WO1997008163A1 - Process for producing thiochroman derivatives - Google Patents

Abstract

A process for easily producing alkoxythiochroman-carboxylic acids, which are used in the production of pyrazole derivatives having a thiochroman ring and useful as a herbicide, via the hydrolysis of alkoxythiochroman-carboxylic acid esters without resort to any costly step such as Grignard reaction.

Description

 Itoda β

.Methods of producing chiochroman derivatives

 The present invention relates to a method for producing a thiochroman derivative used for producing a birazol derivative useful as a herbicide. * ΐ Technology

 Conventionally, triadine herbicides atrazine and acid anilide herbicides araclor and metolachlor have been used for cultivation of tumorges and the like, but atrazine is an active against grass weeds! 1: · is low, whereas arak d-mole and metolachlor have low activity against plant weeds. Under these circumstances, a herbicide consisting of a single substance that can simultaneously control both difficult-to-control weeds, ie, grass weeds and broadleaf weeds, has not yet been put to practical use.

 Published at the same time: According to WO 93/18031, a pyrazole derivative having a thiochroman skeleton has been questioned, and this pyrazole derivative may damage corn, barley, and barley. It has been shown to have excellent selectivity for herbicidal activity at low dose in both stalk treatment and soil treatment against grasses and weeds. .

 However, according to the method described in the above-mentioned International Publication, a Grignard reaction must be carried out when synthesizing the alkoxythiochroman carboxylic acid, which is an intermediate for producing the virazole derivative, which is industrially difficult. It cannot be said that this is a useful method for producing a virazol derivative. In addition, the Grignard reaction has high reactivity and may not be included 1 ′ depending on the kind of the substituent of the target intermediate. Disclosure of the invention

The ultimate object of the present invention is to provide an alkoxythiochroman carboxylic acid derivative used for industrially advantageously producing the above pyrazole derivative by a Grignard reaction or the like. It is an object of the present invention to provide a method for easily manufacturing without using expensive steps.

 The present inventors have conducted intensive studies in order to achieve the above object, and consequently found that (i) a benzoate ester represented by the following general formula (I) as a raw material, which contains no Grignard reaction. Through the above steps, an alkoxythiochromancarponic acid derivative represented by the following general formula (VIII), which is a final substance, is obtained. (Ii) Each of the above five steps is performed in each step. Considering the starting material and the target substance, this is a new reaction step, and (Hi) the following general formula (III-1) obtained in the first, second, third and fourth steps of the above five steps ), (IV-1), (V) and (VII) are new substances.

 The present invention has been completed based on these findings, and the present invention provides

 (1) General formula (I)

R ¹

General formula (III) using benzoic acid ester of

For producing phenylthiopropionic acid derivatives (hereinafter referred to as the method (a) of the present invention)

(2) The general formula (IV) using the phenylthiopropionic acid derivative of the general formula (III)

9-

(Hereinafter referred to as the method (b) of the present invention)

 (3) The general formula (V) using the thiochromanone derivative of the general formula (IV)

(Hereinafter referred to as the method (c) of the present invention); (4) a general formula (VII) using the hydroxythiochroman derivative of the above general formula (V)

 Method for producing phenylthiopropionic acid derivative of (VII) (hereinafter referred to as method (d) of the present invention)

(5) The general formula (V III) using the phenylthiopropionic acid derivative of the general formula (VII)

 For producing alkoxythiochroman carboxylic acid (hereinafter referred to as the method (e) of the present invention)

(6) General t (III-1)

(7)-General formula (IV-1) '

R ¹

Thiochromanone derivative (hereinafter referred to as the present substance (X))

 (8) — General formula (V)

one (9) a hydroxythiochroman derivative represented by the following formula (hereinafter referred to as the substance (y) of the present invention):

An alkoxythiochroman derivative represented by the formula (hereinafter referred to as the present substance (z)) is required.

 More specifically, the method (a) of the present invention comprises a compound represented by the general formula (I)

(Wherein, R ¹ is a C, to C 4 alkyl group; X ¹ is an alkyl group, a halogen atom or a C, to C, alkyl group; m is 0 or an integer of 1 to 3; X ² is a halogen atom) represented by the general formula (エ ス テ ル)

R ⁴ R ²

(Wherein R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or a ^4- alkyl group). General formula (III)

— _

(Wherein, R ′, RRRR ′ X ^: and m are the same as defined above).

 The method (b) of the present invention comprises the general formula (ΙΠ)

(In the formulas, R ¹ is-alkyl group; R ^2, RR ^4, and R ⁵ is it that an independent Hydrogen atom ho ~ (^ alkyl group; ¹ is ₁ ～〇 ₄ Arukiru group, C Wherein m is 0 or an integer of 1 to 3), wherein the phenylthiopropionic acid derivative represented by the general formula (IV)

(Wherein, II ¹ , R ² , R ³ , RR ⁵ , X ¹ and m are as defined above).

The method (c) of the present invention is represented by the general formula (IV)

Wherein R ¹ is a C! -C ₄ alkyl group; R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or a C! -C., Alkyl group; X ¹ is a C!-(^ Alkyl group, halogen atom or C '.- C4 haloalkyl group; m is 0 or an integer of 1-3), which reduces the thiochromanone derivative represented by The general formula

(Wherein, R ′, R \ R \ R \ R ⁵ , X ¹ and m are as defined above).

 The method (d) of the present invention is represented by the general formula (V)

(Wherein P is (! ~ Alkyl group; R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or Ci-C ₄ alkyl group; X ¹ is C! C ^ An alkyl group, a halogen atom or a C, to C haloalkyl; m is 0 or an integer of 1 to 3 To the hydroxythiochroman derivative represented by the general formula (VI) R ^fi OH

 (VI)

Wherein R ⁶ is an alkyl group, an alkoxyalkyl group, or a CG haloalkyl group. The general formula (VII)

(Wherein, RR ² , RRR ⁵ , R \ X ¹ and m are as defined above).

 The method (e) of the present invention is represented by the general formula (VII)

R

Wherein R ¹ is a C, -C ₄ alkyl group; R ² , RR ^4, and R ⁵ are each independently a hydrogen atom or an alkyl group; R ⁶ is a-( ₆ alkyl group, !!! C alkoxyalkyl -, or C: be a ~ haloalkyl group; X 'is an C-C ₄ alkyl group, a halogen atom or C ~ C. haloalkyl group; m is 0 or is an integer from 1 to 3 ) Wherein the alkoxythiochroman derivative represented by the general formula (VIII) is hydrolyzed. H〇 ₂ C

(Wherein, R ² , R ^: ′, RRRX ¹ and m are as defined above).

The substance (w) of the present invention has the general formula (III-1)

(Wherein R ¹ is (^-( ₄ alkyl group; R ² , R ³ , R ⁴ and R ⁵ are each independently a purple atom or C, -C ₄ alkyl); X ¹ - ₍₄ alkyl group, a c androgenic atoms or (- ^ haloalkyl group; m ¹ is a phenylene thio propionic acid derivative represented by a 1 to 3) integer.

