KR860000173B1 - Process for preparing alpha-aromatic group substituted alkanoic acids or esters thereof - Google Patents

Abstract

The title compds. I (Ar = aromatic gp.; R1 = H or saturated aliphatic gp.; R2 = H, alkyl, hydroxyalkyl; R3, R4 = alkyl; R5 = alkyl or aromatic ring) were prepd. by the hydrolysis of α- sufonyloxyketoneacetal (II). Thus, 0.991g -(methanesulfonyloxy)p- isobutylpropiophenonedimethylacetal and 0.3g calcium carbonate were refluxed in a mixture of H2O and methanol for 72hr, to give 0.519g α- (4-isobutylphenyl) propionic acid. I have pharmacological action.

Description

Preparation of α-aromatic group substituted alkanoic acid and esters thereof

The present invention relates to a novel process for preparing α-aromatic group substituted alkanoic acid and esters thereof.

In particular, this invention relates to the manufacturing method of the (alpha)-aromatic group substituted alkanoic acid represented by following formula (I), and its ester.

In the above formula,

Ar represents an aromatic group, R ¹ represents a hydrogen atom or a saturated aliphatic group, or Ar and R ¹ together may form a condensed ring,

R ² represents a hydrogen atom, an alkyl group or a hydroxy alkyl group.

Many kinds of compounds of the general formula (I) are commercially available.

For example, α- (4-isobutylphenyl) propionic acid, a compound of formula (I) wherein Ar is a 4-isobutylphenyl group, R ¹ is a methyl group, and R ² is a hydrogen atom, is an anti-inflammatory agent called "Ibuprofen". ) ".

Α- (6-methoxy-2-naphthyl) propionic acid, wherein the compound of formula (I) wherein Ar is a 6-methoxy-2-naphthyl group, R ¹ is a methyl group, and R ² is a hydrogen atom, (Naproxen) ".

Α- (4-difluoromethoxyphenyl) isovaleric acid, a compound of formula (I) wherein Ar is a 4-difluoromethoxyphenyl group, R ¹ is an isopropyl group, and R ² is a hydrogen atom, is a pyrethroid insecticide It is very effective as an acid moiety.

Various methods have been carried out so far to prepare α-aromatic substituted alkanes. Representatively, examples for the preparation of α- (4-isobutylphenyl) propionic acid (ibuprofen) are described below.

(1) 4-isobutylphenyl acetic acid ester produced from 4-isobutylacetophenone in two steps with alkylcarbonate in the presence of a base to form the corresponding malonic acid ester, which is converted to methyl iodide. Methylation and hydrolysis of the methylated product, followed by pyrolysis of the product to yield the desired propionic acid (British patent 971,700).

(2) converting isobutyl acetophenone to the corresponding hydantoin by the action of potassium cyanide and ammonium carbonate, hydrolyzing the hydantoin to α-amino acid, alkylating it with a dialkyl amino compound and reducing it to α- A process characterized by forming (4-isobutylphenyl) propionic acid (British patent 111167192).

(3) Darzens reaction with 4-isobutylacetophenone and monochloroacetic acid ester to form the corresponding epoxy carboxylic acid ester, hydrolyze the ester and decarboxylate the hydrolysis product to A process characterized by forming a-(4-isobutylphenyl) propion aldehyde and oxidizing the aldehyde with the desired propionic acid (British Patent No. 1160725).

(4) 4-isobutylbenzaldehyde is side-linked with formaldehyde mercaptal s-oxide to form a ketene mercaptal s-oxide, which is reacted with thionyl chloride to form α-chloroketene mercaptal which is alcoholized to α- A method characterized by forming a (4-isobutylphenyl) -α-alkylthioacetic acid ester and reacting the ester in the order of methylation, hydrolysis and reductive desulfurization to obtain the desired propionic acid (US patent) 4,242,519).

The methods of (1) and (4) are industrially disadvantageous because they go through several steps. Method (2) is also industrially disadvantageous because it involves the use of toxic substances such as potassium cyanide.

