KR101493488B1 - Novel pyridine derivatives and method for preparation of intermediate compound for producing sulfonylurea herbicides using the same - Google Patents

Abstract

[화학식 3]

상기 식에서, A, D, E 및 Y는 발명의 상세한 설명에 정의된 바와 같다.The present invention relates to a new method for preparing a core intermediate compound for producing a fluoroalkylpyridine-sulfonylurea derivative having excellent herbicidal activity, a novel pyridine derivative and a method for preparing the same, According to the method using the novel pyridine derivative compound of formula (3), the compound of formula (2), which is a production intermediate of flutosulfuron, can be produced in a high yield by a simple process.
(2)

(3)

Wherein A, D, E and Y are as defined in the description of the invention.

Description

TECHNICAL FIELD [0001] The present invention relates to novel pyridine derivatives, and to a process for producing a sulfonylurea herbicide using the pyridine derivatives. [0002] The present invention relates to novel pyridine derivatives,

The present invention relates to a novel process for preparing a core intermediate compound for producing a fluoroalkylpyridine-sulfonylurea derivative exhibiting excellent herbicidal activity, and a novel pyridine derivative and a process for producing the same.

The following formula (1) is a compound with excellent herbicidal activity known as flucetosulfuron (WO 2002-030921). According to the method disclosed in the prior art JP 2003-335758, the compound of the formula (1) can be synthesized via a compound of the following formula (2) which is a key intermediate.

In this formula,

A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl Lt; / RTI >

Y represents a fluorine, chlorine or bromine atom.

That is, for introduction of the fluorine group which is the core of the compound of the formula (1), an intermediate of the formula (2a) in which Y is fluorine is required which is obtained by reacting the compound of the formula (4) 5) with a copper (II) salt to produce a compound of formula (2b) and then reacting it with a compound of formula (6) optionally in the presence of a phase transfer catalyst in a solvent.

[Reaction Scheme 1]

In the above Reaction Scheme 1, A is as described above, Y 'represents a chlorine or bromine atom, and M represents an alkali metal such as sodium, potassium or cesium.

In this process, the structure of the compound of formula (4) is already equipped with the skeleton of formula (2a), which is the target compound, but two additional steps are necessary to simply introduce the fluorine group. In addition, the by-product of Cu inevitably generated during the reaction is not only completely removed but also affects the fluorination reaction in the next step, resulting in a low yield of the fluorination reaction. On the other hand, pyridyl ketone derivatives of the formula (4) used as starting materials are known or can be found in the literature (US 5,354,749 A1, Kevin A. Memoli, Tetrahedron Lett. 1996, 37, 3617; or DE 4,304,007 A1) , All of which are disadvantageous in that they can be obtained only after a long process of four steps.

In view of the above problems, the present inventors conducted intensive studies to find a method for more easily preparing a compound of formula (2), which is a key intermediate in the production of flutosulfuron of formula (1) As a result, a method of introducing a C (= O) CHYCH ₃ group (Y represents a fluorine, chlorine or bromine atom) at the C-2 position of pyridine was introduced at once. Also, the present invention has been accomplished by developing a method for producing a target compound of formula (2) from a commercially available starting material using only this two step process.

It is an object of the present invention to provide a novel method for preparing a core production intermediate compound of flutosulfuron useful as a herbicide. Another object of the present invention is to prepare novel pyridine derivatives used in the preparation of said intermediate compounds and their preparation.

In order to achieve the above object, the present invention provides a pyridine derivative of the following formula (3) used for the production of flutosulfuron

In this formula,

D represents a fluorine or chlorine atom, represents S-A,

A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl .

E represents a bromine atom or a C (= O) CHYCH ₃ group,

Y represents fluorine, chlorine or bromine atom.

Among the above pyridine derivatives, preferred compounds are pyridyl ketone derivatives of the formula (3a) and 2-bromopyridine derivatives of the formula (3b).

[Chemical Formula 3]

In this formula,

D represents fluorine or chlorine

Y represents fluorine, chlorine or bromine atom.

(3b)

In this formula,

A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl .

A preferred compound of formula (3a) is 1- (3-fluoropyridin-2-yl) -2-fluoropropane- 1-one or 1- (3-chloropyridin-2-yl) -2-chloropropan- .

