WO1993020035A1 - Process for producing cyclopropane derivative - Google Patents

Abstract

A process for producing a compound represented by general formula[I] according to scheme (A), wherein R1 represents alkyl; R2 represents alkyl, optionally substituted phenyl, optionally substituted aralkyl or optionally substituted heterocycle; R?3 and R4¿ represent each alkyl; X?1 and X2¿ represent each halogen; L represents a leaving group; and M represents a metal atom.

Description

 Specification

 Method for producing cyclopropane derivative

Technical field:

 The present invention relates to a method for producing a cyclopropane derivative useful as a herbicide.

Technical background:

 W091 / 0260, JP-A-5-70426 describes that the following cyclopropane derivatives are useful as herbicides.

[In the formula, G ¹ represents a lower alkyl, an optionally substituted phenyl, an optionally substituted aralkyl, or an optionally substituted heterocycle. G ² is the same or different and represents a halogen, an alkoxy, an alkylthio, an alkylsulfonyl, an alkyl, an alkoxyalkyl, an alkoxycarbonyl, and n is 0-4. G ³ and are the same or different and represent hydrogen or lower alkyl. ]

 A stereoisomer exists between the substituent at the 5-position and the cyclic propane ring in the bicycling portion of the synthetic propane derivative.

 When the substituent at the 5-position is alkyl, derivatives having a cyclopropane ring and an alkyl at the 5-position as cis have better properties as a selective herbicide. It is useful.

 The following literature describes reactions related to reaction A (described below) used in the present invention.

W 0 921 3 8 2 1 discloses the following production method. 'CH ₃ CH (COO C ₂ H ₅ ) ₂ C 1 CH ₂ CH = CHCOCH ₃

 N a 0 r

上記反応においては、 C1CH₂CH=CHC0CH₃ は不安定な物質であり、 反 応のコントロールおよび収率のフレなどに問題を持っていた。

In the above reaction, C1CH ₂ CH = CHC0CH ₃ was an unstable substance, and had problems in the control of the reaction and the yield fluctuation.

 The following is described in Tezioy, Dokl. J. 3rd 1978, 6-8.

riCOCHzCHCHzClriCOCl + CH ₂ = CHCH ₂ Cl ——-rjCOCHzCHClCHzCl

riCOCHzCHCHzCl

しかし、 実際には COCHaCHClCHiiCl は不安定であり、 単離すること は困難である。

However, in practice, COCHaCHClCHiiCl is unstable and difficult to isolate.

In addition, there is W0913821 as a document describing a reaction related to reaction B (described later) used in the present invention, and USP4 is described as a document describing a reaction related to reaction C (described below). 6995673, Japanese Patent Laid-Open No. 4-247053, US Pat. No. 4,780,127, US Pat. Among these, in the case of using the substituted base Nzoirushianai de uses a Z n C 1 ₂ as catalyst.

References describing reactions related to the reactions D and E (described below) used in the present invention include WO91 / 02026, WO92 / 13821, and JP-A-4-24. 7053 and JP-A-5-704426. Among these, to obtain the target compound in the form of c 原料 s from the starting compound in which the cyclopropane ring of the cyclopropane derivative and the alkyl at position 5 are cis, it is necessary to add hydrochloric acid during decarboxylation. However, there was a problem that a seven-membered ring was produced as a by-product.

 The present invention provides a method for producing a desired cyclopropane derivative in high yield and high purity.

Disclosure of the invention:

 The present invention comprises the steps of the following reactions A to G;

(I)

[In the formula, R ¹ represents an alkyl group; R ² represents an optionally substituted phenyl group, an optionally substituted aralkyl group or an optionally substituted heterocyclic ring. ] It is a manufacturing method of the compound represented by these.

Reaction A:

CHz ^ CHCHzX ¹ + R ⁵ CH ₂ C0X ²

 [H] [ΠΓ]

CR'CHzCOCHzCHX ^ HzX ¹ )

 1st step

式中、 X〗 、 X² は同一又は相異なってハロゲン原子、 R¹ 、 R³ R⁴ 、 R⁵ は同一又は相異なって水素又はアルキルを示す。 第一工程においては、 溶媒として、 塩化メチレン、 クロ口ホルム、 ジクロロェタン、 ニトロベンゼンなどの不活性溶媒を用い、 触媒とし て、 A l C l ₃ 、 A l B r ₃ 、 S nC l ₄ 、 T I C 1₄ 等のルイス酸 の存在下で、 反応温度は一 2 0 °C〜溶媒の沸点まで、 好ましく は 0 °C 〜室温までで行われる。

In the formula, X〗 and X ² are the same or different and represent a halogen atom, and R ¹ , R ³ R ⁴ and R ⁵ represent the same or different and represent hydrogen or alkyl. In the first step, as a solvent, using methylene chloride, black hole Holm, Jikuroroetan, an inert solvent such as nitrobenzene, as a _{catalyst, A l C l 3, A} l B r 3, S nC l 4, TIC 1 _In the presence of a Lewis acid such as ₄ , the reaction is carried out at a temperature of from 120 ° C to the boiling point of the solvent, preferably from 0 ° C to room temperature.

