8 is used in an amount of 1.0 to 1.5 equivalent, preferably 1.0 to 1.1 equivalent based on the starting compound of formula 10.
The compound of formula 3 which is used for the preparation of the compound of formula 2 is a novel pyridine derivative. The present invention provides the compound of formula 3, especially the compounds of formulas 3a and 3b which are used in the above reaction schemes 2 and 3, and a method of preparing the same.
[Formula 3]
wherein,
D represents fluorine or chlorine, or represents S-A,
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy,
E represents bromine or C(=O)CHYCH3 , and
Y represents fluorine, chlorine or bromine.
The pyridyl ketone derivatives of formula 3a are the compound of formula 3 in which D is fluorine or chlorine and E is C(=O)CHYCH3. Furthermore, the 2-bromopyridine derivatives of formula 3b are the compound of formula 3 in which D is an S-A radical and E is bromine.
[Formula 3a]
wherein,
D represents fluorine or chlorine, and
Y represents fluorine, chlorine or bromine.
Examples of preferable compounds of formula 3a are 1-(3-fluoropyridin-2-yl)-2-fluoropropan-1-one, 1-(3-chloropyridin-2-yl)-2-fluoropropan-1-one, 1-(3-chloropyridin-2-yl)-2-chloropropan-1-one and 1-(3-chloropyridin-2-yl)-2-bromopropan-1-one. More preferable is the compound of formula 3a in which D is chlorine and Y is fluorine.
[Formula 3b]
wherein,
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy.
The novel compound of formula 3b in which A is isopropyl, sec-butyl, t-butyl, sec-pentyl, t-amyl, cyclohexyl or benzyl is preferred. Examples of preferable compounds of formula 3b are 2-bromo-3-isopropylthiopyridine, 2-bromo-3-benzylthiopyridine, 2-bromo-3-(4-methoxybenzyl)thiopyridine, 2-bromo-3-(t-butylthio)pyridine and 2-bromo-3-cyclohexylthiopyridine. More preferable is the compound of formula 3b in which A is isopropyl, t-butyl or benzyl.
According to the method using the novel pyridyl ketone derivatives or 2-bromopyridine derivatives of the present invention, the key intermediate of formula 2 for producing flucetosulfuron can be prepared through a simple processing step, with a yield equivalent or superior to those of conventional methods.
The present invention is explained in more detail by the following Examples. However, these Examples seek to illustrate the present invention only, and the scope of the present invention is not limited by them.
Example 1: Preparation of the compound of formula 3a
[Formula 3a]
Example 1-1: Preparation of 1-(3-chloropyridin-2-yl)-2-fluoropropan-1-one (D=chlorine, Y=fluorine)
Hexane (40 mL) and N,N-dimethylaminoethanol (3.14 g, 35.2 mmol) were added into a reaction vessel under a nitrogen atmosphere and cooled to -5℃. n-Butyllithium (2.5 M in hexane, 70 mmol) was added dropwise to the reaction solution, and the mixture was stirred for 1 hour and cooled to -41℃. 3-Chloropyridine (2.04 g, 18 mmol) in hexane was added dropwise to the mixture. After the addition, the reaction mixture was cooled to -78℃ and 2-fluoropropionic acid morpholine amide (5.64 g, 35 mmol) in hexane was added dropwise to the mixture. The reaction mixture was stirred for 2 hours and then heated to -20℃. Propionic acid (9.13 g, 123 mmol) was added dropwise to the mixture to terminate the reaction. The reaction solution was heated to 0℃. After the addition of water, the solution was extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate and then distilled to remove the solvent. The resultant was purified by silica gel column chromatography to obtain the title compound (2.29 g, 68%).