Preferred compounds of formula (3b) are the 2-bromo-3-isopropylthiopyridine, 2-bromo-3-benzylthiopyridine, 2-bromo-3- (4-methoxybenzyl) (T-butylphenylthio) pyridine or 2-bromo-cyclohexylthiopyridine.

The compound of formula (3a) according to the present invention is characterized in that the compound of formula (7) is reacted with n-butyllithium and N, N-dimethylaminoethanol (DMAE) . ≪ / RTI >

(7)

[Chemical Formula 8]

In this formula,

D represents a fluorine or chlorine atom,

Y represents a fluorine, chlorine or bromine atom,

W represents C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -dialkylamine or a morpholine group.

The compound of the formula (3b) according to the present invention is obtained by reacting the compound of the formula (10) with a strong base of the lithium amide of the formula (11) and then reacting with the electrophile of the formula (12) .

[Chemical formula 10]

(11)

[Chemical Formula 12]

A-S-X

In this formula,

n represents 0 or 3,

A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl Lt; / RTI >

X represents a chlorine atom or an S-A group, and in particular, when X represents an S-A group, the compound of the formula (12) forms a disulfide compound of a symmetrical structure of the following formula (12a).

[Chemical Formula 12a]

A-S-S-A

A method for preparing a compound of formula (2), which is a production intermediate of flutosulfuron for achieving another object of the present invention, comprises reacting a compound of formula (3a) with a compound of formula (9) under Cu catalyst, ligand, With a compound of formula < RTI ID = 0.0 >

[Chemical Formula 3]

[Chemical Formula 9]

A-SH

(2)

In this formula,

D represents a fluorine or chlorine atom,

Y represents a fluorine, chlorine or bromine atom,

A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl .

Another method of preparing the compound of formula (2), which is an intermediate for the production of flutosulfuron according to the present invention, comprises reacting the compound of formula (3b) with n-butyllithium, And the reaction is carried out.

(3b)

[Chemical Formula 8]

(2)

In this formula,

W represents C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -dialkylamine or a morpholine group,

Y represents a fluorine, chlorine or bromine atom,

A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl .

Hereinafter, the present invention will be described more specifically.

The process for preparing the compound of formula (2), which is a flutosulfuron production intermediate according to the present invention, comprises the steps of introducing a C (= O) CHYCH ₃ group at the C-2 position of pyridine and an SA group at the C- Two methods, A and B, are possible.

[Method A]

The first method according to the present invention in the preparation of the compound of formula (2) is a method in which a C (═O) CHYCH ₃ group is first introduced at the C-2 position of pyridine and then a SA group is introduced at the C-3 position. That is, the compound of formula (7), which is readily available, is reacted with n-butyllithium and N, N-dimethylaminoethanol (DMAE) as a starting material to selectively introduce lithium into the C- With a compound of formula (8) to produce a CC bond to produce a novel compound of formula (3a). The target compound of formula (2) can then be prepared by a short process step in which the compound of formula (3a) is reacted with a compound of formula (9) under Cu catalyst, ligand, base and solvent conditions. The compound of formula (2b) wherein Y is a chlorine or bromo atom can be prepared by reacting a compound of formula (6) with a compound of formula (6) optionally in the presence of a phase transfer catalyst in a solvent as shown in Scheme 1, ) ≪ / RTI > compound.

The reactions are shown in the form of reaction schemes and the detailed reaction conditions are as follows.

[Reaction Scheme 2]

In this formula,

D represents a fluorine or chlorine atom,

Y represents a fluorine, chlorine or bromine atom,

W represents C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -dialkylamine or a morpholine group,

A is C ₃ -C ₅ - alkyl, C ₃ -C ₆ - cycloalkyl, or represent alkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - ₁ to 5 is substituted by a substituent selected from alkoxy or unsubstituted Benzyl.

The substituents referred to herein have the following meanings.

C ₃ -C ₅ -alkyl represents propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, pentyl, sec-pentyl or t-amyl;

C ₃ -C ₆ -cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

C ₁ -C ₂ -alkyl represents methyl, ethyl;

C ₁ -C ₂ -alkoxy represents methoxy or ethoxy.