 The substance (X) of the present invention has the general formula (IV-1)

R ¹

(In the formula, R ¹ is an alkyl group; R ^2, RR ⁴ and R ⁵ are that it independent a hydrogen atom or a C C alkyl group;! X ¹ is

Alkyl group, a C androgenic atom or ～〇 ₄ haloalkyl group; m ¹ is a Chiokuromanon derivative represented by a 1 to 3) integer. The substance (y) of the present invention has the general formula (V)

(In the formulas, R ¹ is-alkyl ^{group; R 2, R 3, R} 4 and R ⁵ is each independent hydrogen atom or ~ alkyl group; X ¹ is ～〇 ₄ alkyl group, C port Gen atom or C, be ~ C ₄ Soso Roarukiru group; m is a hydroxy Chio chromans derivative represented by 0 or 1 of 3 integer).

 The substance (2) of the present invention has the general formula (VII)

(Wherein, R ¹ is a C! To C ₄ alkyl group; R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or a C! Ct alkyl group; R ^f ′ is ~ C ₆ alkyl group, C alkoxyalkyl group or (^ ~ (^ noloalkyl group; X ¹ is Ci ~

C ₄ alkyl group, a halogen atom or Roarukiru group; 111 is alkoxy Chio chroman derivatives衷0 or an integer of 1 to 3). BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 is a reaction scheme showing the methods (a) to (e) of the present invention.

FIG. 2 is a process chart for producing a benzoic acid ester (I) used as a starting material in the method (a) of the present invention. FIG. 3 is a process chart for producing ethyl 3,4-dichloro-6-methylbenzoate, which is the final product of Production Reference Example 1.

 FIG. 4 is a process chart for producing the final target product of Production Reference Example 2, 3,4-difluoro-6-methylethyl benzoate.

 FIG. 5 is a process chart for producing 8-chloro-6-hydroxypropyloxy-5-methyl-4-methoxythiochroman from 3,4-dichloro-6-methylbenzoate in Production Examples 1 to 5.

 FIG. 6 is a process chart for producing 8-fluoro-6-ethoxycarbonyl 5-methylthiochroman-1-one from ethyl 3,4-difluoro-6-methylbenzoate in Production Examples 6 and 7. It is. Ming »The best form to apply

 Hereinafter, the present invention will be described in detail with reference to embodiments.

In order to facilitate the understanding of the present invention, a benzoic acid ester represented by the general formula (I) was used as a raw material, and an alkoxythiochroman carboxylic acid (VIII) represented by the general formula (VIII), which is the final product, was converted to Figure 1 shows the manufacturing process. The method of the present invention (a) to (e) is illustrated in the process diagram of FIG. 1, so that the present invention methods (a) to (e) will be sequentially described based on FIG. In the process diagram shown in FIG. 1, R ¹ is a C! To C ₄ alkyl group, R ² , R \ R ⁴ and are each independently a hydrogen atom or a C, to C ₄ alkyl group, and R ^B is ( ~ ( "alkyl group, (^ ~ (^ alkoxyalkyl group, (^ ~ (^ c opening alkyl group, X ¹ is c! ~ c ₄ alkyl group, a halogen atom, c t~ 〇 ₄ cutting edge alkyl group, m is 0 or an integer of 1 to 3, and X ² is a halogen atom.

 (a)

 The method (a) of the present invention comprises condensing a benzoate (I) with a mercaptopropionic acid derivative (II) to obtain a phenylthiopropionic acid derivative (III). Benzoic acid ester (I) used as a starting material has the general formula (1)

-11-

Replacement W paper (Rule 26)

(Wherein, R ¹ is ~ ( ₄ alkyl group '; X ¹ is ~ (^ alkyl group, halogen

-11-2

Replacement form (Rule 26) An atom or (^ to (, an alkyl group; m is 0 or an integer of 1 to 3; X ² is a halogen atom); and the condensation reaction with the benzoate (I) The provided mercaptopropionic acid derivative (II) has the general formula (II)

R ⁴ R ²

HS-C-C-C0 ₂ H

^RR (II)

(Shikihaba, R \ RR ^'1 and R ⁵ is represented by it it independently hydrogen or (^ ~. ^! A § alkyl group).

 The condensation reaction is carried out in a solvent inert to the reaction, such as toluene, N-methylpyrrolidone, N, N-dimethylformamide. This reaction is preferably performed in the presence of a base, and examples of the base used include sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate. The base is used in an amount of 2.0 to 5.0 equivalents, preferably 2.0 to 3.0 equivalents, based on the benzoate (I). The reaction temperature ranges from room temperature to the reflux temperature of the solvent, but is preferably from 80 to 130 ° C. The reaction time is generally 1 to 8 hours, preferably 1 to 3 hours.

 After the completion of the reaction, the reaction solution is cooled to about 50 ° C, and an organic solvent such as ethyl acetate and water are added to remove the reaction solvent and neutral components. The removal is performed by sequentially washing the aqueous layer with a polar organic solvent such as ethyl acetate and a non-polar organic solvent such as hexane. Further, a strong acid such as concentrated hydrochloric acid is added to the obtained aqueous layer to precipitate crystals. The precipitated crystals are collected by filtration and washed with water. The obtained crystals are dissolved in a polar organic solvent such as ethyl acetate, and the solution is washed with a saturated saline solution and dried with anhydrous sodium sulfate. By evaporating the solvent, the desired phenylthiobrobionic acid derivative (III) is obtained. The obtained phenylthiopropionic acid derivative has the general formula (I II)

-12 63 CT / JP9 / 02

(Wherein, R ¹ R ² , RRR ⁵ , X ¹ and m are as defined above) o

 The phenylthiopropionic acid derivative (III) may be further purified as necessary, but can usually be used in the method (b) of the present invention without purification.

The method of the present invention (b)

In the method (b) of the present invention, the phenylthiopropionic acid derivative (III) obtained in the method (a) of the present invention is condensed and cyclized to obtain a thiochromanone derivative (IV). Examples of the condensed cyclization method include (i) converting phenylthiopropionic acid derivative (III) to hydrogen fluoride, sulfuric acid, fuming sulfuric acid, phosphorus pentachloride, phosphoric acid, polyphosphoric acid, tin chloride, zinc chloride, or chloride. A method of dehydration cyclization in the presence of an acid catalyst such as an acidic ion exchange resin represented by aluminum or Amberlyst; (ii) a phenylthiopropionic acid derivative (III) using a chlorine such as thionyl chloride; A method of reacting with an agent to form an acid chloride, and cyclizing in the presence of an acid catalyst similar to the method (i) above. The solvent used in the reaction is not particularly limited as long as it is inert under the reaction conditions. However, hydrocarbon solvents such as pentane and hexane, and halogen solvents such as dichloromethane and 1,2-dichloroethane are used. preferable. Further, a method using polyphosphoric acid as a solvent and an acid catalyst is also suitable. In the above method (i), the acid catalyst is used in an amount of 0.01 to 20 equivalents, preferably 1.0 to 10 equivalents, based on the phenylthiopropionic acid derivative (III). The reaction temperature is usually in the range of 0 ^e C~l 20 ° C, preferably 0 ° C ~ 100 ° C. The reaction {1, ./.] Is generally 30 minutes to 8 hours (¾, but preferably 30 minutes to 2 hours. In the above-mentioned condensed cyclization method (ii), the chlorinating agent is phenylthiopropion. The acid derivative (ΠΙ) is used in an amount of 1.0 to 3.0 equivalents, preferably 1.1 to 1.5 equivalents, and the reaction temperature of the acid chloride is usually in the range of 0 to 120 ° C. The reaction time is usually 30 minutes to 8 hours, preferably 30 minutes to 2 hours, and the acid catalyst used in the cyclization method (ii) is an acid. It is used in an amount of 0.01 to 1.0 equivalent, preferably 0.1 to 1.0 equivalent, based on the chloride.The reaction temperature of the acid-catalyzed reaction is usually from room temperature to 120 ° C., preferably room temperature. The reaction time is generally 30 minutes to 8 hours, preferably 2 to 4 hours.