Processes (1) and (3) are economically disadvantageous because the ethoxycarbonyl groups introduced in the initial stage are removed by decarboxylation in the final stage.

Therefore, it is evident that the provision of new methods advantageous for the industrial production of compounds of general formula (I) will greatly contribute to the advancement of the technology in this field.

One object of the present invention is to provide a unique and industrially advantageous process for the preparation of compounds of general formula (I).

Other objects and advantages of the present invention will become apparent from the following description.

The present invention relates to a method for producing α-aromatic group substituted alkanoic acid and esters thereof of the following general formula (I) by hydrolysis of α-sulfonyloxyketone acetal of the following general formula (II).

In the above formula,

Ar represents an aromatic group, R ¹ represents a hydrogen atom or a saturated aliphatic group, or Ar and R ¹ may combine with a carbon atom to form a condensed ring,

R ² represents a hydrogen atom, an alkyl group, or a hydroxyalkyl group,

R ³ and R ⁴ each independently represent an alkyl group, or together form an alkylene group,

R ⁵ represents a substituted or unsubstituted alkyl group or an aromatic group.

As used herein and in the claims, the term "aromatic group" means a cyclic compound having aromaticity. Aromaticity refers to a phenomenon in which a ring is stable by delocalization of π electrons. In general, a ring having (4n + 2) conjugated π electrons is stable and exhibits aromaticity, so the aromatic group used here is a group of a compound having a conjugated π electron of (4n + 2) in the main ring. .

It may be roughly classified into aryl groups optionally having one or more substituents and heteroaromatic groups optionally having one or more substituents, which are described below.

(a) An aryl group optionally having one or more substituents.

Aryl groups are, for example, monocyclic, polycyclic or condensed polycyclic aromatic hydrocarbon groups such as phenyl, biphenyl and naphthal.

The aryl group is unsubstituted or has one or more substituents on the aromatic ring. Specific examples of the substituent include halogen atoms such as chlorine, bromine, fluorine and iodide, lower alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl; Cycloalkyl groups such as cyclohexyl and cyclopentyl; Aralkyl groups such as benzyl; Lower alkoxy groups such as methoxy, ethoxy, n-propoxy and isopropoxy; Lower alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio and butylthio; Arylthio groups such as phenylthio, tolylthio and naphthylthio; Alkenylthio groups such as allylthio; Aralkylthio groups such as benzylthio; Acyloxy groups such as acetoxy; Aroyloxy groups such as benzoyloxy; Silyloxy groups such as trimethylsilyloxy; Lower alkenyl groups such as allyl and prenyl [(CH ₃ ) ₂ C═CH—CH ₂ —]; Lower alkenyloxy groups such as allyloxy; Aralkyloxy such as benzyloxy and phenethyloxy; Aryloxy groups such as phenoxy; Lower haloalkoxy groups such as trifluoroethyl and trifluoropropyl; 4- to 6-membered heterocyclic groups such as indolinyl, oxo-isoindolinyl thienyl, piperidino and phthalimido; 4- to 6-membered heterocycleoxy groups such as thiazoyloxy and pyridyloxy; Nitro group; Aroyl groups such as benzoyl; Acylamino groups such as acetylamino and propionylamino; Aroylamino groups such as benzoyl amino and dialkyl amino groups such as dimethylamino and dibenzylamino and the like.

When these substituents are present, it is preferable that 1 to 5, preferably 1 to 3 of them are present on the aromatic ring.

