WO2006013920A1

WO2006013920A1 - 2-substituted-3-(4-tetrahydropyranyl)-3-oxopropanoic ester and process for producing the same

Info

Publication number: WO2006013920A1
Application number: PCT/JP2005/014289
Authority: WO
Inventors: Shigeyoshi Nishino; Kenji Hirotsu; Hidetaka Shima; Keiji Iwamoto
Original assignee: Ube Industries, Ltd.
Priority date: 2004-08-04
Filing date: 2005-08-04
Publication date: 2006-02-09
Also published as: JP4552939B2; JPWO2006013920A1

Abstract

This invention provides a 2-substituted-3-(4-tetrahydropyranyl)-3-oxopropanoic ester represented by general formula (1) wherein Y represents a halogen atom or an acyloxy group, and R represents a hydrocarbon group, and a process for producing the same.

Description

Specification

2-substituted 1_ (4-tetrahydrobiranyl) _3_oxopropanoate and process for producing the same

Technical field

[0001] The present invention relates to 2-substituted-3- (4-tetrahydrovinyl) -3-oxopropanoic acid ester and a process for producing the same, and more specifically, 2-halogeno-3- (4-tetrahydroviral). ) 3-oxopropanoic acid ester or 2-acyloxy-3- (4-tetrahydrobiral) -3-oxopropanoic acid ester and their production method. 2-Substituted-3- (4-tetrahydrobiranyl) -3-oxopropanoic acid ester is a useful compound as a raw material for pharmaceuticals and agricultural chemicals and as a synthetic intermediate. Background art

[0002] The 2-substituted-3- (4-tetrahydrovinyl) -3-oxopropanoic acid ester of the present invention is a novel compound, and its existence and production method have never been known so far.

Disclosure of the invention

Problems to be solved by the invention

[0003] An object of the present invention is to solve the above-mentioned problems and to produce 2-substituted-3- (4 by a simple method.

Providing industrially suitable 2-substituted-3- (4-tetrahydrobiral) -3-oxopropanoic acid ester and its production process, which can produce 3-tetrapropanoic acid ester in high yield It is to be.

Means for solving the problem

[0004] In view of the above problems, as a result of intensive studies by the present inventors, the yield of 2-substituted-3- (4-tetrahydrovinyl) -3-oxopropanoic acid ester was increased by the following simple method. A method that can be manufactured at a high rate has been found, and the present invention has been completed.

That is, the subject of the present invention is the general formula (1):

[0007] In the formula, Y represents a halogen atom or an acyloxy group, R represents a hydrocarbon group,

It is solved by 2-substituted-3- (4-tetrahydrovinyl) -3-oxopropanoate (hereinafter referred to as compound (1)).

In the present invention, in the compound (1) represented by the above formula (1), the following general formula (la):

In the formula, X represents a halogen atom, R is as defined above,

2-halogeno-3- (4-tetrahydrovinyl) -3-oxopropanoic acid ester (hereinafter referred to as compound (la)) or Y is an acyloxy group represented by the following general formula (lb):

In the formula, R ¹ represents a hydrogen atom or a hydrocarbon group, and R is as defined above. 2-Asiloxy-3- (4-tetrahydrovinyl) -3-oxopropanoic acid ester represented by Compound (lb) is preferred.

The subject of the present invention is also the general formula (2):

In the formula, R is as defined above.

A general formula (la) characterized in that a halogenating agent is reacted with 3- (4-tetrahydrovinyl) -3-oxopropanoic acid ester (hereinafter referred to as compound (2)) represented by the general formula (la):

[0013] It can also be solved by a process for producing the compound (la) represented by

[0014] The subject of the present invention is further a 2-halogeno-3- (4-tetrahydropyral) -3-oxopropanoate represented by the above general formula (la), and a general formula (3):

R ¹ C0 ₂ H (3) wherein R ¹ is as defined above,

2-acyloxy-3- (4-tetrahydrobilanyl represented by the general formula (lb), characterized by reacting with an organic carboxylic acid represented by the following formula (hereinafter referred to as compound (3)) or a salt thereof: ) It can also be solved by the production method of -3 -oxopropanoic acid ester (I compound (lb)).

The invention's effect

[0015] According to the present invention, it is possible to produce 2-substituted-3- (4-tetrahydrobiranyl) -3-oxobutanoic acid ester in a high yield by a simple method, and industrially. It is possible to provide 2-substituted-3- (4-tetrahydrovinyl) -3-oxopropanoate suitable for use in the present invention and a process for producing the ester.

BEST MODE FOR CARRYING OUT THE INVENTION

[0016] The novel compound (1) of the present invention is represented by the general formula (1). In the general formula (1), Y is a halogen atom or an acyloxy group, and specific examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Of these, a chlorine atom and a bromine atom are preferred. R ¹ in the acyloxy group is a hydrogen atom or a hydrocarbon group. Specifically, for example, a hydrogen atom; methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl Group, octyl group, nonyl group, decyl group and the like alkyl group having 1 to 12 carbon atoms; cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclonyl group Group, cycloalkyl group having 3 to 12 carbon atoms such as cyclodecyl group; benzyl group, Forces such as aralkyl groups such as a netyl group; aryl groups such as a phenyl group, a tolyl group, a xylyl group and a naphthyl group, preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, and a carbon atom number of 3 to 8 And most preferably a hydrogen atom, a methyl group, a t-propyl group, or a cycloheptyl group. These groups include various isomers.