Fort et al. Introduced a method for introducing lithium ions out selectively removing the hydrogen atoms of the C-2 position in formula (7) compound (literature;... Eur J. Org Chem 2001, 603;. Lett Org. Chem . 2009, 6 , 50). In the first step in Scheme 2, the compound of formula (7) is reacted with a mixture of n-butyllithium and N, N-dimethylaminoethanol using Fort's method to selectively remove the hydrogen atom at C-2 to form lithium Ions. Once an intermediate in the lithium ion state is generated, it can be reacted with an electrophilic compound of the formula (8) in the same reaction vessel to prepare a novel intermediate of the formula (3a). The solvent used in this reaction may be a conventional solvent that does not participate in the reaction itself, preferably an alkane such as hexane or heptane, an ether such as dimethyl ether, diethyl ether, methyl t-butyl ether, dimethoxyethane, tetrahydrofuran , Dioxane and the like are used singly or in combination. The reaction temperature may be in the range of 0 ° C to -90 ° C, preferably in the range of -20 ° C to -90 ° C, more preferably -40 ° C to -78 ° C. Compounds of formula (8) can be obtained commercially or obtained from commercially available corresponding organic acids by conventional ester synthesis methods or amide synthesis methods. The amount of the electron donor represented by formula (8) is preferably 0.9 equivalents to 1.5 equivalents, more preferably 1.0 equivalents to 1.1 equivalents, relative to the compound represented by formula (7) as a starting material.

In a second step, the desired compound of formula (2) can be prepared by reacting a novel intermediate of formula (3a) with a compound of formula (9) under base, solvent, ligand and copper catalysts to produce a CS bond . The base may be an inorganic base such as cesium carbonate, potassium carbonate or sodium hydrogencarbonate or an organic base such as triethylamine, pyridine or diazabicyclo dodecane (DBU). Cesium carbonate, potassium carbonate and triethylamine are preferable, and cesium carbonate or potassium carbonate is more preferably used. As the Cu catalyst, copper oxide (Cu ₂ O), copper iodide (CuI), copper chloride (CuCl) and copper bromide (CuBr) can be used, and copper oxide (Cu ₂ O) or copper iodide . The amount of the Cu catalyst to be used may be 0.01 to 0.5 equivalents, preferably 0.05 to 0.2 equivalents. The solvent may be an aprotic polar solvent such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAC) or N-methylpyrrolidine (NMP), or a solvent such as benzene, toluene, xylene And the like can be used. Preferred solvents are dimethylsulfoxide, dimethylformamide, N-methylpyrrolidine or toluene, more preferably dimethylsulfoxide or dimethylformamide. The reaction temperature may be in the range of 0 ° C to 60 ° C, preferably in the range of 15 ° C to 25 ° C. As the ligand, 2- (ethoxycarbonyl) cyclohexanone, 1,2-cyclohexanediamine, N, N-diethylamine and the like can be used.

[Method B]

A second method according to the present invention for preparing the compound of formula (2) is a method of introducing C (= O) CHYCH ₃ group at C-2 position after first introduction of SA group at C-3 position of pyridine. That is, the readily available starting material of formula (10) is reacted with a strong base of lithium amides of formula (11) at -40 to -90 < 0 > C in an appropriate solvent, introducing lithium at the C- 12) with an electrophilic compound of formula (3b) to synthesize a novel intermediate of formula (3b). Subsequently, lithium is introduced into the C-2 position from the compound of formula (3b) via a bromine-lithium exchange reaction and reacted with the electrophile of formula (8) to give the target compound of formula (2) can do.

The reactions are shown in the form of reaction schemes and the detailed reaction conditions are as follows.

[Reaction Scheme 3]

Wherein n represents 0 or 3;

X represents a chlorine atom or an S-A group, and particularly when X represents an S-A group, the compound of the formula (12) forms a disulfide compound of a symmetrical structure,

Y represents a fluorine, chlorine or bromine atom,

W represents C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -dialkylamine or a morpholine group,

A is C ₃ -C ₅ - alkyl, C ₃ -C ₆ - cycloalkyl, or represent alkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - ₁ to 5 is substituted by a substituent selected from alkoxy or unsubstituted Benzyl.