- 13 - Time.

 After the reaction is completed, the reaction product is left to cool, then poured into ice water, and neutralized with a basic aqueous solution such as potassium carbonate or sodium carbonate to neutralize the acid catalyst used in the reaction. Next, extraction is performed with an organic solvent such as ethyl acetate and dichloromethan. The obtained organic layer is washed with saturated saline and dried with a desiccant such as anhydrous sodium sulfate. By evaporating the solvent, a crude product of the intended product can be obtained. When an acidic ion exchange resin such as Amberlyst is used, it is preferable to separate the resin before processing PI !. The thiochromanone derivative thus obtained is represented by the general formula (IV)

R ¹

(In the formula, R ¹ is C, ~ an alkyl ^{group;. R 2, R 3,} R 4 and R ⁵ is it that independent a hydrogen atom or a C ~ C ₄ alkyl group;! X ¹ is ～〇 ₄ alkyl group, a C androgenic atom or C ~ C ₄ Nono Roarukiru group; m is represented by an integer of 0 or from 1 to 3).

A particularly preferred embodiment of the method (b) according to the present invention is represented by the general formula (Ilia)

 (l I I a)

(Wherein, R ¹ is an alkyl group; X ^la and X ^lb are an alkyl group, a halogen atom or an alkyl group, which may be the same or different). Cyclization in the presence of fuming sulfuric acid using a propionic acid derivative as an acid catalyst-General formula (IVa)

- 14 -

 (i Va)

(Wherein, RX ^la and X ^lb are as defined above).

The method of the present invention (c) '

 In the method (c) of the present invention, the thiochromanone derivative (IV) obtained in the method (b) of the present invention is reduced to obtain a hydroxythiochroman derivative (V).

There are no particular restrictions on the reduction method, but (i) a method using a reducing agent such as sodium borohydride in a reaction inert solvent such as alcohol or dichloromethane, or (ii) a method using palladium or nickel or the like. A method in which hydrogenation is carried out at normal pressure or under pressure in the presence of a reduction catalyst may be mentioned. In the reduction method (i), the reducing agent is used in an amount of 1.0 to 5.0 equivalents, preferably 1.1 to 2.0 equivalents, relative to the thiochromanone derivative (IV). The reaction temperature is usually from 20 to 50, but preferably from 0 to 20 ° C. The reaction time is usually from 30 minutes to 8 hours, preferably from 30 minutes to 2 hours. In the above reduction method (ii), the reduction catalyst is used in an amount of 1 to 50% by weight, preferably 10 to 20% by weight, based on the thiochromanone derivative (IV). The hydrogen pressure is usually from normal pressure to 100 kg / cm ² , preferably from 10 to 5 Okg / cm ² . The reaction temperature is from room temperature to 100 ° C, and the reaction time is from 1 to 8 hours.

 A preferred embodiment of the method (c) of the present invention is a method in which ethanol and dichloromethane are used as a solvent and reduction is carried out using sodium borohydride. In this case, the reaction temperature is preferably 0 ° C. to room temperature, and the reaction time is preferably 30 30 to 2 hours.

 When the reduction reaction is performed with sodium borohydride, after the reaction is completed, the reaction solution is poured into ice water and extracted with dichloromethane. The obtained organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain a crude product. This crude product can be directly used for the next reaction without purification.

15- 遝 When a raw catalyst is used, a crude product is obtained by separating the catalyst and distilling off the solvent. This crude product can be directly used for the next reaction without purification.

 The hydroxythiochroman derivative thus obtained has the general formula (V)

(Wherein, R ¹ is a (^-^ alkyl group; R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or a C! Ca alkyl group; X ¹ is a -alkyl group) , Nono port Gen atom or C, be ~ C ₄ haloalkyl group; m is ¾ by an integer of 0 or from 1 to 3).

Finding method (d)

 In the method (d) of the present invention, the hydroxythiochroman derivative (V) obtained in the method (c) of the present invention is dehydrated and condensed with an alcohol (VI) to obtain an alkoxythiochroman derivative (VII).

 In the method (d) of the present invention, the alcohol used for the reaction with the hydroxythiochroman derivative (V) is represented by the general formula (VI)

 R ° OH

 (VI)

(Wherein, R ⁶ is represented by —C _c alkyl group, C; —C ₆ alkoxyalkyl group, or C! — (A _6- alkyl group).

 As a reaction solvent used in the dehydration condensation reaction, an aromatic hydrocarbon solvent such as benzene, toluene, xylene and the like, and a halogenated hydrocarbon solvent such as 1,2-dichloroethane and carbon tetrachloride can be used. Alcohol (VI), which is a reaction reagent, can be used in excess as a solvent. As the catalyst, for example, an acid catalyst such as sulfuric acid, -aromatic sulfonic acid, sulfonic acid halide, boron trifluoride, and aluminum chloride is used.

-16- By using this, the dehydration condensation reaction proceeds smoothly. The acid catalyst is used in an amount of 0.01 to 0.2 equivalent relative to the hydroxythiochroman derivative (V). The reaction temperature is usually in the range of 60 ^E C to the boiling point of the solvent, but preferably the reflux temperature of the solvent used or the alcohol (VI) used also as the solvent.

 After completion of the reaction, the reaction solution is poured into a large excess of ice water, and extracted with an organic solvent such as ethyl acetate and dichloromethane. The obtained organic layer is sequentially washed with a 5% aqueous potassium carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. By distilling off the solvent, a crude product of interest can be obtained.

 The alkoxythiochroman derivative thus obtained is represented by the general formula (VII)

R ¹

 (VII)

Wherein R ¹ is a C! CA alkyl group; R ² , R ³ , R ⁴ and R ³ are each independently a hydrogen atom or a C! -C ₄ alkyl group; R 6 is a C! ! ~ C ₆ alkyl group, C, be -C _G alkoxyalkyl group or C ₁ -C ₆ Nono Roarukiru group; X ¹ is (^ ~ C. alkyl group, a halogen atom or the C: ~ C ₄ Nono Roarukiru group Yes; 111 is 0 or an integer of 1 to 3).

Method of the present invention (e)

 The process (e) of the present invention comprises hydrolyzing the alkoxythiochroman derivative (VII) obtained by the process (d) of the present invention to obtain an alkoxythiochroman carboxylic acid derivative (VIII) as the final product. is there.