[0017] R is a hydrocarbon group. Specifically, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, An alkyl group having 1 to 12 carbon atoms such as a ruthel group; a aralkyl group such as a benzyl group or a phenethyl group; a force such as an aryl group such as a phenyl group, a tolyl group, a xylyl group, or a naphthyl group; -6 alkyl groups, most preferably a methyl group or an ethyl group. These groups include various isomers.

[0018] In the compound (1) of the present invention, the compound (la) represented by the formula (la) in which Y is a halogen atom is obtained by reacting the compound (2) with a halogenating agent.

The compound (2) used in the reaction of the present invention is represented by the general formula (2). In the general formula (2), R has the same meaning as described above. Compound (2) is represented by reaction process formula (1)

[0020]

[Reaction L equation (1)]

[0021] In the formula, R is as defined above.

As shown in the above, it is a compound that can be obtained by reacting 4-acetyltetrahydropyran (compound (4)) with a carbonic acid diester (compound (5)) (see Reference Example 1 below). Note).

[0022] As the compound (2) used in the present invention, for example,

Methyl 3- (4-tetrahydrovinyl) -3-oxopropanoate,

3- (4-tetrahydrovinyl) -3-oxopropanoate

N-propyl 3- (4-tetrahydrovinyl) -3-oxopropanoate, 3- (4-Tetrahydr, Lovira :: Ninole) -3-Isopropylpropanoate,

3- (4-Tetrahydr, Lovira :: Ninole) -3- -Oxopropanoic acid n-butyl,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Butyl isopropanoate,

3- (4-Tetrahydr, Lovira :: Ninole) -3- -Oxopropanoic acid sec-butyl,

3- (4-Tetrahydr, Lovira :: Ninole) tert-Butyl-3-oxopropanoate,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Oxopropanoic acid n-pentyl,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Oxopropanoate n-xyl,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Oxopropanoic acid n-ptyl,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Oxopropanoic acid n-octyl,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Ethoxyhexyl oxopropanoate,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Oxopropanoic acid n-Noel,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Oxopropanoic acid n-decyl,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Benzoxopropanoate,

3- (4-Tetrahydr, Lovira :: Ninole) -3-ethyl oxopropanoate,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Oxopropanoic acid phenol,

3- (4-Tetrahydr, Lovira :: Ninole) -3- Toxol-oxopropanoate,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Xyloxyxopropanoate and

3- (4-Tetrahydr, Lovira :: Ninole) -3-Oxopropanoic acid naphthyl

3- (4-Tetrahydr, Lovira :: Ninole) -3-Oxopropanoic acid methyl ester,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Ethoxypropanoate,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Oxopropanoic acid n-propyl,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Isopropyl oxo-propanoate,

3- (4-Tetrahydr, Lovira :: Ninole) -3- -Oxopropanoic acid n-butyl,

3- (4-Tetrahydr, Lovira :: Ninole) -3-Butyl isopropanoate,

3- (4-Tetrahydr, Lovira :: Ninole) -3--Oxopropanoic acid sec-butyl and

3- (4-Tetrahydride, Lovira :: Ninole) tert-butyl-3-oxopropanoate and the like are preferable. [0023] The halogenating agent used in the reaction of the present invention is not particularly limited as long as it is a halogenating agent capable of leading compound (2) to compound (1). However, in view of ease of reaction operation and post-treatment, Fluorine fluoride such as hydrofluoric acid, pyridinium fluoride, N-fluorobis (trifluoromethyl) sulfonamide; chlorine molecule, phosphorus oxychloride, sulfuryl chloride, thiol chloride, N-chlorosuccinimide, Chlorinating agents such as 1,3-dichloro-5,5-dimethylhydantoin, pentasalt phosphorus, concentrated hydrochloric acid, perchloric acid t-butyl ester, copper chloride, iron chloride; bromine molecule, oxyodor Brominating agents such as phosphorus, sulfuryl bromide, thionyl bromide, N-bromosuccinimide, hydrobromic acid, copper bromide, iron bromide, etc .; iodizing agents such as iodine molecule, N-odosuccinimide, etc. Force Fluorine molecule, salt Molecule, sulfuryl chloride, chlorothionyl, odor molecule, sulfuryl bromide, thiobromide, N-bromosuccinimide, iodine molecule, N-dosuccinimide, more preferably chlorine molecule, sulfuryl chloride, salt匕 thionyl, bromine molecule, odorous sulfuryl, thionyl bromide, N-promosuccinimide are used.

[0024] The amount of the halogenating agent to be used is preferably 0.5 to 2.0 mol, more preferably 0.8 to 1.5 mol, per 1 mol of compound (2).