 In the second step, an inert solvent such as methylene chloride, ether, or BTX is used as a solvent, and an organic base such as DBU, a base such as potassium carbonate, sodium carbonate, sodium ethylate, and potassium ethylate are used as bases. The reaction is carried out at a temperature of from 120 ° C. to the boiling point of the solvent, preferably from 0 ° C. to room temperature, using an inorganic base such as a metal alcohol such as a metal alcoholate. It can also be obtained by a two-phase reaction using a catalyst such as BTEC and a hydroxylation power, sodium hydroxide or the like as a base.

Reaction B:

式中、 R¹ 、 R³ 、 R⁴ は前記と同じ意味を示す ₍ 反応は式 〔V〕 で表わされるシクロプロパン誘導体を塩基の存在下、 適当な溶剤中で行なわれる。

In the formula, R ¹ , R ³ and R ⁴ have the same meanings as described above ₍ The reaction is carried out using a cyclopropane derivative represented by the formula [V] in the presence of a base in a suitable solvent.

 As a solvent, alcohols such as methanol and ethanol, DMF or a mixed solvent thereof, and as a base, a sodium alcohol or a potassium alcohol is used.

 The reaction is carried out at room temperature to 150 ° C., preferably at the boiling point of the alcohol used.

The amount of the base is 1 to 5 moles, preferably 1 to 2 moles, per mole of the cyclopropane derivative.

Reaction C:

J COR ² CW]

J COR ² [W ']

In the formula, R ¹ , R ² , and R ³ have the same meanings as described above, and L ′ represents a leaving group such as halogen, alkylcarbonyloxy, alkoxycarbonyloxy, and benzoyloxy.

Route 1: [VI-1] → [XI_1] → [[1-1] or [VI-2] → [XI-2] → [«-2]

In the first half of the reaction, the compound [V [-1] or [VI-2] and the compound IW] are reacted in a solvent in the presence of an equimolar or excess base. Bases et al used, KOH, N a 0 an alkali metal hydroxide such as H, an alkaline earth metal hydroxide, tri (C, one C ₆ alkyl) § Mi emissions, pyridinium Jin, carbonate sodium phosphate Sodium, methylene chloride, methylene chloride, chloroform, toluene, ethyl acetate, dimethylformamide, THF, dimethoxetane, acetonitrile and the like. The reaction mixture is stirred at 0 ° C to 50 ° C until the reaction is completed. It can also be obtained by reacting in a two-phase system using a phase transfer catalyst such as BTEAC.

 The latter rearrangement is carried out in the presence of a cyano compound and a mild base. The above compound [XI-1] or compound [XI-2] can be prepared by, for example, converting 1 mol of the compound [X1 ^ 1] or compound [XI-2] to 1 to 4 mol of a base, preferably 1 to 2 mol. The reaction is carried out with 0.1 mol of the base and 0.1 mol to 0.5 mol or more, preferably 0.1 mol. As the base used here, any of the above bases can be used. Further, as the cyano compound, a polymer holding lithium cyanide, acetate cyanohydrin, hydrogen cyanide, or potassium cyanide is used.

The reaction is completed in a shorter time by adding a small amount of a phase transfer catalyst such as a crown ether. The reaction is carried out at a temperature lower than 80 ° C, preferably at 20 ° C to 40 ° C. Solvents used are 1,2-dichloroethane, toluene, acetonitril, methylene chloride, ethyl acetate, Examples include dimethylformamide, methylisobutyl ketone, THF, and dimethoxyethane.

Route 2: CE-1] → [XI-1] → [old 1] or [VI-2] → CXI-2] → [[-2]

 The reaction in the first half can be obtained by reacting compound [VI-1] or ["VI-2"] with compound [''! "] In a solvent with an equimolar or excess of dicyclohexylcarpoimide (DCC). Can be

 As a solvent used in the reaction with DCC, methylene chloride, toluene, ethyl acetate, dimethylformamide, THF, dimethoxetane, acetonitrile and the like are used. The reaction mixture is stirred at 0 ° C to 50 ° C until the reaction is completed.

 The rearrangement reaction in the latter half is performed in the same manner as described above.

Route 3; [VI-1] → [cover-1] or [^ 1 2] → [old-2] The compound represented by the formula [lone '' '] is produced by the following method.

XC 0 R ² ——-NC COR ²

 [XII] [11 ',']

In the formula, R ² has the same meaning as described above, and X represents a halogen atom.

① The compound of formula [XI] is reacted with cyanide in an inert solvent in the presence of a catalyst. Examples of the inert solvent include BTX solvents such as benzene and toluene, and halogenated hydrocarbons such as methylene chloride and chloroform. As the cyanide, for example, trialkylsilyl cyanide can be cited (Reference: Synthesis, 1979,

5 2 3) o

② The compound represented by the formula [ΧΙΠ] is reacted with a cyanide under an inert gas atmosphere at 140 to 200 ° C., preferably at I 50 to 170. Examples of cyanide include copper (I) cyanide, mercury cyanide, silicon Examples of the inert gas include nitrogen gas (reference: Angew. Chem., 68, 425 (1956)).