1H NMR (CDCl3, δ): 8.54 (dd, J=1.2, 4.3 Hz, 1H), 7.83 (dd, J=1.2, 8.0 Hz, 1H), 7.42 (dd, J=4.3, 8.0 Hz, 1H), 6.05 (dq, J=6.7, 48.9 Hz, 1H), 1.63 (dd, J=6.7, 23.8 Hz, 3H)
Example 1-2: Preparation of 1-(3-fluoropyridin-2-yl)-2-fluoropropan-1-one (D = fluorine, Y = fluorine)
3-Fluoropyrine (1.75 g, 18 mmol) instead of 3-chloropyridine was reacted according to the same procedure as in Example 1-1 to give the title compound (2.00 g, 65%).
1H NMR (CDCl3, δ): 8.51-8.50 (m, 1H), 7.60-7.54 (m, 2H), 6.15 (dq, J=6.7, 48.9 Hz, 1H), 1.67 (dd, J=6.7, 23.8 Hz, 3H)
Example 1-3: Preparation of 1-(3-chloropyridin-2-yl)-2-chloropropan-1-one (D=chlorine, Y= chlorine)
3-Chloropyridine (2.04 g, 18 mmol) was reacted according to the same procedure as in Example 1-1 except that ethyl 2-chloropropionate (4.78 g, 35 mmol) was used as electrophile compound instead of 2-fluoropropionic acid morpholine amide to give the title compound (1.91 g, 52%).
1H NMR (CDCl3, δ): 8.55 (d, J=4.9 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.41 (dd, J=4.3, 8.0 Hz, 1H), 5.73 (q, J=6.7 Hz, 1H), 1.74 (d, J=6.8 Hz, 3H)
Example 2: Preparation of the compound of formula 3b
[Formula 3b]
Example 2-1: Preparation of 2-bromo-3-isopropylthiopyridine (disulfide method)
n-Butyllithium (2.5 M hexane solution, 28 mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpyridine (3.94 g, 28 mmol) in tetrahydrofuran (12 mL) at -20℃, and the mixture was stirred for about 1 hour. The reaction mixture was cooled to -78℃, and 2-bromopyridine (3.95 g, 25 mmol) was added dropwise thereto. After the formation of slurry was observed, the solution of diisopropyl disulfide (3.76 g, 25 mmol) in tetrahydrofuran was added dropwise thereto, maintaining the temperature. After the addition was completed, the mixture was stirred additionally for 30 minutes. Ethanol (2 mL) was added thereto, and the reaction mixture was heated to a room temperature. Water was added to the mixture to separate layers, and the organic layer was washed sequentially with diluted sodium hydroxide solution, water and diluted hydrochloride solution, and then distilled under reduced pressure. The resultant was purified by silica gel column chromatography to obtain the title compound (4.80 g, 83%).
1H NMR (CDCl3, δ): 8.16 (dd, J=2.0, 4.8 Hz, 1H), 7.58 (dd, J=2.0, 7.6 Hz, 1H), 7.23 (dd, J=4.8, 7.6 Hz, 1H), 3.50 (m, J=8.0 Hz, 1H), 1.38 (d, J=8.0 Hz, 6H)
Examples 2-2 to 2-5
Instead of diisopropyl disulfide, each disulfide electrophile compound as shown in the following Table 1 was reacted according to the same procedure as in Example 2-1 to give the corresponding title compound.
Table 1 
Example 2-6: Preparation of 2-bromo-3-isopropylthiopyridine (sulfenyl chloride method)
n-Butyllithium (2.5 M hexane solution, 28 mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpyridine (3.94 g, 28 mmol) in tetrahydrofuran (12 mL) at -20℃, and the mixture was stirred for about 1 hour. The reaction mixture was cooled to -78℃, and 2-bromopyridine (3.95 g, 25 mmol) was added dropwise thereto. After the formation of slurry was observed, the solution of isopropyl sulfenyl chloride (3.10 g, 28 mmol) in hexane (4 mL) was added dropwise thereto, maintaining the temperature. After the addition was completed, the mixture was stirred additionally for 30 minutes. Ethanol (2 mL) was added thereto, and the reaction mixture was heated to a room temperature. Water was added to the mixture to separate the layers, and the organic layer was washed sequentially with diluted sodium hydroxide solution, water and diluted hydrochloride solution, and then distilled under reduced pressure. The resultant was purified by silica gel column chromatography to obtain the title compound (3.46 g, 60%).