Specific examples of the aryl group having such a substituent in the aromatic ring include chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, tolyl, ethylphenyl, isopropylphenyl, isobutylphenyl, t-butylphenyl, cyclohexylphenyl , Methoxyphenyl, ethoxyphenyl, isopropoxyphenyl, methylthiophenyl, ethylthiophenyl, n-propylthiophenyl, isopropylthiophenyl, butylthiophenyl, phenylthiophenyl, tolylthiophenyl, allylthiophenyl, benzyl Thiophenyl, acetoxyphenyl, trimethylsilyloxyphenyl, benzoyloxyphenyl, benzylphenyl, prenylphenyl, allyloxyphenyl, benzyloxyphenylphenoxyphenyl, tetrafluoroethoxyphenyl, trifluoroethylphenyl, trifluorome Oxyphenyl, difluoromethoxyphenyl, oxo-isoyldolinylphenyl, thioazolyloxyphenyl, nitrophenyl, benzoylphenyl, acetylaminophenyl, piperidinophenyl, fluorobiphenyl, acetylaminobi Carbonyl, and methoxy-naphthyl, methyl thienyl-phenyl, acetylamino-chloro-phenyl- chloro-cyclohexyl-phenyl, etc. belong.

(b) heteroaromatic groups optionally having one or more substituents.

The heteroaromatic group may be either monocyclic or condensed polycyclic. The hetero atom of the heteroaromatic ring may be nitrogen, oxygen or sulfur. Heteroaromatic rings generally comprise 1 to 4, preferably 1 to 3, heteroatoms, usually 5- or 14-membered, with 5- to 9-membered being particularly preferred. Specific examples of heteroaromatic groups include thienyl, furyl, pyrrolyl, indolyl, petothiazinyl, pyridyl, thiazolyl and benzothiazolyl and the like.

Heteroaromatic groups are unsubstituted or contain one or more substituents on the ring. Examples of substituents present in the heteroaromatic cyclic include lower alkyl groups such as methyl, ethyl, propyl and butyl, allyl groups such as phenyl and fluorophenyl; Halogen atoms such as chlorine and fluorine, lower alkoxy groups such as methoxy, ethoxy and propoxy; Aryloxy groups such as phenoxy; Lower alkyl groups such as methyl, ethyl, propyl and butyl; Aralkyl groups such as benzyl; Aryl groups such as phenyl, tolyl and fluorophenyl; Halogen atoms such as chlorine, fluorine and bromine; Lower alkoxy groups such as methoxy, ethoxy and propoxy; Cycloalkyl groups such as cyclohexyl and cyclopentyl; Lower alkenyl groups such as allyl and prenyl; Lower alkenyloxy groups such as allyloxy; Aralkyloxy groups such as benzyloxy; An aryloxy group such as phenoxy; Lower alkyl thi groups such as lower haloalkyl group methylthio such as trifluoromethyl; Allylthio groups such as phenylthio; Aroyl groups such as benzoyl, toluoyl and chlorobenzoyl; Acyl groups such as acetyl; And lower haloalkyl groups such as trifluoromethyl and cycloalkyl groups such as cyclohexyl.

These substituents are 1 to 8, preferably 1 to 3.

Examples of heteroaromatic groups having such a ring include methylphenothiazinyl, methoxymethyl-phenothiazinyl, methylpyrrolyl, toluoyl-methylpyrrolyl, phenylthienyl, bromothienyl, trifluoromethylthienyl , Benzoylthienyl, cyclohexylthienyl, methoxythienyl, methyl-methoxy-indolyl, chlorobenzoyl-indolyl, acetyl-pyrrolyl, methyl-toluoyl-pyrrolyl, benzylpyrrolyl and the like.

As used herein and in the claims, the term "saturated aliphatic group" means a linear, branched or cyclic saturated aliphatic hydrocarbon containing 1 to 10, preferably 1 to 6 carbon atoms.

Examples of such saturated aliphatic groups include linear or branched alkyl groups of 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl And lower alkyl groups such as isoamyl and n-hexyl, and cycloalkyl groups such as 3 to 10 carbon atoms, especially 3 to 7 carbon atoms such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl.

Examples of the substituents present on the alkyl group in the "substituted alkyl group" include halogen atoms such as chlorine, bromine and fluorine; Aryl groups such as phenyl; Alkoxy groups such as methoxy and ethoxy; And alicyclic groups such as [1R, 4R] or [1S, 4S] -7,7-dimethyl-2-oxobicyclo [2,2,1] -heptan-1-yl and the like.