[0025] The reaction of the present invention is carried out in the presence or absence of a solvent. When a solvent is used, the type of the solvent is not particularly limited as long as it does not inhibit the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; black benzene, dichlorobenzene, etc. Halogenated aromatic hydrocarbons such as nitrobenzene, etc .; Halogenated aliphatic hydrocarbons such as methylene chloride and 1,2-dichloroethane; Ν, Ν-dimethylformamide, Ν, Ν -Amides such as dimethylacetamide, ethers such as diisopropyl ether, dioxane, cyclopropyl methyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; Aromatic hydrocarbons, halogenated aliphatic hydrocarbons, ethers, more preferably aromatic hydrocarbons, Rogeni spoon aliphatic hydrocarbons are used. These solvents may be used alone or in combination of two or more.

[0026] The amount of the solvent to be used is appropriately adjusted depending on the uniformity and stirrability of the reaction solution, and is preferably 0 to 20 g, more preferably 0 to 5 g, relative to compound (2) lg.

[0027] The reaction of the present invention is carried out, for example, by mixing the compound (2) and the halogenating agent and stirring them. It is performed by a method such as adapting. The reaction temperature at that time is preferably −30 to 100 ° C., more preferably −20 to 50 ° C., and the reaction pressure is not particularly limited!

[0028] The compound (la) is obtained by the above reaction of the present invention, and this is generally performed after the reaction, such as neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography, etc. Isolated and purified by appropriate methods.

[0029] The compound (la) represented by the formula (la) obtained by the present invention includes, for example,

Methyl 2-fluoro-3- (4-tetrahydrovinyl) -3-oxopropanoate,

2-fluoro-3- (4-tetrahydrovinyl) -3-ethyl oxopropanoate,

2-Fluoro-3- (4-tetrahydrovinyl) -3-propyl oxopropanoate,

2-fluoro-3- (4-tetrahydrovinyl) -3-butyl oxopropanoate,

2-chloro-methyl 3- (4-tetrahydrovinyl) -3-oxopropanoate,

2-black mouth-3- (4-tetrahydrovinyl) -3-ethyl oxopropanoate,

2-black mouth-3- (4-tetrahydrovinyl) -3-propyl oxopropanoate,

2—Black mouth— ₃ — ( ₄ —Tetrahydroviral) — ₃ —Butyl oxopropanoate,

Methyl 2-bromo-3- (4-tetrahydrovinyl) -3-oxopropanoate,

2-bromo-3- (4-tetrahydrovinyl) -3-oxopropanoate ethyl,

2-bromo-3- (4-tetrahydrovinyl) -3-propylpropanoate,

2-bromo-3- (4-tetrahydrovinyl) -3-butyl oxopropanoate,

Methyl 2-iodo-3- (4-tetrahydrovinyl) -3-oxopropanoate,

2-iodo-3- (4-tetrahydrovinyl) -3-ethyl oxopropanoate,

2-iodo-3- (4-tetrahydrovinyl) -3-propylpropanoate and

2-Oodo-3- (4-tetrahydrovinyl) -3-butyl oxopropanoate

Among these, among these,

2-chloro-methyl 3- (4-tetrahydrovinyl) -3-oxopropanoate,

2-black mouth-3- (4-tetrahydrovinyl) -3-ethyl oxopropanoate,

Methyl 2-bromo-3- (4-tetrahydroviral) -3-oxopropanoate and

2-Bromo-3- (4-tetrahydrovinyl) -3-oxopropanoate

Etc. are preferred. [0030] In the compound (1) of the present invention, the compound (lb) represented by the formula (lb) wherein Y is an acyloxy group is the compound (la) and the organic carboxylic acid compound (3 ) To react.

[0031] The organic carboxylic acid compound (3) used in the reaction of the present invention is represented by the general formula (3). In the general formula (3), R ¹ has the same meaning as described above. Examples of the salt of the organic carboxylic acid compound (3) include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt; There are quaternary ammonia salts such as -um salt.

[0032] Examples of the organic carboxylic acid compound (3) used in the present invention include formic acid, acetic acid, propionic acid, butyric acid, 2-methylpropionic acid, valeric acid, hexanoic acid, bivalic acid, heptanoic acid, Octanoic acid, nonanoic acid, decanoic acid, cyclopentylcarboxylic acid, cyclohexylcarboxylic acid, cycloheptylcarboxylic acid, cyclooctylcarboxylic acid, benzoic acid and their sodium, potassium, calcium, and ammonium salts Or tetrabutyl ammonium salt, etc. Formic acid, acetic acid, bivalic acid, cycloheptyl carboxylic acid and their sodium, potassium, calcium, ammonium or tetrabutyl ammonium salts, etc. More preferably used.

[0033] The amount of the compound (3) or a salt thereof used is preferably 0.

1-10 mol, more preferably 0.1-5.0 mol.

[0034] Desirably, the reaction of the present invention is carried out in the presence of a base. Examples of the base used include tertiary amines such as triethylamine and tributylamine; pyridines such as pyridine, methylpyridine and dimethylaminopyridine. ; Alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal carboxylates such as sodium acetate and potassium acetate; sodium methoxide and potassium methoxide Powers that can be used are preferably tertiary amines and pyridines.