In the first step of Scheme 3, the compound of formula (10) is reacted with a strong base of the lithium amide of formula (11) at low temperature to introduce lithium at the C-3 position of pyridine. At this time, lithium diisopropylamide ( n = 0) or lithium 2,2,6,6-tetramethylpiperazide ( n = 3) can be used as the strong base of formula (11). The solvent used in this reaction may be a conventional solvent that does not participate in the reaction itself. Preferred solvents include alkanes such as hexane and heptane, dimethyl ether, diethyl ether, methyl t-butyl ether, dimethoxyethane, tetrahydrofuran, Ethers such as 2-methyltetrahydrofuran, dioxane and the like are used alone or in combination. The reaction temperature may be in the range of -40 캜 to -90 캜, preferably in the range of -60 캜 to -90 캜, and more preferably in the range of -78 캜 to -90 캜. Once a lithium ion intermediate is formed, it can be reacted with an electrophilic compound of formula (12) in the same reaction vessel to produce a novel compound of formula (3b). The disulfide or sulfenyl chloride compound of formula (12) is commercially available or can be prepared by known synthetic methods (Gillis, HM, Greene, L., Thompson, A. Synlett , 2009, 112; Leino, R., Lonngvist, J.-E. Tetrahedron Lett . 2004, 8489). The amount of the electron donor represented by formula (12) is preferably 0.9 equivalents to 1.5 equivalents, more preferably 1.0 equivalents to 1.1 equivalents, relative to the compound of formula (10) as a starting material. The solvent used in the first step is not changed and is used as it is.

In the next step, a novel compound of formula (3b) prepared according to the present invention is reacted with n-butyllithium in a suitable solvent to introduce lithium at the C-2 position via a bromine-lithium exchange reaction, Lt; / RTI > can be prepared via a short process step in which the compound of formula (2) is reacted with an electrophile of formula < RTI ID = 0.0 > The solvent used in this reaction may be a conventional solvent that does not participate in the reaction itself, preferably an alkane such as hexane or heptane, an ether such as dimethyl ether, diethyl ether, methyl t-butyl ether, dimethoxyethane, tetrahydrofuran , Ethers such as 2-methyltetrahydrofuran and dioxane, aromatic hydrocarbons such as toluene and xylene are used alone or in combination. The reaction temperature can be -40 ° C to -90 ° C, preferably -50 ° C to -80 ° C, and more preferably -60 ° C to -78 ° C. Once lithium is introduced at the C-2 position, the reaction with the electrophilic compound of formula (8) is carried out under the same solvent and at the same temperature. The amount of the compound of the formula (8) used as the proton electron is preferably 1.0 equivalents to 1.5 equivalents, more preferably 1.0 equivalents to 1.1 equivalents, relative to the compound of the formula (10) as a starting material.

The compound of formula (3) used in the preparation of the compound of formula (2) according to the present invention is a pyridine derivative of novel structure. In the present invention, the compound of formula (3) ) And (3b) compounds and a process for their preparation.

(3)

In this formula,

D represents a fluorine or chlorine atom, represents S-A,

A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl .

E represents a bromine atom or a C (= O) CHYCH ₃ group,

Y represents fluorine, chlorine or bromine atom.

Wherein D is a fluorine or chlorine atom and E is a pyridyl ketone derivative of formula (3a) when it represents a C (= O) CHYCH ₃ group. D is SA, and E is a 2-bromopyridine derivative of formula (3b) when it represents a bromine atom.

[Chemical Formula 3]

In this formula,

D represents fluorine or chlorine

Y represents fluorine, chlorine or bromine atom.

A preferred compound of formula (3a) is 1- (3-fluoropyridin-2-yl) -2-fluoropropane- 1-one or 1- (3-chloropyridin-2-yl) -2-chloropropan- , D is a chlorine atom, and Y is a fluorine atom.

(3b)

In this formula,

A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl .

Among the novel compounds of formula (3b) according to the present invention, the preferred compounds are the novel compounds wherein A represents isopropyl, sec-butyl, t-butyl, sec-pentyl, t-amyl, cyclohexyl, Bromo-3-isopropylthiopyridine, 2-bromo-3-benzylthiopyridine, 2-bromo-3- (4-methoxybenzyl) ) Pyridine or 2-bromo-cyclohexylthiopyridine. More preferred compounds of formula (3b) are those in which A represents isopropyl, t-butyl or benzyl.

According to the method using the novel pyridyl ketone derivative or 2-bromopyridine derivative compound according to the present invention, the compound of formula (2), which is a production intermediate of flutosulfuron, is equivalent to the conventional method through a simpler process step Can be produced at a higher yield.

Hereinafter, the present invention will be described more specifically based on the following Production Examples and Examples. However, these preparation examples and examples are only for the understanding of the present invention, and the scope of the present invention is not limited by them in any sense.