 The hydrolysis reaction can be achieved under both acidic conditions and basic conditions. Preferably, the reaction is carried out using a base catalyst such as sodium hydroxide in the presence of a large excess of water. The acid catalyst or the base catalyst is used in an amount of 0.01 to 1 equivalent, preferably 0.1 to 1 equivalent, relative to the alkoxythiochroman derivative (VII). Reaction temperature is usually room temperature

-17 To the reflux temperature of the solvent, preferably the reflux temperature of the solvent. The reaction time is generally 1 to 8 hours, preferably 1 to 4 hours.

 After completion of the reaction, the solvent is distilled off from the reaction solution, ice water is added to the obtained residue, and neutral impurities are removed with an organic solvent such as ethyl acetate or dichloromethane. Next, the obtained aqueous layer is neutralized with concentrated hydrochloric acid, and extracted with an organic solvent such as ethyl acetate and dichloromethane. The obtained organic layer is washed with a saturated saline solution, dried over anhydrous sodium sulfate or the like, and the solvent is distilled off, whereby a crude product of the desired product can be obtained.

 The alkoxythiochroman carboxylic acid thus obtained is the final product and has the general formula (VIII)

(Wherein, R ² , R ³ ,: ⁴ and R ⁵ are each independently a hydrogen atom or

R ^B is a Ct Cs alkyl group, a C ₁ -C ₆ alkoxyalkyl group or a C! -C ₆ haloalkyl group; X ¹ is a C! -C ₄ alkyl group, a halogen atom or ( ^ To 〇 is a _4- alkyl group; m is 0 or an integer of 1 to 3).

The benzoate (I) used as a starting material in the method (a) of the present invention can be produced by various known methods. For example, the benzoate (I) may be produced through the steps (1) to (3) shown in FIG. Can be manufactured. In the process diagram shown in FIG. 2, R ¹ is a C i -C ₄ alkyl group, X ¹ is a (^-(^ alkyl group, a halogen atom, (^-(^ a haloalkyl group, m is 0 or 1- X is an integer of 3, X ² is a halogen atom, L is a chlorine atom, a bromine atom, a 10H group or an OCOCH ₃ .

 Hereinafter, the steps (1) to (3) will be described in detail.

Process (1) One 18-

Street Paper (Rule 26) A halogen-substituted benzene derivative represented by the formula (i) (hereinafter referred to as a halogen-substituted benzene (i)) is acetylated with an acetylating agent in the presence of an acid catalyst, and an acetophenone derivative represented by the formula (ii) Acetophenone (ii)).

18-2-

Replacement forms (Rule 26 Examples of the acid catalyst include hydrogen fluoride, sulfuric acid, phosphorus pentachloride, phosphoric acid, polyphosphoric acid, tin chloride, zinc chloride, and aluminum chloride. The acid catalyst is used in an amount of 0.1 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents, based on the halogen-substituted benzene (i). Examples of the acetylating agent include acetic acid, acetic anhydride, acetyl chloride and the like. The acetylating agent is used in an amount of 1.0 to 5.0 equivalents, preferably 1.1 to 1.5 equivalents, based on the halogen-substituted benzene (i). The reaction solvent is not particularly limited as long as it is inert under the reaction conditions. However, hydrocarbon solvents such as pentane and hexane, and halogen solvents such as dichloromethane and 1,2-dichloroethane are preferred. The reaction temperature is not particularly limited within the range of 178 ° C to the reflux temperature of the solvent, but is preferably about 0 to 80 ° C. The reaction time is usually 1 to 20 hours, preferably 2 to 8 hours.

 After completion of the reaction, the reaction solution is poured into ice water, extracted with an organic solvent such as dichloromethane, and the obtained organic layer is washed successively with water, a 5% aqueous potassium carbonate solution and saturated saline, and then sulfuric anhydride is added. Dry with sodium. By distilling off the solvent, a crude product of the desired product can be obtained.

Process (2)

 In this step, acetophenone (Π) is oxidatively cleaved to obtain a benzoic acid derivative represented by the formula (iii) (hereinafter, referred to as benzoic acid derivative (iii)).

 Examples of the oxidative cleavage method include (a) a method using carbon tetrachloride and lithium hydroxide (haloform reaction), (mouth) a method using sodium hydroxide and chlorine (haloform reaction), and (c) iodine. Examples thereof include a method using pyridine (King reaction), and (2) a method using an oxidizing agent such as sodium hypochlorite and potassium hypochlorite (haloform reaction).

 In the above oxidative cleavage method (2), as the solvent, for example, dioxane, water, black holem, or the like can be used. The oxidizing agent is used in an amount of 3.0 to 5.0 equivalents to acetophenone (ii). The reaction temperature is usually from 120 to 60 ° C, preferably from 0 to 20 ° C. The reaction time is usually 1 to 8 hours, but preferably 2 to 4 hours.

 After completion of the reaction, an aqueous solution of sodium sulfite is added to the reaction solution to separate excess oxidizing agent.

-19- Understand. Subsequently, an organic solvent such as dichloromethane is added for washing to remove the organic solvent and neutral components used in the reaction. The remaining aqueous layer is made acidic by adding concentrated hydrochloric acid or the like, and the crystals are precipitated. The obtained crystals are filtered and dried, or extracted with an organic solvent, dried over anhydrous sodium sulfate, and then the solvent is distilled off to obtain the desired product.

Process (3)

 In this step, the benzoic acid derivative (iii) is condensed with an alcohol represented by the formula (iv) (hereinafter, referred to as alcohol (iv)) to obtain a benzoic acid ester (

 Preferred examples of the condensation method include (i) a method in which a benzoic acid derivative (iii) is reacted with a chlorinating agent such as thionyl chloride to react with an alcohol (iv) as an acid chloride, (mouth) sulfuric acid, p-toluene In the presence of an acid catalyst such as sulfonate, a method of dehydrating and condensing with an alcohol (iv) may be mentioned. In the above condensation method (a), the chlorinating agent is used in an amount of 1.0 to 5.0 equivalents, preferably 1.2 to 2.0 equivalents, relative to the benzoic acid derivative (iii). The alcohol (iv) is allowed to react with the obtained acid compound in an amount of 1.0 to 100 equivalents, preferably 5 to 50 equivalents. Examples of the reaction solvent include solvents inert to the reaction, such as dichloromethane and 1.2-dichloroethane. The reaction temperature is usually 0 to 100 ° C, preferably 0 to the reflux temperature of the solvent. The reaction time is usually 30 minutes to 8 hours, preferably 2 to 4 hours. In the above condensation method (mouth), the acid catalyst is used in an amount of 0.01 to 5.0 equivalents, preferably 0.05 to 1 equivalent, relative to the benzoic acid derivative (iii). The alcohol (iv) is reacted with the benzoic acid derivative (iii) in an amount of 1 to 100 ff, preferably 5 to 20: The reaction solvent used is the alcohol used for the reaction. The reaction temperature is usually from 0 to the reflux temperature of the solvent, preferably from 20 to 80 ° C. The reaction time is generally 1-24 hours, preferably 2-8 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, ice water was added to the reaction residue, and the mixture was extracted with ethyl acetate. The obtained organic layer is washed successively with an aqueous sodium carbonate solution and a saturated saline solution, and dried over anhydrous sodium sulfate. By evaporating the solvent under reduced pressure, a crude product of the desired product can be obtained.