Specific examples of such substituted alkyl groups include trifluoromethyl, d-or l-10-camphoryl, benzyl and the like.

As used herein and in the claims, the "alkyl group" and "alkylene group" may be either linear or branched, with the alkylene group being a lower alkylene group such as ethylene, propylene, butylene, trimethylene or tetramethylene Do.

The term "lower" as used in this specification and in the claims to designate a group or compound is a group and compound having up to 6, preferably up to 4 carbon atoms.

When a compound of the general formula (II) which is a specific acetal compound having a sulfonyloxy group (OSO ₂ R ⁵ ) in the _2- position and an aromatic group (Ar) in the 1-position according to the method of the present invention, It was found that the sulfonyl oxy group was broken and a unique reaction in which the aromatic group was displaced to the 2-position occurred to produce an α-aromatic group substituted alkanoic acid of the general formula (I).

The hydrolysis reaction can be carried out without solvent. Preferably, however, it is generally carried out in an inert solvent. Examples of inert solvents include dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI), 1,4-dioxane, tetrahydrofuran (THF), Aprotic polar solvents such as diethylene glycol dimethyl ether (diglyme), hexamethylphosphoric triamide (HMPA), 1,2-dimethoxyethane and pyridino; Proton polar polar solvents such as methanol, ethanol, ethylene glycol and acetic acid. These solvents may be used alone or in combination of two or more.

The reaction temperature is not limited, and may vary widely depending on the form of starting material (II) and the like. Generally, 0 ° C.-250 ° C., preferably room temperature to about 200 ° C. In order to enhance the reaction, the reaction is preferably carried out at a temperature between 40 ° C. and the reflux of the reaction mixture, more preferably between about 50 ° C. and about 180 ° C. The reaction can be carried out at atmospheric pressure or under pressure.

The water required for hydrolyzing the compound of formula (II) is premixed with the solvents exemplified above, and the reaction is carried out by mixing the compound of formula (II) with this solvent. Or the compound of Formula (II) is mixed with a solvent, water is mixed with this mixture, and it reacts with compound (II).

Alternatively, the compound of formula (II) is heated to a temperature within the above-mentioned range in the solvent under anhydrous conditions and then water is added to hydrolyze the compound of formula (II) (see Examples 11 and 15 below). .

In view of ease of operation, it is convenient to add the compound of formula (II) to the mixture of water and the polar solvent.

The amount of water required for hydrolysis is not limited and may vary widely depending on the kind of compound (II) used, reaction conditions, and the like.

Generally, it is used in an amount of at least 1 mole, preferably at least 5 moles per unit mole of the compound of formula (II). If an excessive amount of water is used, solubility of the compound of formula (II) decreases, so it is not preferable to use an excessive amount of water.

In order to prevent acid uniformity of the acetal component in the compound of formula (II), it is generally preferred to hydrolyze under neutral or basic (pH about 7-14) conditions.

Since the 2-position sulfonyloxy group (-OSO ₂ -R ⁵ ) is released as sulfonic acid R ⁵ SO ₃ H during hydrolysis, the base is added to the reaction system to maintain the reaction system in neutral to basic conditions during the reaction. It is good to put.

Examples of bases that can be used for this purpose include alkali metal hydroxides such as potassium hydroxide and sodium hydroxide; Alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; Alkali metal carbonates such as potassium carbonate and sodium carbonate, alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate; Alkali metal bicarbonates such as potassium bicarbonate and sodium bicarbonate; Alkali metal carboxylates such as sodium formate, sodium acetate, potassium acetate and sodium propionate; Alkali metal phosphates such as sodium phosphate and potassium phosphate; And organic tertiary amines such as pyridine, triethylamine and tributylamine. These inorganic or organic bases are generally used in an amount of at least 1 equivalent, preferably 1 to 10 equivalents, per unit mole of the compound of formula (II).

The hydrolysis reaction is generally terminated within about 1 to about 250 hours, depending on the kind of starting compound formula (II) and the reaction conditions.