Alkali metal carboxylates, more preferably tertiary amines, particularly preferably triethylamine and triptylamin are used. In addition, you may use these bases individually or in mixture of 2 or more types.

[0035] The amount of the base to be used is preferably 0 to 10 mol, more preferably 1 mol, per 1 mol of compound (la). Preferably it is 0-5.0 mol.

The reaction of the present invention is preferably carried out in a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; amines such as trytylamine, tryptylamine and the like Pyridines such as pyridine, methylpyridine and dimethylaminopyridine; quinolines such as quinoline, isoquinoline and methylisoquinoline; amides such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and Ν-methylpyrrolidone Ureas such as Ν, Ν'-dimethylimidazolidinone; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; alcohols such as _η -propyl alcohol and _η -butyl alcohol; diisopropyl ether, dioxane, cyclohexane Ethers such as propyl methyl ether; aromatic hydrocarbons such as toluene and xylene Carboxylic acid esters such as ethyl acetate and butyl acetate; forces including nitriles such as acetonitrile, propio-tolyl, buthiguchi-tolyl, benzo-tolyl, preferably amides, ureas, sulfoxides And nitriles, more preferably amides and nitriles. In addition, you may use these solvents individually or in mixture of 2 or more types.

[0037] The amount of the solvent to be used is appropriately adjusted depending on the uniformity and stirrability of the reaction solution, but is preferably 0.5 to 50 g, more preferably 1 to 20 g based on the compound (la) lg.

[0038] The reaction of the present invention is carried out, for example, by a method of mixing the compound (la), the compound (3) or a salt thereof, a base and a solvent and reacting them with stirring. The reaction temperature at that time is preferably −20 to 150 ° C., more preferably 0 to 120 ° C., particularly preferably 10 to 100 ° C., and the reaction pressure is not particularly limited!

[0039] The compound (lb) is obtained by the above reaction of the present invention, and this is generally performed after neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography, etc. Isolated and purified by conventional methods.

[0040] The compound (lb) represented by the formula (lb) obtained by the present invention includes, for example,

Methyl 2-formyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate,

2-formyloxy-3- (4-tetrahydrovinyl) -3-ethyl oxopropanoate,

2-formyloxy-3- (4-tetrahydrobiral) -3-propylpropanoate,

2-formyloxy-3- (4-tetrahydrovinyl) -3-butyl oxopropanoate, Methyl 2-acetoxy-3- (4-tetrahydrovinyl) -3-oxopropanoate,

2-acetoxy-3- (4-tetrahydrovinyl) -3-oxopropanoate,

2-acetoxy-3- (4-tetrahydrovinyl) -3-oxopropanoate propyl;

2-acetoxy-3- (4-tetrahydrovinyl) -3-butyl oxopropanoate,

2-Bivaloyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate methyl,

2-bivaloyloxy-3- (4-tetrahydroviranole) -3-oxopropanoate,

2-Bivaloyloxy-3- (4-tetrahydrovinyl) -3-propylpropanoate,

2-Bivaloyloxy-3- (4-tetrahydrovinyl) -3-butyl oxopropanoate,

Methyl 2-cycloheptylcarboxyl-3- (4-tetrahydrovinyl) -3-oxopropanoate,

2-cycloheptylcarbonyloxy-3- (4-tetrahydrovinylyl) -3-oxopropanoate,

2-cycloheptylcarbonyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate propyl and

2-Cycloheptylcarboxyl-3- (4-tetrahydrovinyl) -3-butyl oxopropanoate

Among these, among these,

Methyl 2-formyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate,

2-formyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate

Methyl 2-acetoxy-3- (4-tetrahydrovinyl) -3-oxopropanoate,

2-acetoxy-3- (4-tetrahydrovinyl) -3-oxopropanoate,

2-Bivaloyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate methyl,

2-Bivaloyloxy-3- (4-tetrahydrovillaryl) -3-oxopropanoate

Methyl 2-cycloheptylcarbonyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate and

2-Cycloheptylcarboxyl-3- (4-tetrahydrovinyl) -3-oxopropanoate

Etc. are preferred. Example 1

Next, the ability to specifically explain the present invention with reference to examples The scope of the present invention is not limited to these.

[0042] Reference Example 1 (Compound (2) [R = methyl group]; Synthesis of methyl 3- (4-tetrahydroviranyl) -3-oxopropanoate)

In a glass flask with an internal volume of 500 ml equipped with a stirrer, thermometer, dropping funnel and distillation apparatus, 35.0 g (273 mmol) of 4-acetyltetrahydropyran, 280.0 g (3.1 mol) of dimethyl carbonate and sodium methoxide 16.3 g (302 mmol) was added and reacted at 80 to 85 ° C. for 2 hours while distilling out by-produced methanol. After completion of the reaction, the reaction solution was cooled to 5 to 10 ° C., and then 175 ml of toluene, 55 ml of 6 mol / l hydrochloric acid (330 mmol), and 35 ml of water were added to the reaction solution in this order. After separating the organic layer, the aqueous layer was extracted twice with 70 ml of toluene. After the organic layer was concentrated under reduced pressure, the concentrate was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 1/1 (volume ratio)) to obtain a colorless liquid with a purity of 93.9% (differential refraction) 40.9 g of methyl 3- (4-tetrahydroviral) -3-oxopropanoate was obtained (isolation yield: 76%).