Example  One : Synthesis of Compound (3a)

[Chemical Formula 3]

Example  1-1: 1- (3- Chloropyridine Yl) -2- Fluoropropane -1-one (D = chlorine, Y = fluorine)

Under nitrogen, hexane (40 mL) and N, N-dimethylaminoethanol (3.14 g, 35.2 mmol) were added and cooled to -5 ° C. To the reaction solution, n-butyllithium (2.5 M hexane solution, 70 mmol) was slowly added dropwise. After stirring for 1 hour, the reaction mixture was cooled to -41 DEG C, and 3-chloropyridine (2.04 g, 18 mmol) was dissolved in hexane and slowly added dropwise. After the dropwise addition was completed, the reaction mixture was cooled to -78 deg. C, and 2-fluoropropionic acid morpholine amide (5.64 g, 35 mmol) was dissolved in hexane and slowly added dropwise. After stirring for 2 hours, the temperature was raised to -20 ° C, and propionic acid (9.13 g, 123 mmol) was slowly added dropwise to terminate the reaction. The reaction solution was heated to 0 ° C, water was added, and the mixture was extracted with ethyl acetate. The organic layer was extracted with magnesium sulfate and distilled to remove the solvent. The reaction mixture was separated by column chromatography to give the title compound (2.29 g, 68%).

_{^{1 H NMR (CDCl 3, 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,

Example  1-2: 1- (3- Fluoropyridine Yl) -2- Fluoropropane -L-one (D = fluorine, Y = fluorine)

Proceeding as in Example 1-1, the starting material was reacted with 3-fluoropyridine (1.75 g, 18 mmol) instead of 3-chloropyridine to give the title compound (2.00 g, 65%).

_{^{1 H NMR (CDCl 3, 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: 1- (3- Chloropyridine Yl) -2- Chloropropane 1-one (D = chlorine, Y = chlorine)

Chloropyridine (2.04 g, 18 mmol) as a starting material, ethyl 2-chloropropionate (4.78 g, g, 35 mmol) to give the title compound (1.91 g, 52%).

_{^{1 H NMR (CDCl 3, 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 : Synthesis of compound of formula (3b)

Example  2-1: 2- Bromo -3- Isopropylthiopyridine  synthesis( Disulfide  Way)

N-Butyl lithium (2.5 M hexane solution, 28 mmol) was added dropwise to a tetrahydrofuran (12 mL) solution of 2,2,6,6-tetramethylpiperidine (3.94 g, 28 mmol) And stirred for about 1 hour. The temperature was then cooled to -78 ° C and 2-bromopyridine (3.95 g, 25 mmol) was added dropwise to observe the formation of the slurry. The temperature was maintained at this temperature while diisopropyl disulfide (3.76 g, 25 mmol) The hydrofuran solution was slowly added dropwise. After completion of dropwise addition, the mixture was further stirred for 30 minutes, ethanol (2 mL) was added to the reaction mixture, and the temperature was raised to room temperature. Distilled water was added thereto, followed by layer separation, and the organic layer was washed with 2 N sodium hydroxide, distilled water and 2 N hydrochloric acid in this order and subjected to vacuum distillation. The reaction mixture was separated by column chromatography to give the title compound (4.80 g, 83%).

_{^{1 H NMR (CDCl 3, 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,

Example  2-2 to 2-5

Proceeding in the same manner as in Example 2-1 except that disilicide electrophiles corresponding to A shown in Table 1 were used instead of diisopropyl disulfide to obtain the respective title compounds.

Example A yield(%) ¹ H NMR (CDCl ₃₎ δ 2-2 t-butyl 72 8.36 (dd, J = 2.0, 4.8 Hz, 1H), 7.36 (dd, J = 4.8, 7.6 Hz, 1H), 7.24 (dd, J = 2.0, 7.6 Hz, 1H), 1.63 (s, 9H) 2-3 benzyl 80 8.13 (d, J = 4.0 Hz , 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.30 (m, 5H), 7.14 (dd, J = 4.0, 8.0 Hz, 1H), 4.15 (s, 2H ) 2-4 4-methoxybenzyl 80 8.13 (dd, J = 1.6,4.8 Hz , 1H), 7.44 (dd, J = 1.6, 7.6 Hz, 1H), 7.27 (m, 2H), 7.15 (dd, J = 4.8, 7.6 Hz, 1H), 6.85 (m, 2 H), 4.11 (s, 2 H), 3.79 (s, 3 H) 2-5 Cyclohexyl 78 8.15 (dd, J = 2.0,4.8 Hz , 1H), 7.57 (dd, J = 2.0, 7.6 Hz, 1H), 7.20 (dd, J = 4.8, 7.6 Hz, 1H), 3.24 (m, 1H), 2.10 -1.10 (m, 10 H)