In the above hydrolysis reaction, the 2-position sulfonyloxy group (-OSO2-R ⁵ ) of the compound of formula (II) is released, and the aromatic group (Ar) in 1-position is shifted to 2-position.

At the same time, one of the acetal groups -OR ³ and -OR ⁴ is released and the remaining one acetal group forms the group -OR ² in which R ² is an alkyl group in the compound of formula (I).

Under particularly strong basic conditions, depending on the conditions used for the hydrolysis, the ester (I) formed [the compound of formula (I) wherein R ² is an alkyl group] is hydrolyzed to form a compound of formula (I) wherein R ² is a hydrogen atom. .

When the compound of formula (II) wherein R ³ and R ⁴ together form an alkylene group is hydrolyzed, the corresponding compound of formula (I) is obtained wherein R ² is a hydroxyalkyl group.

Compounds of formula (I) produced according to the invention can be separated from the reaction mixture by known methods such as extraction, chromatographic distillation and crystallization.

Compounds of formula (II) used as starting materials in the process of the invention are novel and not described in the literature and constitute the invention of the divisional application of the invention.

To illustrate the various groups in equation (II):

(1) The aromatic group Ar is preferably an aryl group optionally having one or more substituents. More preferred are groups of the formula R ⁶ -Ar ^1- , wherein Ar ¹ represents a phenylene or naphthylene group, and R ⁶ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkoxy group, a lower group An alkanoylamino group, an oxo-isoindolinyl group, or a phenyl group is represented.

Thienyl groups are also preferred.

(2) The saturated aliphatic group R ¹ is preferably a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl or butyl. As such, hydrogen atoms and lower alkyl groups are preferred as R ¹ .

(3) The alkyl group represented by R ³ and R ⁴ , respectively, is preferably a lower alkyl group. R ³ and R ⁴ as alkylene groups are suitable for lower alkylene groups such as ethylene, propylene and trimethylene.

(4) Examples of preferred substituted or unsubstituted alkyl groups represented by R ⁵ include unsubstituted lower alkyl groups such as methyl, ethyl and butyl, and lower haloalkyl groups such as trifluoromethyl; And d- or l-10-camphoryl and the like.

Preferred as the aromatic group R ⁵ is formula,

Is a substituted or unsubstituted phenyl group, wherein R ¹ represents a hydrogen atom, a halogen atom, a nitro group or a lower alkyl group.

The compound of the following formula is most preferable among the compound of formula (II) provided in this invention.

(Wherein

Ar ² represents a formula R ⁶ -Ar ¹ group or thienyl group,

R ^{1 '} represents a hydrogen atom or a lower alkyl group;

R ^{3 '} and R ^4' each represent a lower alkyl group or each other form a lower alkylene group;

R ^{5 ′} is a lower alkyl group, lower haloalkyl group, d- or l-10-camphoryl group or formula,

Represents a group of;

Ar ¹ , R ⁶ and R ⁷ are as defined above.)

In formula (II), Ar and R ¹ may form a condensed ring with each other. Specific examples of the compound of formula (II) in which Ar and R ¹ form a condensed ring are as follows.

Hydrolysis of the compound according to the method of the present invention yields the following compounds, respectively.

Compounds of formula (I) which can be produced by the process of the invention are included in a variety of compounds useful in such fields as pharmacy and agrochemistry. Representative examples of such useful compounds include ibuprofen, naproxen and α- [4- (1-oxo-2-isoindolinyl) phenyl] propionic acid (anti-inflammatory, indopropene) and the like.

Representative examples also include α- (2-thienyl) propionic acid, methyl α- (4-acetylaminophenyl) propionate, α-4- (t-butyl), which are known as important intermediates for the synthesis of anti-inflammatory and insecticides. ) -Phenyl tersovaleric acid, methyl α- (4-alkoxyphenyl) isovalerate, α- (4-biphenylyl) propionic acid, methyl α- (4-fluoromethoxyphenyl) isovalerate and methyl α- ( 4-alkoxyphenyl) propionate and the like.

The invention is explained in more detail by the following examples.