The physical properties of methyl 3- (4-tetrahydrovinyl) -3-oxopropanoate were as follows.

[0043] 1H-NMR (CDC1, δ (ppm)); 1.68 to 1.82 (4H, m

3), 2.66 ~ 2.72 (lH, m), 3.38 ~ 3.47 (2H, m)

3.51 (2H, s), 3.75 (3H, s), 3.97 ~ 4.04 (2H, m)

CI-MS (m / e); 187 (M + l)

Example 1 (Compound (la) [X = Chlorine Atom, R = Methyl Group]; Synthesis of Methyl 2-Chloro-3- (4-Tetrahydroviral) -3-oxopropanoate)

16 g (85.9 mmol) of methyl 3- (4-tetrahydrovinyl) -3-oxopropanoate synthesized in Reference Example 1 was added to a glass flask having an internal volume of 25 ml equipped with a stirrer, a thermometer and a dropping funnel. Cooled to 0 ° C in an ice-water bath. Next, 11.6 g (85.9 mmol) of sulfuryl chloride was gently added dropwise, followed by reaction at room temperature for 15 hours. After completion of the reaction, the reaction solution was cooled again to 0 ° C., 32 ml of water and 48 ml of toluene were slowly added dropwise and stirred for 10 minutes, and then the organic layer was separated. The aqueous layer was extracted with 16 ml of toluene, and the organic layer and the extract were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure as a light brown oily liquid Thus, 18.5 g of methyl 2-chloro-3- (4-tetrahydrovinyl) -3-oxopropanoate having a purity of 94.6% (area percentage by gas chromatography) was obtained (isolation yield: 92%).

2-Chloro-3-methyl (4-tetrahydrovinyl) -3-oxopropanoate is a novel compound with the following physical properties.

[0045] 1H-NMR (CDC1, δ (ppm)); 1.74 to 1.83 (4H, m), 3.06 to 3.16 (lH, m), 3.41 to 3.50 (2H, m)

Three

3.85 (3H, s), 3.99 ~ 4.05 (2H, m), 4.93 (lH, s) 3.86 (0.50H, s) 12.48 (0.17H, J = 1.46Hz, d)

CI-MS (m / e); 221 (M + l), 223 (M + 3)

[0046] Example 2 (Compound (la) [X = bromine atom, R = methyl group] Synthesis of methyl bromo- ( ₄ -tetrahydropyral) -3-oxopropanoate)

In Example 1, methyl bromide-3- (4-tetrahydrovinyl) -3-oxopropanoate can be synthesized in good yield by carrying out the same reaction by replacing the halogenating agent with bromine.

Example 3 (Compound (lb) [R, = Methyl group]; Synthesis of methyl 2-acetoxy-3- (4-tetrahydroviral) -3-oxopropanoate)

2-Chloro-3- (4-tetrahydroviral) -3-oxopropanoic acid synthesized in the same manner as in Example 1 in a glass flask having an internal volume of 100 ml equipped with a stirrer, a thermometer and a dropping funnel 9.46 g (42.9 mmol) of methyl, 3.0 g (49.8 mmol) of acetic acid and 30 ml of Ν, Ν-dimethylformamide were collected. Next, 5.0 g (49.8 mmol) of triethylamine was slowly added dropwise with stirring, and the mixture was reacted at room temperature for 14 hours. After completion of the reaction, 100 ml of toluene was added to the reaction solution, followed by filtration. The residue was washed with 50 ml of toluene, and the filtrate and the washing solution were combined and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 2/1 (volume ratio;)), and as a colorless liquid, a purity of 99.9% or more (area percentage by gas chromatography) 2 9.2 g of methyl -acetoxy-3- (4-tetrahydrovinyl) -3-oxopropanoate was obtained (isolation yield: 88%).

Methyl 2-acetoxy-3- (4-tetrahydroviranyl) -3-oxopropanoate is a novel compound represented by the following physical properties.