Example  2-6: 2- Bromo -3- Isopropylthiopyridine  synthesis( Sulfhenyl chloride  Way)

N-Butyl lithium (2.5 M hexane solution, 28 mmol) was added dropwise to a tetrahydrofuran (12 mL) solution of 2,2,6,6-tetramethylpiperidine (3.94 g, 28 mmol) And stirred for about 1 hour. The temperature was further cooled to -78 < 0 > C and 2-bromopyridine (3.95 g, 25 mmol) was added dropwise to observe the formation of the slurry. Then, isopropylsulfenylchloride 3.10 g, 28 mmol) in THF (20 mL) was slowly added dropwise. After completion of the dropwise addition, the reaction mixture was further stirred for 30 minutes, ethanol (2 mL) was added to the reaction mixture, and the temperature was raised to room temperature. Distilled water was added thereto, and layer separation was carried out. The organic layer was washed with 2 N sodium hydroxide, distilled water and 2 N hydrochloric acid in this order and subjected to vacuum distillation. The reaction mixture was separated by column chromatography to obtain the same title compound as in Example 2-1 (3.46 g, 60%).

Example  3 : Synthesis of Compound (2) (Method A)

Example  3-1: 1- (3- Benzylsulfanylpyridine Yl) -2- Fluoropropane 1-one

(1.87 g, 10 mmol) was dissolved in dimethylsulfoxide (20 mL) and benzylmercaptan (1.37 g, 11 mmol) was dissolved in dichloromethane , Potassium carbonate (70 mg, 0.5 mmol), 2- (ethoxycarbonyl) cyclohexanone (0.17 g, 1 mmol) and potassium carbonate (2.76 g, 20 mmol) were added and stirred at room temperature for about 2 hours . When the reaction was completed, ethyl acetate (100 mL) and water (50 mL) were added and stirred, followed by layer separation. The organic layer was washed with ammonia water solution and water in this order and subjected to vacuum distillation. The reaction mixture was separated by column chromatography to give the title compound (3.35 g, 61%).

_{H NMR (CDCl 3, 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,

Example  4 : Synthesis of Compound (2) (Method B)

Example  4-1: 1- (3- Isopropylsulfanylpyridine Yl) -2- Fluoropropane 1-one

N-Butyl lithium (2.5 M hexane solution, 22 mmol) was added dropwise to a toluene (10 mL) solution of 2-bromo-3-isopropylthiopyridine (4.72 g, 20 mmol) After stirring, 2-fluoropropanoic acid morpholine amide (3.28 g, 20 mmol) was diluted with toluene in the reaction solution while maintaining the same temperature. When the reaction was completed, ethanol (2 mL) was added to the reaction mixture, and the temperature was raised to room temperature. The organic layer was washed with 6 N hydrochloric acid (9 mL) and distilled water (6 mL), and the solvent was distilled off under reduced pressure. Upon completion of the distillation, crystallization from isopropanol and n-hexane and drying under nitrogen resulted in 3.22 g (70%) of the title compound.

_{^{1 H NMR (CDCl 3, 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 is a comparative example showing the preparation of the compound of formula (2) by conventional methods.

Comparative Example  1-1: 2- Cyano -3- Bromopyridine  synthesis

The title compound was obtained (35.7 g, 195 mmol, 61%) from 3-bromopyridine (50.56 g, 320 mmol) by the same procedure of the prior patent document (US 5,354,749).

Comparative Example  1-2: 2- Cyano -3- Isopropylsulfanyl  synthesis

A mixture of sodium hydride (1.64 g, 41 mmol), tetrahydrofuran (150 mL), isopropanethiol (3.12 g, 41 mmol) was reacted at 50 ° C for 1 hour. 2-Cyano-3-bromopyridine (5.00 g, 27.3 mmol) obtained in Comparative Example 1-1 was added to the tetrahydrofuran reaction solution obtained above and refluxed for 1.5 hours. When the reaction was completed, the tetrahydrofuran solvent was distilled off, and water and toluene were newly added to the reaction mixture. The extracted organic layer was distilled and then crystallized using hexane to obtain the title compound (4.38 g, 24.5 mmol, 90% yield).