 ③ The compound of formula [Χ Π] and cyanide are reacted in a mixed solvent of inert solvent and water in the presence of a phase transfer catalyst. Examples of the cyanide include sodium cyanide and potassium cyanide, and examples of the inert solvent include solvents such as benzene and toluene, and halogenated hydrocarbons such as methylene chloride and chloroform. Examples of the phase transfer catalyst include ammonium salts, phosphonium salts, and crown ethers, which are known as phase transfer catalysts (Reference: Tetrahedron Lett., 1979, 22775).

 化合物 The compound represented by the formula [XI] is reacted with a cyanide in an inert solvent in the presence of a phase transfer catalyst at 50 to 100 ° C, preferably 70 to 90 ° C. Examples of the cyanide include copper cyanide (1), sodium cyanide, and potassium cyanide. Examples of the inert solvent include DMF, DMSO, and acetonitrile, and preferably acetonitrile. Examples of the phase transfer catalyst include ammonium salts, phosphonium salts, and crown ethers, which are known as phase transfer catalysts.

 The compound represented by the formula [W ′ ″] reacts with the compound represented by the formula [XIII] by the following reaction to produce the compound represented by the formula [XIV] in high yield.

[xm] [XIV] In the formula, R ² has the same meaning as described above, and A represents an optionally substituted 5- to 7-membered carbocyclic ring or an optionally substituted 5- to 7-membered heterocyclic ring containing N, 0 or S.

 The reaction is carried out by heating an equimolar mixed solution of ['] and [XIE] and a base. Examples of the base include pyridine, triethylamine, DB エ チ ル and the like. As the solvent, methylene chloride, chloroform, acetonitrile, toluene and the like are used, and the reaction is carried out from room temperature to the boiling point of these solvents.

 The compound represented by the formula (xm) is, for example,

等である。 〔ここで、 R^e 、 R⁷ 、 R⁸ 、 R 0 、 R^{1 0} v R¹¹は同一ま たは相異なってハロゲン原子、 置換されてもよいアルキル基、 アルコ キシカルボニル基、 置換されてもよいアルケニル基、 置換されてもよ いフヱニル基を表し、 また R⁷ と R⁸ で置換されてもよい 3〜7員の 炭素環を形成してもよい。 R^I2、 R^I3、 R¹⁴、 R¹⁵は、 同一又は相異 なって、 水素又は低級アルキルを表す。 R¹⁶は、 水素を表す。 R¹⁷は、 OR¹⁸を表し、 R¹⁸は水素、 低級アルキル、 ァラルキル、 低級ァシル- アルキルスルホニル、 ァリールスルホニルを表し、 または R ¹⁶と R ¹⁷ は一緒になって単結合を表してもよい。 また、 Zは、 酸素、 硫黄又は N— R¹⁹を表し、 R¹⁸は水素、 低級アルキル、 置換されてもよいァラ ルキル、 置換されてもよいシクロアルキル、 置換されてもよいフエ二 ル、 又は置換されてもよい複素環を表す。

And so on. (Where R ^e , R ⁷ , R ⁸ , R 0, R ¹⁰ v R ¹¹ are the same or different and are each independently a halogen atom, an optionally substituted alkyl group, an alkoxycarbonyl group, or an optionally substituted It represents a good alkenyl group or a phenyl group which may be substituted, and may form a 3- to 7-membered carbon ring which may be substituted by R ⁷ and R ⁸ . ^{R I2, R I3, R 14} , R 15 , taken same or different from and represent hydrogen or lower alkyl. R ¹⁶ represents hydrogen. R ¹⁷ represents OR ¹⁸ , R ¹⁸ represents hydrogen, lower alkyl, aralkyl, lower acetyl-alkylsulfonyl, arylsulfonyl, or R ¹⁶ and R ¹⁷ may together represent a single bond. Z represents oxygen, sulfur or N—R ¹⁹ , where R ¹⁸ is hydrogen, lower alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted phenyl, Or a heterocyclic ring which may be substituted.

Oxidation reaction: When an alkylthio group is present in the compound [xw], it can be converted into an alkylsulfonyl group in high yield by oxidation. The reaction is performed by a usual oxidation reaction. For example, the reaction is carried out by heating at least twice the molar amount of hydrogen peroxide and the compound [XIV] using sodium tungstate as a catalyst. As the solvent, water, alcohols, or a mixed solvent thereof is used, and the reaction is carried out at a temperature other than 100 or the boiling point of these solvents.

Reaction D:

[<<-2] [IX-2] In the formula, R ¹ , R ² and R ³ have the same meanings as described above, and M represents a metal atom. Metal atoms are alkali metals and alkaline earth metals. As the solvent, hydrolyzed using alcohol, water, and preferably from room temperature a mixture thereof is used to the boiling point of the solvent at room temperature N a 0 H, KOH, alkali etc. _{Na 2 C0 3. K 2 C} 03 . Reaction ：:

式中、 R ¹ 、 R ² は前記と同じ意味を示す。

In the formula, R ¹ and R ² have the same meaning as described above.

 The reaction is carried out in a solvent in the presence of an organic acid. As the organic acid, acetic acid-formic acid, propionic acid, citric acid and the like are used, and water, alcohols and the like are used as solvents, and the reaction temperature is preferably around room temperature.