 Next, the compounds (ΙΠ-1), (IV-1), (V) and (VII), which are the novel substances (w), (X), (y) and (z) of the present invention, will be described in order.

 The phenylthiopropionic acid of the substance (w) of the present invention is represented by the general formula (III-1).

20- Typing,

In the above formula (ΠΙ-1), R ¹ is an alkyl group. Specific examples of the CCA alkyl group include a methyl group, an ethyl group, a propyl group and a butyl group, and the propyl group and the butyl group may have a branch. Preferably it is an ethyl group.

R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or a C, -C ₄ alkyl group. Specific examples of the C 1 to C ₄ alkyl groups are as described above.

X ¹ is a C i -C ₄ alkyl group, a halogen atom or C! To C ₄ peroxyalkyl group, preferably C: to C ₄ alkyl group or Happagen atom. C! Examples of ~ C ₄ alkyl group is as defined above, preferably a methyl group. Specific examples of the halogen atom include a chlorine atom, a fluorine atom, a bromine atom, an iodine atom and the like, and a chlorine atom or a fluorine atom is preferable. Ci～C ₄ haloalkyl groups are those substituted with at least one halogen atom of the (^ - (^ hydrogen atom in the alkyl group, C i - C ₆ Nono Roarukiru groups described below as specific examples Among them, those having 1 to 4 carbon atoms are mentioned.

m ¹ represents the number of substitutions of X ¹ and is an integer of 1 to 3, preferably 1 or 2. The substitution position of X ¹ is susceptible to 5, 7 and 8 positions of Chiokuroman ring, it is preferred properly is 5 and / or 8-position. That is, when m ¹ is 1, the substitution position of X ¹ is preferably at position 5 or 8 of the chiochroman ring, and when m ¹ is 2, the substitution position of two X ¹ is preferably at positions 5 and 8. When m ¹ is 2 or 3, two or three X ¹ may be the same or different.

 The thiochromanone derivative which is the substance (X) of the present invention is represented by the general formula (IV-1).

- twenty one

R ′ to R ⁵ , X ¹ and m ¹ in the above formula (IV-1) are as described in the phenylthiopionic acid derivative of the formula (ΙΠ-1).

 A particularly preferred embodiment of the substance (X) of the present invention is represented by the general formula (VI-la)

 (V I-1 a)

Mel (wherein,! ^ Is Aru in Rei_1～〇 ₄ Arukiru group) in Chiokuromanon derivative represented by. )

 Inventive Substance (y) Certain hydroxythiochroman derivatives are represented by the general formula (V).

1 ^ to ¹⁵ and X ¹ in the above formula (V) are as described in the phenylthiopropionic acid derivative of the formula (ΙΠ-l), and m is 0 or an integer of 1 to 3 . When m is 0, X ¹ is not substituted on the chiochroman ring, and when m is 1 to 3, it is the same as m ^{1 in} formula (III-1).

 The alkoxythiochroman derivative of the present invention (z) is represented by the general formula (VII)

- twenty two - Represented <

In the above formula (VII), ~1¾ ⁵ and X ¹ are as described in Hue two Ruchiopu Robion acid derivative of the formula (III-1), m is as described in Formula (V).

R ⁶ is a C i -C _G alkyl group, a C! -C 6 alkoxyalkyl group or a C! -C 6 haloalkyl group, preferably a -alkyl group. 〇; ~ (: Specific examples of the ₆ alkyl groups include the above-mentioned specific examples of the c: to c ₄ alkyl groups, and pentyl and hexyl groups having a straight or branched chain, preferably a methyl group. is there.

Specific examples of the C Cc alkoxyalkyl group include, for example, a methoxy-substituted 5-alkyl group such as a methoxymethyl group, a methoxethyl group and a methoxypropyl group; an ethoxy-substituted group such as an ethoxymethyl group, an ethoxyshethyl group and an ethoxypropyl group.

And C 4 alkyl groups. A haloalkyl group is _one in which at least one of the hydrogen atoms in the C ₁ -C ₅ alkyl group has been replaced by a halogen atom (eg, a chlorine atom, a fluorine atom, a bromine atom, an iodine atom). Is, for example, one CH ₂ C 1, —CF, —CH ₂ CH ₂ C 1, — CH ₂ CH ₂ F, etc. 0

 Hereinafter, the present invention will be described in more detail with reference to Production Reference Examples and Production Examples. FIG. 3 shows a manufacturing process diagram of Production Reference Example 1.

Production Reference Example 1: Synthesis of 3,4-dichloro-6-methylethyl benzoate (equivalent to ester (I) benzoate)

Step (1): Synthesis of 3,4-dichloro-6-methylacetophenone (equivalent to acetophenone derivative (ii))

 100 g (1.21 eq, 750 mmol) of aluminum chloride as an acid catalyst

- twenty three - To a 250 ml solution of 1,2-dichlorobenzene is added 80 ml (100 g, 621 mmo1) of 3,4-dichlorotoluene corresponding to the halogen-substituted benzene derivative (i). 55 ml (1.25 eq, 774 mmol) of acetyl was added dropwise at room temperature. After completion of the dropwise addition, the reaction solution was stirred at room temperature for 10 minutes, and then stirred at 0 to 75 ° C for 5 hours. After cooling the reaction solution, it was gradually poured into 300 ml of ice water. Two-layer separation was performed, and the obtained organic layer was concentrated. The obtained aqueous layer was extracted with ethyl acetate, and the obtained organic layer was combined with the concentrated organic layer. The organic layer was washed once with 5% hydrochloric acid, twice with an aqueous solution of sodium carbonate and once with a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 3,4-dichloro-6-methylacetophenone 125.1-(yield 86%).

N.M.R. (solvent: heavy acetone, internal standard: tetramethylsilane): 2.47

(3H, s), 2, 58 (3H, s), 7.50 (1H ₃ s), 7.97 (1H, s) Step (2): 3-4-Diclo mouth— 6-methylbenzoic acid Synthesis of benzoic acid derivative (iii)

1350 ml (1.96 mo Is 3 eq) of a 12. '9% sodium hypochlorite aqueous solution as an oxidizing agent was diluted with 400 ml of water, and cooled to 8 ° C under ice cooling. Here, the Jiokisan solution 130 m 1 of a part of the step (1) 2问行not obtained 3 ₅ 4 dichloroethane port one 6- Mechirua Setofuenon crude product 132. 3 g (652 mmo 1) 10 ° C, and then dioxane (130 ml) was added. Thereafter, the ice-water bath was removed and the mixture was stirred at room temperature. When the temperature in the reaction system reached 15 C, the mixture was again stirred under ice-cooling for 1 hour, and the ice-water bath was removed, followed by stirring at room temperature for 3.0 hours. Thereafter, 50 ml of an aqueous solution of 10.0 g (79 mmo 1) of sodium sulfite was added to the reaction solution. After washing the reaction solution twice with methylene chloride, 170 ml of concentrated hydrochloric acid was added under ice-cooling. After extraction with ethyl acetate three times, the obtained organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 119.3 g of a crude product of 3,4-dichloro-6-methylbenzoic acid (yield: 3%).