Example 3: Preparation of the compound of formula 2 (method A)
Example 3-1: Preparation of 1-(3-benzylsulfanylpyridin-2-yl)-2-fluoropropan-1-one
1-(3-Chloropyridin-2-yl)-2-fluoropropan-1-one (1.87 g, 10 mmol) was dissolved in dimethyl sulfoxide (20 mL), and benzyl mercaptan (1.37 g, 11 mmol), copper oxide (70 ㎎, 0.5 mmol), 2-(ethoxycarbonyl)-cyclohexanone (0.17 g, 1 mmol) and potassium carbonate (2.76 g, 20 mmol) were added thereto. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate (100 mL) and water (50 mL) were added thereto, and the mixture was stirred to separate the layers. The organic layer was washed sequentially with ammonia water and water and then distilled under reduced pressure. The resultant was purified by silica gel column chromatography to obtain the title compound (1.68 g, 61%).
1H NMR (CDCl3, δ): 8.38 (dd, J = 1.2, 4.4 Hz, 1H), 7.74 (dd, J = 1.2, 8.4 Hz, 1H), 7.45~7.27 (m, 6H), 6.27 (dq, J = 6.8, 49.6 Hz, 1H), 4.16 (s, 2H), 1.66 (dd, J = 6.8, 23.6 Hz, 3H)
Example 4: Preparation of the compound of formula 2 (method B)
Example 4-1: Preparation of 1-(3-isopropylsulfanylpyridin-2-yl)-2-fluoropropan-1-one
n-Butyllithium (2.5 M hexane solution, 22 mmol) was added dropwise to a solution of 2-bromo-3-isopropylthiopyridine (4.72 g, 20 mmol) in toluene (10 mL) at -70℃, and the mixture was stirred for 30 minutes. 2-Fluoropropanic acid morpholine amide (3.28 g, 20 mmol) in toluene was added dropwise thereto, maintaining the temperature. After completion of the reaction, ethanol (2 mL) was added thereto, and the reaction mixture was heated to a room temperature. The organic layer was washed sequentially with 6N hydrochloride (9 mL) and distilled water (6 mL), and then distilled under reduced pressure to remove the solvent. After the distillation was completed, crystallization was carried out with isopropanol and n-hexane. The crystallized product was dried under nitrogen gas to obtain the title compound of white crystal (3.22 g, 70%).
1H NMR (CDCl3, δ): 8.38 (dd, J=1.2, 4.4 Hz, 1H), 7.78 (dd, J=1.2, 8.4 Hz, 1H), 7.23 (dd, J=4.4, 8.4 Hz, 1H), 6.25 (dq, J=8.0, 48.0 Hz, 1H), 3.52 (m, J=8.0 Hz, 1H), 1.65 (dd, J=8.0, 24.0 Hz, 3H), 1.41 (d, J=8.0 Hz, 3H), 1.39 (d, J=8.0 Hz, 3H)
The following comparative examples show the preparation of the compound of formula 2 by conventional methods.
Comparative Example 1-1: Preparation of 2-cyano-3-bromopyridine
According to the method described in US 5,354,749, the title compound was prepared from 3-bromopyridine (50.56 g, 320 mmol) through a two-step reaction (35.7 g, 195 mmol, 61%).