Reaction F:

式中、 R ¹ 、 R ² 、 Μは前記と同じ意味を示す。

In the formula, R ¹ , R ² and Μ have the same meanings as described above.

The reaction is carried out by adjusting the solution to an acidic or neutral condition with an acid ₍ usually, the reaction solution of the reaction D is used as it is. The acid is an inorganic acid such as hydrochloric acid, sulfuric acid or the like. Is fine. Reaction G

式中、 R¹ 、 R² は前記と同じ意味を示す。

In the formula, R ¹ and R ² have the same meaning as described above.

 The reaction is performed in a solvent in the presence of a base. As the base, an organic salt group such as ammonia, (C, -C) alkylamine, di (C, -C) alkylamine, tri (C, -C) alkylamine, pyridine, or DBU is used. The reaction is carried out in an organic solvent such as alcohols, ethers and THF under cooling to the boiling point of the solvent, preferably at room temperature.

 After completion of the reaction, the desired product can be obtained by performing ordinary post-treatment. The synthesized compound was identified by NMR, IR, MS and the like. The compounds according to the present invention include a number of tautomeric forms, for example,

の形で存在し得る 発明を実施するための最良の形態：

Can exist in the form of BEST MODE FOR CARRYING OUT THE INVENTION

 Next, the present invention will be described more specifically with reference to examples.

Example 1 (Reaction A)

 Synthesis of (2-acetylcyclopropyl) methylmalonate getyl

CHsCOCl + CH ₂ = CHCH ₂ C1 → CCH ₃ C0CH ₂ CHC1CH ₂ C1]

塩化メチレン 6 0 m 1中に塩化アルミニウム 8. 7 gを加え、 さらに 氷冷下ァセチルク口ライ ド 5. 1 gおよびァリルクロライ ド 10. 0 gを 滴下し、 その後室温で 3時間反応を続けた。 反応終了後、 氷水にあけ 分解し、 塩化メチレンで抽出、 水洗、 乾燥を行なった。 次にこの中間 体 5, 4 —ジクロロペンタノン一 2を単離することなく、 この溶液を エタノール 6 O m l中ソジゥムエトキサィ ド 14. 4 %エタノール溶液 を 67. 5 g.およびメチルマロン酸ジェチルエステル 11. 3 gを溶解さ せた液に氷冷下滴下し、 その後室温で 1時間反応を続けた。 反応終了 後、 氷水に入れ塩化メチレン抽出し、 水洗、 乾燥、 溶媒を留去の後、 得られたオイル状物をカラムクロマ トグラフィ一により分離精製を行 なって目的物 14. 1 gを得た。 b. p. 1 3 0〜 1 3 5 V/ 2 mmHg. 得ら れた化合物はすべて t r a n s配置であつた。

8.7 g of aluminum chloride was added to 60 ml of methylene chloride, and 5.1 g of acetyl chloride and 10.0 g of aryl chloride were added dropwise under ice cooling, and the reaction was continued at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water, decomposed, extracted with methylene chloride, washed with water, and dried. Then, without isolating the intermediate 5,4-dichloropentanone-12, this solution was mixed with 67.5 g of a 14.4% solution of sodium methoxide in 6 O ml of ethanol and 67.5 g of methylmalonone. The solution in which 11.3 g of acid getyl ester was dissolved was added dropwise under ice cooling, and the reaction was continued at room temperature for 1 hour. After completion of the reaction, the reaction mixture was placed in ice water, extracted with methylene chloride, washed with water, dried, and the solvent was distilled off. The obtained oil was separated and purified by column chromatography to obtain 14.1 g of the desired product. bp 130-135 V / 2 mmHg. All the compounds obtained were in the trans configuration.

Example 2 (Reaction B)

E and Z—5-ethoxycarbone 5-methylbisic mouth [4,1,0] heptane 1,2,4-dione

 (E) (Z)

(2-Acetylcyclopropyl) 330.7 g of methylethyl malonate was placed in 97.5.6 g of a 14.4% sodium ethylethanol solution and heated under reflux for 3 hours. After cooling, the mixture was placed in cold hydrochloric acid, extracted with methylene chloride, and washed with saturated saline. After dehydration with magnesium sulfate, the solvent was distilled off under reduced pressure, and ether was added to the remaining solution to give E-form as white crystals.

[trans-ethoxycarbonyl cis-methyl form / cyclopropane; the same applies hereinafter) 87.6 g was obtained.

 The filtrate was further separated by silica gel chromatography to obtain 8.1 g of the E-form and 27.8 g of the Z-form [cis-ethoxycarbonyl trans-methyl-form Z-cyclopropane pan; the same applies hereinafter).

Example 3 (Reaction C related)

 Synthesis of 3-Methoxy-2-methyl-4-methylthiobenzoyl cyanide

(Reference: Tetrahedron Lett., 26, 2275 (1974))

3-Methoxy-2-methyl-4-methylthiobenzoic acid (23 g) and tetrabutylammonium bromide (3 g) in a 200 ml solution of dichloroethane in 0 ml, 10% sodium cyanide under a nitrogen stream at 0 50 g of the aqueous solution is added dropwise over 1 hour. After stirring for 1 hour, separate the organic layer. Wash sequentially with water and saturated aqueous sodium chloride solution, and dry with magnesium sulfate.