^{1 H 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,

Comparative Example  1-3: 1- (3- Isopropylsulfanylpyridine Yl) -2- Fluoropropane 1-one

The title compound was obtained from the 2-cyano-3-isopropylsulfanyl (3.56 g, 20 mmol) obtained in Comparative Example 1-2 by the same procedure as in the preceding patent (JP 2003-335758) 2.61 g, 11.5 mmol, yield 58%).

As described above, the method using the novel pyridyl ketone derivative or the 2-bromopyridine derivative compound according to the present invention allows the compound of the formula (2) to be obtained by a conventional method Method can be produced at a higher or equivalent yield.

Claims (10)

A pyridine derivative compound represented by the following formula (3) for use in the production of flutosulfuron.
(3)

In this formula,
D represents a fluorine or chlorine atom, represents SA,
A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl Lt; / RTI >
E represents a bromine atom or a C (= O) CHYCH ₃ group,
Y represents fluorine, chlorine, bromine atom,
However, compounds in which E represents C (= O) CHYCH ₃ group when D is SA are excluded. The pyridyl ketone derivative compound according to claim 1, which is represented by the following formula (3a).
[Chemical Formula 3]

In this formula,
D represents fluorine or chlorine
Y represents fluorine, chlorine or bromine atom. The method of claim 2, wherein the compound is 1- (3-fluoropyridin-2-yl) -2-fluoropropan- -One, 1- (3-chloropyridin-2-yl) -2-chloropropan-1-one or 1- (3-chloropyridin-2-yl) -2-bromopropane-1-one. The 2-bromopyridine derivative compound according to claim 1, which is represented by the following formula (3b).
(3b)

In this formula,
A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl . The compound according to claim 4, which is 2-bromo-3-isopropylthiopyridine, 2-bromo-3-benzylthiopyridine, 2-bromo-3- (4-methoxybenzyl) -3- (t-butylphenylthio) pyridine or 2-bromo-cyclohexylthiopyridine. A process for the preparation of a compound of formula (VIII) according to claim 2, characterized in that a compound of formula (7) is reacted with n-butyl lithium and N, N- dimethylaminoethanol (DMAE) 3a). ≪ / RTI >
[Chemical Formula 3]

(7)

[Chemical Formula 8]

In this formula,
D represents a fluorine or chlorine atom,
Y represents a fluorine, chlorine or bromine atom,
W represents C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -dialkylamine or a morpholine group. The compound of formula (3b) according to claim 4, wherein the compound of formula (10) is reacted with a strong base of a lithium amide of formula (11) and then reacted with an electrophile of formula (12) -Bromopyridine derivative compound.
(3b)

[Chemical formula 10]

(11)

[Chemical Formula 12]
ASX
In this formula,
n represents 0 or 3,
A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl Lt; / RTI >
X represents a chlorine atom or a SA group. The process according to claim 7, wherein the electrophile compound of formula (12) is a compound of formula (12a).
[Chemical Formula 12a]
ASSA
In this formula,
n represents 0 or 3,
A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl . A process for preparing a compound of formula (2) which is a production intermediate of flutosulfuron, characterized by reacting a compound of formula (3a) with a compound of formula (9) under Cu catalyst, ligand, base and solvent.
[Chemical Formula 3]

[Chemical Formula 9]
A-SH
(2)

In this formula,
D represents a fluorine or chlorine atom,
Y represents a fluorine, chlorine or bromine atom,
A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl . A process for the preparation of a compound of formula (2) which is a production intermediate of flutosulfuron, characterized by reacting a compound of formula (3b) with n-butyllithium followed by reaction with an electrophile of formula (8).
(3b)

[Chemical Formula 8]

(2)

In this formula,
W represents C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -dialkylamine or a morpholine group,
Y represents a fluorine, chlorine or bromine atom,
A is C ₃ -C ₅ - alkyl, C ₃ -C _6, or represent cycloalkyl, C ₁ -C ₂ - alkyl, and C ₁ -C ₂ - by a substituent selected from alkoxy of 1 to 5, a substituted or unsubstituted benzyl .