N.M.R. (solvent: heavy acetone, internal standard: tetramethylsilane): 2.59

twenty four (3H, s), 7. 52 (1H, s), 8. 04 (1H, s) Step (3): 3 ₅ 4 Jikuroko 6-methyl benzoate Echiru (benzoic acid ester

Synthesis of phase (I))

 The 3,4-dichloro-6-methylbenzoic acid 92.1 (42 lmmo 1) obtained in the above step (2) was dissolved in 550 ml of ethanol corresponding to the alcohol (iv) and also as a solvent. 20 ml of concentrated sulfuric acid as a catalyst was added, and the mixture was heated under reflux for 7 hours. After the ethanol was distilled off under reduced pressure, ice water was added thereto, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with an aqueous solution of sodium carbonate and a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 103.4 g of a crude product of ethyl 3,4-dichloro-6-methylbenzoate (97% yield).

 NMR, (solvent: heavy acetone, internal standard: tetramethylsilane): 1.39 (3H, t), 2.57 (3H, s), 4.35 (2H, s), 7.52 (1H, s), 7.98 (1 H, s) FIG. 4 shows a production process diagram of Production Reference Example 2.

Production Reference Example 2: Synthesis of 3,4-difluoro-6-methylethyl benzoate (phase with ester (I) benzoate)

Step (1): Synthesis of 3,4-difluoro-6-methylacetophenone (corresponding to acetophenone derivative (ii))

 To a solution of 10.0 g (l. 9 eq, 75 mmol) of aluminum chloride, an acid catalyst, in 20 ml of 1,2-dichloroethane, 5.5 m1 (2.0 eq, 77 mmo1) of acetyl chloride, an acetylating agent, was added. 5.0 g (39 mmo 1) of 3,4-difluorotoluene corresponding to the halogen-substituted benzene derivative (i) was dropped under ice. After the addition was completed, the reaction solution was stirred at room temperature for 5 hours. After cooling, the reaction solution was gradually poured into 100 ml of ice water. Two-layer separation was performed, and the obtained organic layer was concentrated. The obtained aqueous layer was extracted with methylene chloride, and the obtained organic layer was combined with the concentrated organic layer. The organic layer was washed once with 5% hydrochloric acid, twice with an aqueous sodium hydrogen carbonate solution and once with a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure

- twenty five - As a result, 6.77 g (yield 100%) of a crude product of 3,4-difluoro-6-methylacetophenone was obtained.

NMR (solvent: double-mouthed form, internal standard: tetramethylsilane): 2.49 (3H, s), 2.55 (3H, s); 7.04 (1H, dd, J = 7. · 7, 11.1), 7.55: synthesis of (1 [Eta], dd, J = 8. 2) step (2) 3 ₃ 4-difluoromethyl over 6-methyl benzoic acid (benzoic acid derivative (iii) corresponding to)

30 ml of a 3.77 g (39 mm 01) dioxane solution of 3,4-difluoro-6-methylacetophenone obtained in the above step (1) was cooled to 30 ml with ice cooling. Cooled to C. Was added dropwise below 5 ^e C herein is an oxidizing agent 6.3% The following ¾ chlorate Natoriumu solution 130ml (11 Ommo 1). Thereafter, the reaction solution was stirred in an ice water bath for 2 hours, and then 5 ml of an aqueous solution of 1. Og (7.9 mmo 1) of sodium sulfite was added. After washing the reaction solution twice with methylene chloride, 2 Oml of concentrated hydrochloric acid was added under ice cooling. After extraction with ethyl acetate three times, the obtained organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5.1 g of a crude product of 3,4-difluoro-6-methylbenzoic acid (yield 79%).

 NMR (solvent:; black form, internal standard: tetramethylsilane): 2.60 (3H, s), 7.07 (1H, dd, J = 7.7, 10.8), 7.89 (1H , Dd, J = 8.4) Step (3): Synthesis of 3,4-difluoro-6-methylethyl benzoate (corresponding to ester (I) benzoate)

 Dissolve 5.41 g (31 mmo 1) of 3,4-difluoro-6-methylbenzoic acid obtained in the above step (2) in 40 ml of ethanol corresponding to alcohol (iv), and add 6 ml of concentrated sulfuric acid as an acid catalyst. Was added and the mixture was heated under reflux for 7 hours. After ethanol was distilled off under reduced pressure, ice water was added thereto, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with an aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and ethyl 3,4-difluoro-6-methylbenzoate is removed.

One 26 6.29 g (yield 100%) of a crude product was obtained.

 N.M.R. (solvent: chloroform-form, internal standard: tetramethylsilane): 1.39 (3H, t, J = 7.0), 2.57 (3H, s), 4.35 (2H, q),

7.03 (1H, dd, J = 7.7, 11.1), 7.77 (1H, dd, J =

8.4) Manufacturing Examples 1 to 5 are shown in! 5.

Production Example 1: Production of 3- (2-chloro-4-ethoxyethoxycarbonyl-5-methylphenylthio) propionic acid (phenylthiopropionic acid (III-1)) corresponding to the method (a) of the present invention An example

3,4-Dichloromouth ethyl-6-methylbenzoate obtained in Production Reference Example 1 (corresponding to benzoate (I)) 53.7 g (23 Immo 1), base potassium carbonate 37.0 g (1 l eq, 268 mm o 1) in N, N-dimethylformamide (DMF) solution 2 in 15 ml at room temperature 3-mercaptopropionic acid (equivalent to mercaptopropionic acid (II)) 23.4 ml (1 After adding leq, 268 mmo1), the mixture was heated and stirred at 120 to 125 ° C for 2 hours and 20 minutes. The reaction solution was cooled to about 50 ^e C and, after addition of acetic acid Echiru and water, to remove the DMF and neutral components, four times, hexane with 1 Kaiarai ^ was to in acetic acid Echiru. Concentrated hydrochloric acid was added to the obtained aqueous layer to precipitate crystals. After leaving for a while, the crystals were collected by filtration and washed three times with water. The obtained crystals were dissolved in ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 50.4 g (yield: 60%) of a crude product of 3- (2-chloro-4-ethoxycarbonyl-5-methylphenylthio) propionic acid (III).

 NMR (solvent: heavy acetone, internal standard: tetramethylsilane): 1.38 (3H, t), 2.58 (3H, s), 2.79 (2H, t), 3.35 (2H, t) , 7.33 (1H, s), 7.87 (1H, s) Preparation Example 2: 8-chloro-6-ethoxycarbo-2-yl 5-methylthiochroman 1-4 corresponding to the method (b) of the present invention One on (equivalent to Ziochromanone (IV-1))

-27- Manufacturing example

 To 167 g of polyphosphoric acid heated to 80 to 85 C, which is an acid catalyst, 3- (2-chloro-4-ethoxyethoxycarbonyl-5-methylphenylthio) propionic acid (III) obtained in Production Example 1 above was added. After adding 47.7 g (157 mmo 1) over 5 minutes, the mixture was heated and simulated for 1 hour and 20 minutes. After allowing the reaction solution to cool to room temperature, it was gradually added to a mixture of 191 g (1.8 Omo 1) of sodium carbonate and ice, and stirred at room temperature until sodium carbonate was almost dissolved. Extraction was performed twice with ethyl acetate, and the obtained organic layer was washed twice with an aqueous solution of sodium carbonate, twice with water and once with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 41.3 g (yield: 85%) of a crude product of 8-chloro-6-ethoxycarbonyl 5-methylthiochroman-1-one (IV). ^