 6

Dried. The solvent was distilled off under reduced pressure to obtain 14.8 g of the desired product. mp 115-8 ° C.

Example 4 (reaction)

 t r ans— 5-ethoxyethoxycarbonyl 3— (3-Methoxy-12-methyl-4-methylthiobenzoyl) -c i s—5-Methyl-12-bicyclo [4.1.0] Synthesis of heptene-1,2,4-dione

 (E)

(E) 2.2 g of 3-methoxy-2-methyl-1-methylthiobenzoyl cyanide obtained in Example 3 and trans-5-ethoxycarbonyl-cis-15-methyl-2-bicyclo [4.1.0] heptene-1 2 Dissolve 2.1 g of, 4 dione in 20 ml of methylene chloride. To this solution, 1.2 g of triethylamine was added at room temperature. After stirring at room temperature for 18 hours, the mixture was poured into iced water, acidified with concentrated hydrochloric acid, and the organic layer was separated. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.5 g of the desired product (E-form). mp 1 1 1 to 1 1 2 ° C (E type)

Example 5 (Reaction C)

 cis—5—Ethoxycarbonyl 3 -— (3-Methoxy-2-methyl 4-methylthiobenzoyl) -trans—5-Methyl-2-bicyclo [4.1.0] Synthesis of heptene-1,2, dione

 5-Ethoxycarbonyl 5-methyl-2-bicyclo [4.1.0] to 2,4-dione butene 2.1 reaction except that the Z-isomer is used in place of the E-form of 2.1 g. After post-treatment, 3.4 g (Z form) of the desired product was obtained. .

Example 6 (oxidation reaction)

tra n. s—5—ethoxycarbonyl-3- (4-mesyl-3-methoxy1-2-methylbenzoyl) cis—5-methyl-12-bisic mouth [4.1.0] heptene 1,2,4 —Synthesis of dione

 (E)

 (E) 0.16 g of sodium tungstate was added to a 2 Om1 methanol solution of 2.2 g of the bicyclo compound obtained in Example 4, and 1.7 g of 35% aqueous hydrogen peroxide was added at room temperature. Was added. After refluxing for 2 hours, dilute hydrochloric acid was added, and the organic layer was separated. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.83 g of the desired product.

Example 7 (oxidation reaction)

 5—cis—ethoxycarbone 3— (4—mesyl 3—methoxy 1—2-methylbenzoyl) 1 trans—5—methyl 1 2 _bisik mouth [4.1.0] 1-heptene 2,4-dione Synthesis

 The reaction and work-up were conducted in the same manner as in Example 6 except that the Z-form (obtained in Example 5) was used instead of the E-form of 2.2 g of the bicyclo ring compound to obtain 1.94 g of the desired product (Z-form).

Example 8 (Reaction C)

trans-5-ethoxycarbonyl-2- 3- (4-mesyl-3-methoxy-2-methylbenzoyl) -cis-5-methyl-2-bisic Mouth [4.1.0] Synthesis of Heptene-2,4-dione

 (E)

0.2 ml of tin tetrachloride was added to 50 ml of a methylene chloride solution of 2.6 g of 2-methyl-4-methylsulfonyl-3-cyclomethoxybenzoic acid chloride and 1.1 g of trimethylsilyl cyanide. It was added at room temperature under a nitrogen atmosphere. After stirring for 20 hours, the reaction solution was poured into water. The aqueous layer was separated, and the organic layer was washed twice with 50 ml of water, and then dried and concentrated to obtain a crude product of 3-methoxy-2-methyl-4-mesylbenzoyl cyanide. Triethylamine was added to a solution of this crude product and 1.2 g of t.rans-5-ethoxycarboxyl cis-5-methyl-12-bicyclo [4.1.0] heptene-12,4-dione in 20 ml methylene chloride. 0.9 ml was added. After stirring the reaction mixture at room temperature for 5 hours, it was poured into 1N hydrochloric acid. The aqueous layer was separated, and the organic layer was washed with saturated saline. After drying and concentration, the residue was purified by silica gel column chromatography (eluent: hexane monoacetate) to obtain 1.2 g of the target compound (E-form).

Example 9 (Reaction C)

3— (3-Methoxy-2-methyl-4-methylsulfonylbenzoyl) 1 t 3 11 8 — 5—ethoxycanolebonyl 0 is — 5—methyl cis-Bicyclo [4.1.0] heptane-1,2,4-dione and 3 (3-methoxy-2-methyl-4-methylsulfonylbenzoyl) Synthesis of cis bicyclo [4.1.0] heptane-1,2,4-dione

 (E, Z) Dissolve 0.79 g of metallic soda in 13.7 g of ethanol and add DMF

Under reflux of the mixed solution to which 1.46 g was added, (2-acetylcyclopropyl) methylmalonate getyl was added dropwise over 10 minutes. After refluxing for 3 hours, the mixture was poured into ice-cooled diluted hydrochloric acid and extracted twice with methylene chloride. The methylene chloride layers were combined, washed sequentially with water and saturated sodium chloride, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. E- and Z-forms of 5-ethoxyethoxycarbonyl-5-methylbicyclo [4.1.0] heptane-1,2,4-dione

4.8 4 g of a mixture of the following compounds were obtained.