[0048] 'H-NMRCCDCl, δ (ppm)); 1.68 to 1.87 (4H, m), 2.24 (3H, s) 2.99 to 3.06 (lH, m), 3.40

Three

~ 3.51 (2H, m), 3.83 (3H, s) 3.98 ~ 4.03 (2H, m), 5.66 (lH, s) CI-MS (m / e); 245 (M + l)

Example 4 (Compound (lb) [R, R ¹ : Methyl group]; Synthesis of methyl 2-acetoxy-3- (4-tetrahydrobiral) -3-oxopropanoate)

2-Black neck-3- (4-tetrahydrovinyl) -3- synthesized in the same manner as in Example 1 in a glass flask with an internal volume of 30 ml equipped with a stirrer, thermometer and reflux condenser Methyl oxopropanoate 3.0 g (13.6 mmol), potassium acetate 1.47 g (15.0 mmol), acetic acid 10.5 g (174.7 mmol) and acetic anhydride l.lg (10.6 mmol) were added and stirred at 115-120 ° C. The reaction was allowed for 8 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 60 ml of toluene was added, followed by filtration. The filtrate was washed with 20 ml of toluene, and the filtrate and washings were combined and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 1/1 (volume ratio)) and obtained as a colorless liquid with a 2-acetate purity of 97.2% (area percentage by gas chromatography). 1.49 g of methyl methoxy-3- (4-tetrahydrovinyl) -3-oxopropanoate was obtained (isolation yield: 45%).

Example 5 (Compound (lb) [R = Methyl Group, 1 ^ = Butyl Group]; Synthesis of Methyl 2-Bivaloyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate)

2-Chloro-3- (4-tetrahydroviral) -3-oxopropanoic acid synthesized in the same manner as in Example 1 in a glass flask having an internal volume of 100 ml equipped with a stirrer, a thermometer and a dropping funnel Methyl 8.0 g (36.3 mmol), bivalic acid 4.7 g (46.3 mmol) and Ν, Ν-dimethylformamide 40 ml were added. Next, 4.7 g (46.3 mmol) of triethylamine was gently added dropwise with stirring and allowed to react at room temperature for 16 hours. After completion of the reaction, 100 ml of ethyl acetate and 100 ml of water were added to the reaction solution, and the organic layer was separated. Next, the aqueous layer was extracted with 100 ml of ethyl acetate, and the organic layer and the extract were combined and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 2/1 (volume ratio)), and was obtained as a colorless liquid with a purity of 9 9.1% (area percentage by gas chromatography) 2-Bivaloyloxy- 10.4 g of methyl 3- (4-tetrahydrobiral) -3-oxopropanoate was obtained (isolation yield: 99%).

2-Bivaloyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate methyl is a novel compound represented by the following physical properties.

[0051] 'H-NMRCCDCI, δ (ppm)); 1.30 (9H, s) ゝ 1.68 to 1.87 (4H, m), 2.96 to 3.03 (lH, m), 3.39 ~ 3.50 (2H, m), 3.82 (3H, s) ゝ 3.98 ~ 4.03 (2H, m), 5.59 (lH, s)

CI-MS (m / e); 287 (M + l)

Example 6 (Compound (la) [X = chlorine atom, R = methyl group]; toluene solution of methyl 2-chloro-3- (4-tetrahydroviral) -3-oxopropanoate Synthesis)

Methyl 3- (4-tetrahydrovinyl) -3-oxopropanoate synthesized in the same manner as in Reference Example 51 in a glass flask having an internal volume of 50 ml equipped with a stirrer, a thermometer and a dropping funnel (51.lg) 274 mmol) and 51 ml of toluene were added and cooled to −15 to −10 ° C. in an ice water bath. Next, 38.8 g (176 mmol) of sulfuryl chloride was slowly dropped while maintaining the liquid temperature at −15 to −5 ° C., and then reacted at room temperature for 19 hours. After completion of the reaction, the reaction solution was cooled to −10 to −5 ° C., 153 ml of water was slowly added dropwise and stirred for 30 minutes. Next, after separating the organic layer, 153 ml of a saturated aqueous sodium chloride solution, 153 ml of a 5% by weight aqueous sodium bicarbonate solution, 153 ml of a saturated aqueous sodium bicarbonate solution, and 153 ml of a 5% by weight aqueous sodium bicarbonate solution in this order. By washing, 83.9 g of a toluene solution of methyl 2-chloro-3- (4-tetrahydrovinyl) -3-oxopropanoate was obtained.

Example 7 (Compound (lb) [R = methyl group, R ¹ : hydrogen atom]; Synthesis of methyl 2-formyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate)

In a glass flask equipped with a stirrer, a thermometer and a dropping funnel with an internal volume of 200 ml, 7.57 g (165 mmol) of formic acid, 16.6 g (165 mmol) of triethylamine and 82 ml of Ν, Ν-dimethylformamide were calcined. 33.5 g of a toluene solution of the synthesized 2-chloromethyl-3- (4-tetrahydroviranyl) -3-oxopropanoate in toluene was slowly added dropwise and allowed to react overnight at room temperature with stirring. After completion of the reaction, 168 ml of saturated sodium chloride aqueous solution and 168 ml of ethyl acetate were added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with 168 ml of ethyl acetate. Next, the organic layer and the extract were combined, washed with 67 ml of saturated aqueous sodium chloride solution and 67 ml of saturated aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 10/1 → 10/3 (volume ratio)) to give 2- 11.0 g of methyl formyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate was obtained (isolation yield based on methyl 3- (4-tetrahydrovinyl) -3-oxopropanoate: 43%) . Methyl 2-formyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate is a novel compound represented by the following physical properties.