 NMR (solvent: Φacetone, internal standard: tetramethylsilane): 1.38 (3H, t), 2.58 (3H, s), 2.9-3.1 (2H, m), 3.3 -3.5 (2H, m), 4.34 (2H, q), 7.81 (1H, s) Production Example 2-2: 8-chloro-6-ethoxyca corresponding to the method (b) of the present invention Example of production of luponil 5-methylthiochroman-1-one (corresponding to thiochromanone (IV-1)) (acid chloride method)

 3-(2-Chloro-41-ethoxycarbonyl-5-methylphenylthio) propionic acid 2. g (δ. 2mmo 1), thionyl chloride 0.57ml (7.8mm o 1) in 1, 2-dichloro mouth The mixture was heated and refluxed for 1 hour and 15 minutes in 6 ml of water. When gas generation ceased, excess thionyl chloride and solvent were distilled off, and 1,2-dichloromethane (6 ml) and Amberlyst (60 Omg) were added. The mixture was refluxed for 2 hours and 40 minutes. When the generation of gas was completed, the reflux was stopped, and the reaction solution was allowed to cool to room temperature. The amber list was filtered off, washed with ethyl acetate, and the washing solution and the reaction solution were combined, washed three times with an aqueous solution of sodium carbonate and once with a saturated saline solution. Then, after drying over anhydrous sodium sulfate, the solvent was distilled off to obtain a crude product 1.21 (yield 73%) of 8-chloro-6-ethoxycarbonyl-15-methylthiochroman-14one. .

One 28 Production Example 2-3: Example of production of 8-chloro-6-ethoxyca-ni ^ -tilchioc.guchiman1.4-one (corresponding to thiochromanone (IV-1)) corresponding to the method (b) of the present invention ( Fuming sulfuric acid method)

 3- (2-Chloro-41-ethoxycarbonyl-5-methylphenylthio) Propionic acid 2.0 g (5.7 mmo 1) is suspended in 1,2-dichloroethane (10 ml) and placed on ice for 20 minutes. % Fuming sulfuric acid 1.4 ml (6.8 mmo 1) was added dropwise. After stirring for 30 minutes, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with an aqueous sodium carbonate solution and once with a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.39 (yield: 82%) of a crude product of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-1-one. Production Example 3: Production Example of 8-chloro-6-ethoxycarbo-2-yl 5-methylthiochroman-14-ol (corresponding to hydroxythiochroman (V)) corresponding to the method (c) of the present invention

 88.4 g (31 lmmo 1) of 8-cyclohexyl-6-ethoxycarbonyl-5-methylthiochroman 4-IV (IV) obtained in Production Example 2 above was dissolved in 200 ml of ethanol, and further dissolved in 20 ml of dichloromethane. Was dissolved. 5 to 10 of this solution. After cooling to C, 5.9 g (155 mmo 1) of sodium borohydride was added thereto. After stirring the reaction solution at the same temperature for 30 minutes, it was further stirred at room temperature for 3 hours. Thereafter, the reaction solution was poured into 40% of 5% aqueous hydrochloric acid, extracted with 900 ml of dichloromethane, and the obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 86.8 g (97% yield) of 8-chloro-6-ethoxycarbone-5-methylthiochroman-1-ol (V).

NMR (solvent: @ acetone, internal standard: tetramethylsilane): 1.35 (3H, s), 1.6-3.7 (5H, m), 2.62 (3H, s), 4.1 4.8 (1H, bs), 4.32 (2H ₃ q), 5.13 (lH, m), 7.71 (IK, s)

-29 Production Example 4: Production example of 8-chloro-6-ethoxycarbo-2-yl 5-methyl-4-methoxythiochroman (corresponding to alkoxythiochroman (VII)) corresponding to the method (d) of the present invention

 83 g (289 mmo 1) of 8-chloro-6-ethoxycarbonyl 5-methylthiochroman-4-ol (V) obtained in the above Production Example 3 was dissolved in 60 Oml of methanol, which is equivalent to alcohol (VI) and also a solvent. Then, 17 ml of sulfuric acid as a catalyst was added, and the mixture was heated under reflux for 5 hours. After completion of the reaction, the reaction solution was poured into 1 liter of ice water and extracted with 1 liter of ethyl acetate. The obtained organic layer was washed twice with water, twice with 300 ml of 3% sodium carbonate, twice with saturated saline, and dried over anhydrous sodium sulfate. 86 g (98% yield) of 8-chloro-6-ethoxycarbonyl 5-methyl-4-methoxythiochroman (VII) was obtained by blowing the solvent.

 NMR (solvent: deuterated acetone, internal standard: tetramethylsilane): 1.35 (3H, t), 1.3-3.5 (3H, m), 2.53 (3H, s), 3.43 ( 3H, s), 3.84 (3H, s), 4.34 (2H, q), 4.60 (1H, m), 7.71 (1H, s) J ^ M .5 ... * ¾n |例 ..Le.) ..Tffl ¾ .¾>--2 .. 2. Preparation of A-dicarboxyl-5-methyl-4-methoxythiochroman (equivalent to alkoxythiochromancarboxylic acid (VIII))

 84 g (254 mmo 1) of 8-chloro-6-ethoxycarbone 5-VII obtained in Production Example 4 above (254 mmo 1), 80 g of hydroxide hydroxide as a base catalyst, 300 ml of ethanol, and 150 ml of water Mix and heat at 80 ° C for 2 hours. After completion of the reaction, ethanol was distilled off, 500 ml of water was added thereto, and the aqueous layer was washed with ethyl acetate. The obtained aqueous layer was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 66 g (95% yield) of 8-chloro-6-carboxyl-5-methyl-14-methoxythiochroman (VIII).

N. M. R. (solvent: heavy acetone, internal standard: tetramethylsilane): 2.3

-30- 4.0 (5H, m), 2.59 (3H, s), 4.70 (1H, m), 7.90 (1H, s) Figure 6 shows the manufacturing process diagrams of Production Examples 6 and 7. .

Production Example 6: Production example of 3- (2-fluoro-4-ethoxycarboxy-5-methylphenylthio) propionic acid (corresponding to phenylthiopropionic acid (III)) corresponding to the method (a) of the present invention.