 2.7 g of 3-methoxy-2-methyl-methylthiobenzoyl cyanide and triethylamine in 5 O ml of methylene chloride solution of this product

1.5 g were added sequentially at room temperature. After stirring at room temperature for 18 hours, The mixture was acidified with hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. 5-Ethoxycarbonyl-3- (3-Methoxy-1-methyl-4-methylthiobenzoyl) -1-5-methyl-bicyclo [4.1.0] Heptene 1,2,4-dione E-form and Z-form about 3: 1 crew 5.8 g of the metal mixture was obtained. N a ₂ W0 ₄ in methanol solution 1 0 0 ml of the crude product 5. 8 g (evening tungsten Sansoichida) 0. 0 6 g and 3 0% hydrogen peroxide 4. sequentially chamber to 1 g Was added warm. This solution was heated under reflux for 2 hours to complete the reaction. The reaction solution was poured into ice water, acidified with hydrochloric acid, and extracted twice with methylene chloride. The separated organic layer was washed sequentially with a hypo aqueous solution, water and a saturated aqueous sodium chloride solution. After the organic layer was dried over magnesium sulfate, the E-form and Z-form of the target compound in the solution were analyzed by HPLC. *

 As a result, it was confirmed that 2.2 g of the E form and 0.9 g of the Z form were present.

 * Absolute value using E and Z samples

Example 10 (Reaction C)

3- (3-Methoxy-2-methyl-4-methylsulfonylbenzoyl) -1-trans-5-ethoxycanolebonyl cis-5-methyl-cis-bicyclo [4.1.0] heptane-1,2,4-dione And 3-((3-Methoxy-2-methyl-4-methylsulfonylbenzoyl) -cis-5-ethoxycarbonyl-2-trans-5-methyl-cis-bicyclo [4.1.0] heptane-1,2,4-dione Synthesis of

 (E, Z)

 (E, Z)

E- and Z-forms of 5-ethoxycarbonyl-1-5-methylbicyclo [4.1.0] heptane-2,4-dione

 Triethylamine ァ .8 was added to 2.49 g and 0.83 g of methylene chloride solution, respectively, and then 2-methyl-14-methylsulfonyl-3-methoxybenzoic acid chloride 4.2 g of methylene chloride solution 1 was added to this solution. 0 ml was added dropwise at 10 ° C for 0.1 hour. After stirring at room temperature for 2 hours, the mixture was poured into 1N hydrochloric acid and the organic layer was separated. After washing sequentially with water and a saturated aqueous sodium chloride solution, the mixture was dried over magnesium sulfate and concentrated to obtain 6.9 g of a mixture of E-form and Z-form of 0-acyl form.

0.1 g of KCN was added to 25 ml of an acetonitrile solution of 6.9 g of this crude product and 2.0 g of triethylamine, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and methylene chloride and water were added to adjust the pH to 1. The organic layer was separated, washed sequentially with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. 7.2 g of the desired E-form and Z-form crystals were obtained. Example 11 (Reaction D, E)

 Synthesis of 3- (3-methoxy-2-methyl-1-methylsulfonylbenzoyl) -1-cis-5-methyl-cis-bicyclo [4.1.0] heptane-1,2,4-dione

メ タノール 5 O m l中 3— （ 3—メ トキシ一 2—メチルー 4ーメチ ルスルホニルべンゾィル） 一 t r a n s— 5—エ トキシカルボニル— c i s— 5—メチル一 c i s —ビシクロ 〔4.1.0 〕 ヘプタ ン一 2 , 4 ージオン 21. 1 g ( 5 0 mmol) を溶かした溶液に水 5 0 m l中に NaOH 6. 0 g ( 1 5 0匪 ol) を溶かした液を室温で滴下し、 その後一夜、 攪 拌を続けた。 翌日冷却下水 1 0 0 m l 中に酢酸 9. 0 g ( 1 5 0 mmol) を溶かした液を 4 0分にわたり滴下し、 その後濃塩酸で p H 2— 3に すると白色結晶が析出した。 析出した結晶を口過し、 冷メタノール洗 浄、 乾燥することにより目的物 17.3 g (m. p. 1 5 0— 1 5 3 °C) を 得た。

3- (3-Methoxy-2-methyl-4-methylsulfonylbenzoyl) mono trans-5-ethoxycarbonyl cis-5-methyl cis bicyclo [4.1.0] heptane in 5 ml of methanol A solution prepared by dissolving 20.1 g (50 mmol) of 2,4 dione and 6.0 g (150 bandol) of NaOH in 50 ml of water was added dropwise at room temperature, and then stirred overnight. Stirring was continued. The next day, a solution of 9.0 g (150 mmol) of acetic acid dissolved in 100 ml of chilled water was added dropwise over 40 minutes, and then concentrated hydrochloric acid was added to pH 2-3. Then, white crystals precipitated. The precipitated crystals were collected, washed with cold methanol, and dried to obtain 17.3 g of the desired product (mp 150-153 ° C).