[0054] 1H-NMR (CDC1, δ (ppm)); 1.52 to 2.08 (4H, m), 2.99 to 3.12 (lH, m), 3.41 to 3.52 (2H, m)

Three

3.85 (3H, s) ゝ 4.01 ~ 4.09 (2H, m), 5.76 (lH, d, J = 0.9Hz), 8.17 (lH, d, J = 0.7Hz)

CI-MS (m / e); 231 (M + l)

Example 8 (Compound (la) [X = chlorine atom, R = methyl group]; Toluene solution of methyl 2-chloro-3- (4-tetrahydroviral) -3-oxopropanoate Synthesis)

Methyl 3- (4-tetrahydroviral) -3-oxopropanoate synthesized in the same manner as in Reference Example 1 in a glass flask having an internal volume of 50 ml equipped with a stirrer, thermometer and dropping funnel 4.79 g ( 25.7 mmol) and 4.8 ml of toluene were added and cooled to −15 to −10 ° C. in an ice water bath. Next, 3.65 g (27.0 mmol) of sulfuryl chloride was slowly added dropwise while maintaining the liquid temperature at −15 to −5 ° C., followed by reaction at room temperature for 19 hours. After completion of the reaction, the reaction solution was cooled to −10 to −5 ° C., and 14 ml of water was slowly added dropwise and stirred for 30 minutes. Next, after separating the organic layer, 14 ml of saturated aqueous sodium chloride solution, 14 ml of 5% by weight aqueous sodium hydrogen carbonate solution and 4.8 ml of saturated aqueous sodium hydrogen carbonate solution, 9.6 ml of 5% by weight aqueous sodium hydrogen carbonate solution Then, 4.8 ml of a saturated aqueous sodium chloride solution was washed in that order to obtain 4.8 ml of a toluene solution of methyl 2-chloro-3- (4-tetrahydrovinyl) -3-oxopropanoate.

Example 9 (Compound (lb) [R = methyl group, R ¹ : cycloheptyl group]; 2-cycloheptylcarboxyl-3- (4-tetrahydrovinyl) -3 -Synthesis of methyl oxopropanoate) Into a 200 ml glass flask equipped with a stirrer, thermometer and dropping funnel, put 4.76 g (33.5 mmol) of ptylcarboxylic acid, 3.38 g (33.4 mmol) of triethylamine and Ν, After adding 19 ml of Ν-dimethylformamide, slowly add 4.8 ml of toluene solution of methyl 2-chloro-3- (4-tetrahydrovinyl) -3-oxopropanoate synthesized in Example 8 and stir. The reaction was allowed to proceed for 18 hours at room temperature. After completion of the reaction, 24 ml of water and 24 ml of ethyl acetate were added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with 24 ml of acetyl acetate. Next, the organic layer and the extract were combined, washed twice with 9.8 ml of saturated aqueous sodium chloride solution, and then concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (developing solvent; hexane / ethyl acetate = 10 / 1 → 10/3 (volume ratio)) and purified as a colorless liquid, 2-cycloheptylcarboro 3.68 g of methyl 3- (4-tetrahydrovinyl) -3-oxopropanoate was obtained (isolated yield based on methyl 3- (4-tetrahydrobiral) -3-oxopropanoate: 44%) .

Methyl 2-cycloheptylcarboxy-3- (4-tetrahydrovinyl) -3-oxopropanoate is a novel compound represented by the following physical properties.

[0057] 1H-NMR (CDC1, δ (ppm)); 1.52 to 2.06 (16H, m), 2.64 to 2.73 (lH, m), 2.97 to 3.07 (lH, m

Three

), 3.40 ~ 3.50 (2H, m), 3.82 (3H, s), 4.00 (2H, d, J = 11.7Hz), 5.63 (lH, s)

CI-MS (m / e); 327 (M + l)

Example 10 (Compound (lb) [R, R ¹ : Methyl Group]; Synthesis of methyl 2-acetoxy-3- (4-tetrahydrovinyl) -3-oxopropanoate)

Add 1462 g of acetonitrile and 872 g (14.52 mol) of acetic nitrile and 872 g (14.52 mol) of acetic acid to a 20 L glass flask equipped with a stirrer, thermometer and dropping funnel, while maintaining the liquid temperature at 20-40 ° C, 1102 g of triethylamine ( 10.89 mol) was slowly added dropwise. Next, 3262 g of a toluene Z-acetonitrile mixed solution of 1509.1 g (6.84 mol) of 2-chloromethyl-3- (4-tetrahydroviral) -3-oxopropanoate synthesized in the same manner as in Example 1 was slowly dropped. Then, 73.5 g (0.73 mol) of triethylamine and 43.6 g (0.73 mol) of acetic acid were added dropwise at 39 to 41 ° C. with stirring, and reacted for 1 hour with stirring. After completion of the reaction, 3515 g of toluene was added, and while maintaining the liquid temperature at 5 ° C. or lower, 743 g of water and 2231 g of a 20 wt% sodium chloride aqueous solution were dropped in this order and the mixture was stirred for 5 minutes. Liquid separation was performed. While maintaining the liquid temperature of the obtained organic layer at 5 ° C. or lower, 3110 g of 20% by weight saline was gently dropped and stirred for 5 minutes, and then the organic layer was separated (this operation was repeated twice). . The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and the residue was washed with 1169 g of toluene. Thereafter, the filtrate and the washing solution were combined and concentrated under reduced pressure to obtain 1750 g of a brown liquid containing 1532.6 g of methyl 2-acetoxy-3- (4-tetrahydrovinyl) -3-oxopropanoate (isolation yield; 92%).