Comparative Example 1-2: Preparation of 2-cyano-3-isopropylsulfanylpyridine
The mixture of sodium hydride (1.64 g, 41 mmol), tetrahydrofuran (150 mL) and isopropanthiol (3.12 g, 41 mmol) was reacted at 50℃ for 1 hour. 2-Cyano-3-bromopyridine (5.00 g, 27.3 mmol) obtained in Comparative Example 1-1 was added thereto, and the reaction mixture was refluxed for 1.5 hour. After the reaction was completed, tetrahydrofuran solvent was distilled out, and water and toluene were newly added thereto for extraction. The extracted organic layer was distilled, and then crystallization was carried out with hexane to obtain the title compound (4.38 g, 24.5 mmol, 90%).
1H NMR (CDCl3, δ): 8.54 (dd, J=4.8, 1.8 Hz, 1 H), 7.84 (dd, J=8.0, 1.8 Hz, 1 H), 7.44 (dd, J=8.0, 4.8 Hz, 1 H) 3.57 (sep, J=6.7, 1 H), 1.37 (d, J=6.7 Hz, 6 H)
Comparative Example 1-3: Preparation of 1-(3-isopropylsulfanylpyridin-2-yl)-2-fluoropropan-1-one
According to the method described in JP 2003-335758, the title compound was prepared from 2-cyano-3-isopropylsulfanyl (3.56 g, 20 mmol) obtained in Comparative Example 1-2 through a three-step reaction (2.61 g, 11.5 mmol, 58%).
As described above, according to the method using the novel pyridyl ketone derivatives or 2-bromopyridine derivatives of the present invention, the compound of formula 2 can be prepared, through a simple processing step, with a yield equivalent or superior to those of conventional methods.
Claims (10)
- Pyridine derivative compounds of the following formula 3 for the preparation of flucetosulfuron.[Formula 3]
wherein,D represents fluorine or chlorine, or represents S-A,A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy,E represents bromine or C(=O)CHYCH3 , andY represents fluorine, chlorine or bromine. - The compounds according to claim 1, which are pyridyl ketone derivatives of the following formula 3a.[Formula 3a]
wherein,D represents fluorine or chlorine, andY represents fluorine, chlorine or bromine. - The compounds according to claim 2, which are 1-(3-fluoropyridin-2-yl)-2-fluoropropan-1-one, 1-(3-chloropyridin-2-yl)-2-fluoropropan-1-one, 1-(3-chloropyridin-2-yl)-2-chloropropan-1-one or 1-(3-chloropyridin-2-yl)-2-bromopropan-1-one.
- The compounds according to claim 1, which are 2-bromopyridine derivatives of the following formula 3b.[Formula 3b]
wherein,A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy. - The compounds according to Claim 4, which are 2-bromo-3-isopropylthiopyridine, 2-bromo-3-benzylthiopyridine, 2-bromo-3-(4-methoxybenzyl) thiopyridine, 2-bromo-3-(t-butylthio)pyridine or 2-bromo-3-cyclohexylthiopyridine.
- Method of preparing the pyridyl ketone derivative compounds of formula 3a according to claim 2, which comprises the steps of reacting the compound of the following formula 7 with n-butyllithium and N,N-dimethylaminoethanol (DMAE) and then reacting with the compound of the following formula 8.[Formula 3a]
[Formula 7]
[Formula 8]
wherein,D represents fluorine or chlorine,Y represents fluorine, chlorine or bromine, andW represents C1-C4-alkoxy, C1-C4-dialkylamine or morpholine. - Method of preparing the 2-bromopyridine derivative compounds of formula 3b according to claim 4, which comprises the steps of reacting the compound of formula 10 with a strong base of lithium amides of formula 11 and then with the electrophile compound of formula 12.[Formula 3b]
[Formula 10]
[Formula 11]
[Formula 12]A-S-Xwherein,n represents 0 or 3,A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy, andX represents chlorine or S-A. - The method according to claim 7, wherein the compound of formula 12 is the compound of formula 12a.[Formula 12a]A-S-S-Awherein,A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy.