Example 12 (Reaction D, F)

 3- (3-Methoxy-2-methyl-14-methylsulfonylbenzoyl) -cis-5-hydroxycanolebonyl-trans-5-methynole-cis-bicyclo [4.1.0] heptane-2,4-dione Synthesis of

 (Z)

メタノール 5 Om l中 3— (3—メ トキシー 2—メチルー 4—メチ ルスルホニルベンゾィル） — c i s— 5—エトキシカルボ二ルー t r a n s— 5—メチル一 c i s—ビシクロ 〔4.1.0 〕 ヘプタン一 2 , 4ージオン 21.1 g ( 5 0 mmol) を溶かした溶液に水 5 0 m 1中に NaOH6.0 g ( 1 5 0匪 ol) を溶かした液を室温で滴下し、 その後一夜 攪拌を続けた。

3- (3-Methoxy-2-methyl-4-methylsulfonylbenzoyl) in 5 Oml of methanol — cis—5-ethoxycarbonyl trans—5-methyl-1-cis-bicyclo [4.1.0] heptane 1 2 In a solution of 21.1 g (50 mmol) of 2,4 dione, a solution of 6.0 g (150 marol) of NaOH in 50 ml of water was added dropwise at room temperature, followed by stirring overnight.

When the pH was adjusted to 2-3 with concentrated hydrochloric acid, white crystals precipitated. After completion of the reaction, extraction with dichloromethane, washing with water, and drying were performed, and the solvent was distilled off to obtain 18.7 g of the desired product. ¹ H-NMR (200 MHz) δ; 1.1 (1H, m), 1.6 (3H, s), 1.9 (1H, in), 2.2C3H, s), 2.1-2.3 (2H, m), 3.2 (3H, s), 3.9 (3H, s), 6.9 (1H, d, J = 8Hz), 7.8 (1H, d, J = 8Hz), 17.6-17.8 (1H, brs)

Example 13 (Reaction G)

 Synthesis of 3- (3-Methoxy-2-methyl-4-methylsulfonylbenzoyl) -cis-5-methyl-cis-bicyclo [4.1.0] heptane-12,4-dione

メタノール 4 O m l中に 3— （ 3—メ トキシー 2—メチルー 4ーメ チルスルホニルベンゾィル） — c i s— 5—ヒ ドロキシカルボ二ルー t r a n s— 5—メチル一 c i s—ビシクロ 〔4.1.0 〕 ヘプタン一 2 ， 4ージオン 3. 9 gを入れ、 さらに ト リェチルァ ミ ンを室温で一滴加 える。 その後 6時間反応を続けた。 反応終了後、 溶媒を留去し、 得ら れた結晶をメ夕ノ一ルで再結晶することにより 2. 9 gを得た。 m. p. 1 5 0 - 1 5 3 °C

3- (3-Methoxy-2-methyl-4-methylsulfonylbenzoyl) -cis-5-Hydroxycarbonyl trans-5-Methyl-1-cis-bicyclo [4.1.0] Heptane-1 in 4 O ml of methanol Add 3.9 g of 2,4-dione, and add a drop of triethylamine at room temperature. Thereafter, the reaction was continued for 6 hours. After completion of the reaction, the solvent was distilled off, and the obtained crystals were recrystallized from methanol to obtain 2.9 g. mp 150-15 3 ° C

Example 14 (Reaction D, E, F, G)

3- (3-Methoxy-2-methyl-4-methylsulfonylpentyso 1) Synthesis of 1 cis-5-methyl-1-cis-bicyclo [4.1.0] heptane 2,4-dione

 (E, Z)

3- (3-Methoxy-1-2-methyl-1-methylsulfonylbenzoyl) -1-5-ethoxycarboxy-5-methyl-bicyclo [4.1.0] to butane- E and Z of 2,4-dione A methanol solution (20 ml) of 7.2 g of the crude crystal of the compound (3: 1) was added dropwise to a 2.6 N aqueous sodium hydroxide solution (20 ml) at room temperature for 0.5 hour. Thereafter, the mixture was stirred at 40 ° C for 18 hours, and then, at 5 was added dropwise a 10% aqueous acetic acid solution 30 in 1 over 1 hour. After stirring at the same temperature for 1 hour, the pH was adjusted to 2.2 with concentrated hydrochloric acid. 0.25 ml of 25% aqueous ammonia was further added to the slurry-like reaction solution, and stirring was continued at room temperature for 2 days. After completion of the reaction, the crystals obtained by filtration were washed with methanol and dried to obtain 4.0 g of the desired product.

Industrial applicability:

According to the production method of the present invention, the herbicide represented by the formula (I) can be obtained in high yield and high purity irrespective of the configuration of the compound obtained in the course of the process. Compounds obtained on the way can be intermediates for agricultural chemicals, etc.

Claims

The scope of the claims 1. Formula [I] including the following steps ag

[In the formula, R ¹ represents an alkyl group, and R ² represents an alkyl group, an optionally substituted phenyl group, an optionally substituted aralkyl group, or an optionally substituted heterocyclic ring. ] The manufacturing method of the compound represented by these.  Step a: Formula [H]  H2 — C Γ1 H 2 [I] [In the formula, X ¹ represents a halogen atom. A compound represented by the formula (III): (CH ₃ COX ² CUT) [In the formula, X ² represents a halogen atom. The compound represented by the formula [ΙΠ C 0 OR ⁴ R ¹ CH) C 00 R ³ [Wherein, R ¹ has the same meaning as described above, and R ³ and R ^{4 each} represent an alkyl group. ] Reacting the compound represented by the formula (V) [V]

[Wherein, R ′, R ³ and R ⁴ have the same meaning as described above. A process for producing the compound represented by Step b: The compound represented by the formula [V] is ring-closed to form a compound represented by the formula [? 11] and the formula ["VI-2".