Industrial applicability

[0059] The present invention relates to 2-substituted-3- (4-tetrahydrovinyl) -3-oxopropanoic acid ester and a process for producing the same, and the resulting 2-substituted-3- (4-tetrahydrovinanyl) ) -3-oxopropanoic acid ester is a useful compound as a raw material for pharmaceuticals and agricultural chemicals, and as a synthetic intermediate.

Claims

The scope of the claims

[1]-General formula (1)

In the formula, Y represents a halogen atom or an acyloxy group, R represents a hydrocarbon group,

2-Substituted-3- (4-tetrahydrovinyl) -3-oxopropanoic acid ester represented by

The compound represented by the formula (1) is represented by the general formula (la):

In the formula, X represents a halogen atom, R is as defined above,

2-halogeno-3- (4-tetrahydroviral) -3-oxopropanoic acid ester represented by the above-mentioned 2-substituted-3- (4-tetrahydrobiral) -3- Oxopropanoic acid ester.

The compound represented by the formula (1) is represented by the general formula (lb):

In the formula, R ¹ represents a hydrogen atom or a hydrocarbon group, and R is the same as defined above, 2-acyloxy-3- (4-tetrahydrobiral) -3-oxopropanoic acid ester represented by The 2-substituted-3- (4-tetrahydrovinyl) -3-oxopropanoate according to claim 1.

[4] General formula (2):

In the formula, R represents a hydrocarbon group.

A halogenating agent is reacted with 3- (4-tetrahydrovinyl) -3-oxopropanoate represented by the general formula (la):

In the formula, X represents a halogen atom, R is as defined above,

2-halogeno-3- (4-tetrahydrovinyl) -3-oxopropanoic acid ester represented by the following formula (3):

In the formula, R ¹ represents a hydrogen atom or a hydrocarbon group.

Wherein the organic carboxylic acid represented by the formula (1) is reacted.

()

In the formula, R ¹ and R are as defined above.

A process for producing a 2-substituted-3- (4-tetrahydrovinyl) -3-oxopropanoate represented by the formula: The 2-substituted-3- (4-tetrahydrovinyl) -3-oxopropanoic acid ester according to claim 4, wherein the reaction of the compound of formula (la) and the compound of formula (3) is carried out in the presence of a base. The manufacturing method. General formula (2):

In the formula, R represents a hydrocarbon group.

A general formula (la) characterized in that a halogenating agent is reacted with 3- (4-tetrahydrovinyl) -3-oxopropanoic acid ester represented by:

In the formula, X represents a halogen atom, R is as defined above,

2-halogeno-3- (4-tetrahydrovinyl) -3-oxopropanoate represented by

[7] The amount of halogenating agent used The amount of 2-norogeno-3- (4-tetrahydrovinyl) -3 according to claim 6, which is 0.5 to 2.0 mol per 1 mol of compound (2) -Manufacturing method of oxopropanoic acid ester.

[8] The 2-halogeno-3- (4-tetrahydrovinyl) according to claim 6, wherein the reaction is carried out in a solvent.

) Preparation of 3-oxopropanoic acid ester.

[9] The 2-halogeno-3- according to claim 6, wherein the solvent is at least one solvent selected from the group consisting of aromatic hydrocarbons, halogenated aliphatic hydrocarbons and ethers. (

Preparation of 4-tetrahydrovinyl) -3-oxopropanoate.

[10] General formula (la):

In the formula, X represents a halogen atom, R represents a hydrocarbon group,

2-halogeno-3- (4-tetrahydrovinyl) -3-oxopropanoate represented by general formula (3):

In the formula, R ¹ represents a hydrogen atom or a hydrocarbon group. A reaction with an organic carboxylic acid represented by the formula (lb)

In the formula, R ¹ and R are as defined above.

A process for producing 2-acyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate represented by the formula:

[11] The process for producing 2-acyloxy-3- (4-tetrahydrovinyl) -3-oxopropanoate according to claim 10, wherein the reaction is carried out in the presence of a base.

[12] The process for producing 2-acyloxy-3- (4-tetrahydrobiral) -3-oxopropanoate according to claim 10, wherein the base is a tertiary amine.

[13] The process for producing 2-acyloxy-3- (4-tetrahydropyral) -3-oxopropanoate according to claim 10, wherein the reaction is carried out in a solvent.

14. The 2_acyloxy-3_ (4_tetrahydride according to claim 10, wherein the solvent is at least one solvent selected from the group consisting of amides, ureas, sulfoxides and -tolyls. (Robilal) -3-oxopropanoic acid ester.