- Method of preparing the intermediate compound of formula 2 for the preparation of flucetosulfuron which is characterized in that the compound of formula 3a is reacted with the compound of formula 9 in the presence of a Cu catalyst, a ligand, a base and a solvent.[Formula 3a]
[Formula 9]A-SH[Formula 2]
wherein,D represents fluorine or chlorine,Y represents fluorine, chlorine or bromine, andA represents C3-C5-alkyl or C3-C6-cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy. - Method of preparing the intermediate compound of formula 2 for the preparation of flucetosulfuron which is characterized in that the compound of formula 3b is reacted with n-butyllithium, and then with the electrophile compound of formula 8.[Formula 3b]
[Formula 8]
[Formula 2]
wherein,W represents C1-C4-alkoxy, C1-C4-dialkylamine or morpholine,Y represents fluorine, chlorine or bromine, andA represents C3-C5-alkyl or C3-C6-cycloalkyl, or represents benzyl which is unsubstituted or 1- to 5-substituted with substituents selected from C1-C2-alkyl and C1-C2-alkoxy.
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| CN104829524A (en) * | 2014-02-11 | 2015-08-12 | Fmc公司 | Synthetic method of intermediate of herbicide flucetosulfuron |
| WO2016124563A1 (en) | 2015-02-05 | 2016-08-11 | Bayer Cropscience Aktiengesellschsaft | 2-(het)aryl-substituted condensed bicyclic heterocycle derivatives as pest control agents |
| JP2016538251A (en) * | 2013-10-11 | 2016-12-08 | エルジー・ライフ・サイエンシーズ・リミテッドＬＧ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ Ｌｔｄ． | Method for producing 3-alkylthio-2-bromopyridine |
| EP3581565A1 (en) * | 2018-06-14 | 2019-12-18 | Beijing Zhibo Bio-Medical Technology Co., Ltd. | Phenyl benzyl ether derivative and preparation method and application thereof |
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| KR20030085788A (en) * | 2002-05-02 | 2003-11-07 | 주식회사 엘지생명과학 | Pyridine derivatives, process for the preparation thereof, and use as an intermediate of herbicides |
| JP2003335758A (en) * | 2002-05-20 | 2003-11-28 | Lg Chem Investment Ltd | Pyridine derivative, method for producing the same and use as herbicide intermediate |
| US20040209921A1 (en) * | 2003-04-11 | 2004-10-21 | Gary Bridger | CXCR4 chemokine receptor binding comounds |
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| KR20030085788A (en) * | 2002-05-02 | 2003-11-07 | 주식회사 엘지생명과학 | Pyridine derivatives, process for the preparation thereof, and use as an intermediate of herbicides |
| JP2003335758A (en) * | 2002-05-20 | 2003-11-28 | Lg Chem Investment Ltd | Pyridine derivative, method for producing the same and use as herbicide intermediate |
| US20040209921A1 (en) * | 2003-04-11 | 2004-10-21 | Gary Bridger | CXCR4 chemokine receptor binding comounds |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2016538251A (en) * | 2013-10-11 | 2016-12-08 | エルジー・ライフ・サイエンシーズ・リミテッドＬＧ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ Ｌｔｄ． | Method for producing 3-alkylthio-2-bromopyridine |
| CN104829524A (en) * | 2014-02-11 | 2015-08-12 | Fmc公司 | Synthetic method of intermediate of herbicide flucetosulfuron |
| JP2017506634A (en) * | 2014-02-11 | 2017-03-09 | エフ エム シー コーポレーションＦｍｃ Ｃｏｒｐｏｒａｔｉｏｎ | Process for the synthesis of flucetosulfuron herbicide intermediates |
| WO2016124563A1 (en) | 2015-02-05 | 2016-08-11 | Bayer Cropscience Aktiengesellschsaft | 2-(het)aryl-substituted condensed bicyclic heterocycle derivatives as pest control agents |
| EP3581565A1 (en) * | 2018-06-14 | 2019-12-18 | Beijing Zhibo Bio-Medical Technology Co., Ltd. | Phenyl benzyl ether derivative and preparation method and application thereof |
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