[Wherein, R ¹ and R ³ have the same meaning as described above. The process for producing the compound Step c: a compound represented by the formula [V [-1] and the formula [VI-2]; LC OR ² [W] [Wherein, L represents a leaving group, and R ² has the same meaning as described above. And reacting the compound represented by the formula [1-1] and the formula [¾1-2]

[Wherein, R ¹ , R ² and R ³ have the same meaning as described above. A process for producing the compound represented by Step d: The compound represented by the formula [¾-1] and the formula [1 [1-2] is hydrolyzed with an alcohol to obtain the formula [K-1] and the formula [Κ-2]

 CK-1) CK-2) [Wherein, R ¹ and R ² have the same meanings as described above, and Μ represents a metal atom. A process for producing the compound represented by Step e: The compound represented by the formula [IX-1] is decarboxylated in the presence of an organic acid to obtain a compound represented by the formula [I]

[Wherein, R ¹ and R ² have the same meaning as described above. The process for producing the compound represented by Step f: The compound represented by the formula [K-2] is subjected to neutral or acidic conditions, and the compound represented by the formula [ΙΧ-2 '] CK-2 ')

[Wherein, R ¹ and R ² have the same meaning as described above. A process for producing the compound represented by the formula Step g: Decarboxylation and inversion of the compound represented by the formula [K-I 2 '] in the presence of a base to give a compound of the formula [I]

[Wherein, R ′ and R ² have the same meaning as described above. A process for producing the compound represented by the formula  2. Formula [Π]  C in 2 = D H H2 X 〔 And a compound represented by the formula [ΙΠ '] R ⁵ CH ₂ COX ² cm '] (Wherein X ¹ and X ² represent the same meaning as described above, and R ⁵ represents hydrogen or alkyl). C 00 R ⁴ R ¹ CH C 00 R ³ (In the formula, R ′, R ³ and R ⁴ are the same or different and have the same meaning as described above.) Reacting with the formula [V '] CV]

(Wherein, R ^{1 to} R ⁵ have the same meaning as described above.) <3. Formula [XIE—a]

Wherein R ^2D represents a halogen atom or an alkyl group of R ²¹ and R ²² are the same or different and represent an alkyl group of d-6, p represents an integer of 0 to 2, and Q represents 0 to Indicates an integer of 2. A compound represented by the formula ₍ 4. Equation [ΧΕ '] CXI ']

[Wherein, R ² °, R ²¹ , R ²² , p and q have the same meanings as described above, and X represents a halogen atom. [XH—a], which comprises reacting a compound represented by the formula [ΧΊΙ—a]

[Wherein, R ^2e , R ²¹ , R ²² , p, and q have the same meaning as described above. ] Of the compound to be prepared.  5. Formula [XH—a] [X H—a]

[Wherein, R ^2D , R ²¹ , R ²² , p and Q have the same meaning as described above. And a compound represented by the formula [ΧΠΙ] (Xm)

[In the formula, A represents an optionally substituted 5- to 7-membered carbon ring or an optionally-substituted 5- to 7-membered heterocyclic ring containing N, 0 or S. A compound represented by the formula [XIV-a]: [XIV—a]

[In the formula, R ² °, R ²¹ , R ²² , p, Q and A represent the same meaning as described above. ] The manufacturing method of the compound shown by these. 6. Formula [XI—a '] POR ²¹  2 CXH-a ')

[Wherein, R ² R ²¹ , R ²² and p have the same meaning as described above. And a compound represented by the formula (XII)

[Wherein, A represents the same meaning as described above. A compound represented by the formula [XIV-a '] [XIV-a ']

[Wherein, R ^2D , R ²¹ , R ^2Z , p and A represent the same meaning as described above. ] The manufacturing method of the compound represented by these. 7. Formula 〔— 1〕 (San-ichi 1)

[Wherein, R ¹ , R ² and R ³ have the same meaning as described above. Wherein the compound represented by the general formula [I] is decarboxylated in the presence of an organic acid.

(Wherein, R ¹ and R ² have the same meanings as described above.).  8. Formula [IX-2 '] [K-1 2 ']

[Wherein, R ¹ and R ² have the same meanings as described above. The compound represented by  9. Expression [old—2] [«-2]

(Wherein, R ¹ , R ² and R ³ have the same meanings as described above.) Wherein the compound represented by the general formula [Κ_ 2 '] is hydrolyzed. [K-1 2 ']

(Wherein, R ¹ and R ² have the same meanings as described above.).  1 0. Formula [IX-2 '] [IX-2 ']

(Wherein, R ¹ and R ² have the same meanings as described above.) A compound represented by the general formula [I] characterized by decarboxylation in the presence of a base: (I)

(Wherein, R ¹ and R ² have the same meanings as described above.).