6.29 g (31 mm 01) of 3,4-difluoro 6-methyl benzoate obtained in Reference Example 2 above and 6.0 g (1.4 eq, 43 mmo 1) of potassium carbonate as a salt were obtained. 01 ^? a solution 201,111, (corresponding to mercaptopropionic acid (II)) at room temperature for 3 Mel helmet pro Lactobiono acid 4. 0 g (1. 2 eq, 38mmo 1) after the was pressurized example, 80-90 ^e C For 6 hours. After cooling the reaction solution, ice water was added, and the mixture was washed twice with methylene chloride to remove neutral components. Concentrated hydrochloric acid was added to the obtained aqueous layer, and extraction was performed three times with ethyl acetate. The obtained organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 6.36 g (yield: 70%) of a crude product of 3- (2-fluoro-4-ethoxycarbonyl-5-methylphenylthio) propionic acid (III). '

NMR (solvent: black port Holm, internal standard: _{tetramethylsilane): 1. 38 (3H 3 t} , J = 7. 3), 2. 56 (3H, s), 2. 71 (2H, t, J = 6. 3), 3. 22 ( 2 H, t), 7. 18 (1 H, d 3 J = 7. 3), 7. 62 (1 H, d, J = 10. 4) preparation example 7: Production example of 8-fluoro-6-ethoxyponyl-5-methylthiochroman 141-one (equivalent to thiochromanone (IV)), which corresponds to the present method (b)

 The 3- (2-fluoro-4-ethoxyethoxycarbonyl-5-methylphenylthio) probionic acid (III) 2.0 g (7.Ommol) obtained in Production Example 6 above was added to polyphosphoric acid as an acid catalyst. Add 15 g, 50-60. The mixture was heated and stirred at C for 30 minutes. After allowing the reaction solution to cool to room temperature, it was gradually poured into ice. Extract three times with ethyl acetate and obtain

-31- The obtained organic layer was washed twice with an aqueous solution of sodium hydrogen carbonate, twice with water, and once with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 1.69 g (yield: 90%) of crude 8-fluoro-6-ethoxycarbonyl-5-methylthiochroman-1-one (IV).

 NMR (solvent: chloroform-form, internal standard; tetramethylsilane): 1.39 (3H, t, J = 7.1), 2.66 (3H, s), 2.9-3.1 ( 2H, m), 3.2.3.4 (2H, m), 4.36 (2H, q), 7.51 (1H, d, J = 9.9)

 According to the present findings, virazole derivatives having a thiochroman ring useful as herbicides

 Three

A simpler method that does not include a Grignard reaction and that is used for producing an alkoxythio-2-roman carboxylic acid derivative used for the production of a derivative is provided.

 Further, according to the present invention, there is provided a novel intermediate used for producing the alkoxythiochroman carboxylic acid derivative.

 (Hereinafter the margin)

Claims

Range of word blue general formula

(Wherein IT is a C ^ C alkyl group; X ¹ is a c, -c ₄ alkyl group, a halogen atom or C, -C., Haloalkyl:), and m is 0 or an integer of 1-3. Yes; X ² is a halogen atom, and benzoic acid ester represented by the general formula (II)

(Wherein, wherein the reaction of R ^2, R and R ⁵ mercapto Bro Lactobiono acid derivative represented by each independently a hydrogen atom or a (^ ～〇 is ₄ § alkyl group), General Formula (III)

(Wherein, RR ² , R ³ , R ⁴ , R ⁵ , X ¹ and m are as defined above).

-33

2. —General formula (III)

(Wherein, R ¹ is located at ~ alkyl ^{group; R 2, R 3, R} 4 and R ⁵ which it independently a hydrogen atom or a (^ ～〇 ₄ alkyl ¾; X ¹ is Ct-C. , An alkyl group, a halogen atom or a phenylthiopropionic acid derivative represented by the formula (^ to (^ haloalkyl; m is an integer of 0 or 1 to 3)). Formula (IV)

R ¹

(Wherein, II ¹ , RRR \ R ⁵ , X ¹ and m are as defined above).

3. General formula (Ilia)

 (i l a)

(Wherein, R ¹ is a C! -C ₄ alkyl group; X ^la and X ^lb are (! ~ Alkyl groups, halogen atoms or (^ ~ ( ₄ haloalkyl groups, and may be the same or different

One 34 Cyclization in the presence of fuming sulfuric acid using a phenylthiopropionic acid derivative represented by the formula (IVa) as an acid catalyst:

 (ί Va)

(Wherein, Rj, X ^la and X ^lb is as defined above) Chiokuro Manon derivative ^ body manufacturing method represented by.

4. General formula (IV)

Wherein R ¹ is a C, -C ₄ alkyl group; R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or an alkyl group; X ¹ is C: A general formula characterized by reducing a thiochromanone derivative represented by a C ₄ alkyl group, a halogen atom or C, ~ (^ is an alkyl group; m is 0 or an integer of 1 to 3)

(V)

(Wherein, I ¹ , R ² , R ³ , R \ R′X ¹ and m are as defined above).

-35-

5. General formula (V)

(Wherein is a C! C ^ alkyl group; R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or an alkyl group; X ¹ is an alkyl group, a halogen atom Or C, -C ₄ haloalkyl ^; m is 0 or an integer of 1 to 3), and a hydroxythiochroman derivative represented by the general formula (VI):

R ^c 0H

 (VI)

(Wherein, R ^G is an alkyl group, a C! Cc alkoxyalkyl group or Ci~ C ₆ haloalkyl group), characterized by reacting an alcohol represented by the general formula (VII)

R ¹

(Wherein, IT, RR ³ , R \ R ⁵ , R ^G , X ¹ and m are as defined above).

6. General formula (VII)

-36 one (Wherein R ¹ is a C! C alkyl group; R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or a C! -C ₄ alkyl group; R ⁶ is C Ce alkyl groups, C alkoxyalkyl group or Nono Roarukiru a group; X ¹ is d ~ C ₄ alkyl group, a halogen atom or Ci～C ₄ haloalkyl group; m is 0 or an integer from 1 to 3) Characterized by hydrolyzing an alkoxythiochroman derivative represented by the following general formula (VIII):

(Wherein the formulas B ² , R ² , R ′ \ R \ R ⁵ , R X ″ and m are as defined above).

7. —General formula (III-1)

(Wherein, R ¹ is a Ci-C ₄ alkyl group; R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or an alkyl group; X ¹ is (^ to ( ₄ An alkyl group, a halogen atom or a haloalkyl group; m ¹ is an integer of 1 to 3).

8. —General formula (IV-1)

I 37- R

(In the formula, R ¹ is C:! Be ~ C ₄ alkyl ^{group; R 2, R 3, R} 4 and R ⁵ is it that independent a hydrogen atom or a C C alkyl group; X ¹ is C An alkyl group, a halogen atom or 〇! ~, And an alkyl group; m1 is an integer of ¹ to 3).

9.

-General formula (VI-la)

 (V I-1)

(Wherein R ¹ is a C: to C ₄ alkyl group) c 0. General formula (V)

(Wherein, R ¹ is located at (^ ～〇 ₄ alkyl group; R ^2, RR ^4, and R ⁵ is each independent hydrogen atom or - (^ alkyl group; X ¹ is-alkyl group, C it is androgenic atom or ^ ～〇 ₄ haloalkyl groups; hydroxy Chio chromans derivative m is represented by a 0 or an integer of 1 to 3).

-38-

11. General formula (VII)

(Where R ¹ is

R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or an alkyl group; R ⁶ is a C: -C ₆ alkyl group, C! -C _R alkoxy; alkyl group or C, be -C «haloalkyl group;! XC ~ C ₄ alkyl group, a halogen atom or 0 ^ ～〇 ₄ haloalkyl group; m is represented by 0 or an integer from 1 to 3) Alkoxythiochroman derivatives.

-39- The alkoxythiochroman carboxylic acid used for producing a bilazolyl derivative having a thiochroman ring useful as a herbicide can be obtained by converting an alkoxythiochroman carboxylate without an expensive step such as a Grignard reaction. It can be easily produced by hydrolysis.

 (Hereinafter the margin)

-0