Example 1

0.526 g of α- (p-toluenesulfonyloxy) propiophenonedimethylacetal and 0.150 g of calcium carbonate are refluxed for 72 hours in 10 ml of a mixture of water and methanol (3: 7 weight ratio). Water (10 ml) is added and the mixture is extracted three times with 10 ml of diethyl ether. The extract is washed with 10 ml of water and dehydrated with anhydrous magnesium sulfate.

Quantitative analysis of the product by gas chromatography (internal standard method) reveals that 0.162 g of methyl α-phenylpropionate is included.

Yield: 66%

Example 2

1. 75 g of α- (p-toluenesulfonyloxy) propiophenone dimethylacetal and 0.500 g of calcium carbonate are refluxed in 33 ml of a mixture of water and methanol (weight ratio 3: 7) for 72 hours. Water (50 ml) is added and the mixture is extracted three times with 30 ml of diethyl ether. The extract is washed with 30 ml of water and concentrated under reduced pressure to about 5 ml.

Methanol (12 ml), water (5 ml) and 7 ml of 10% aqueous sodium hydroxide solution are added to the residue and the mixture is refluxed for 5 hours. Water (30 ml) is added and the mixture is washed 5 times with 20 ml of diethyl ether. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid and extracted four times with 20 ml of diethyl ether.

20 ml of the extract was washed with water, dehydrated on anhydrous magnesium sulfate and concentrated under reduced pressure to yield 0.358 g of a colorless oily α-phenylpropionic acid.

Yield: 48%

This product is in full agreement with IR and NMR spectral data from an authentic sample.

Example 3-15

0.526 g of α- (p-toluenesulfonyloxy) propiophenone dimethylacetal and various bases in Table 1 were each heated in an equimolar amount in 10 ml of each of the various solvents in Table 1 and heated in an oil bath.

Water (10 ml) is added and the mixture is extracted three times with 10 ml of diethyl ether.

The extract is washed with 10 ml of water and dehydrated with anhydrous magnesium sulfate.

The product is analyzed to methyl α-phenylpropionate by gas chromatography in the same manner as in Example 1.

The results are shown in Table 1.

TABLE 1

Example 16

0.410 g of α- (p-toluenesulfonyloxy) -p-isobutylpropiophenone dimethylacetal and 0.100 g of calcium carbonate are refluxed for 22 hours in a mixture of water and methanol (weight ratio 3: 7). Water (15 ml) is added and the mixture is extracted three times with 10 ml of diethyl ether. The extract is washed with 10 ml of water, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. Purification of the residue in the oil phase by column chromatography (silica gel, methylene chloride) yielded 0.180 g of colorless oily methyl α- (4-isobutylphenyl) propionate. Yield 81%, this product is in full agreement with the standard by IR and NMR spectrum data.

Example 17

0.910 g of α- (p-toluenesulfonyloxy) -p-isobutylpropiophenone dimethylacetal and 1.25 g of potassium carbonate are refluxed in 26 ml of a mixture of water and methanol (weight ratio 3: 7) for 20 hours. Water (30 ml) is added and the mixture is washed four times with 10 ml of methylene chloride.

The pH of the aqueous layer is adjusted to 2 with dilute hydrochloric acid, and 20 ml is extracted four times with methylene chloride. The extract was washed with 30 ml of water and dehydrated with anhydrous magnesium sulfate to yield 0.335 g of colorless crystalline α- (4-isobutylphenyl) propionic acid having a melting point of 71-75 占 폚.

Yield: 73%

This product is in full agreement with the standards by IR and NMR specification data.

Example 18

0.991 g of α- (methanesulfonyloxy) -p-isobutylpropiophenone dimethylacetal and 0.300 g of calcium carbonate are refluxed in 10 ml of a mixture of water and methanol (weight ratio 3: 7) for 72 hours. When the crude product is subjected to alkaline hydrolysis as in Example 2 and then subjected to a normal operation, 0.519 g of colorless crystalline α- (4-isobutylphenyl) propionic acid having a melting point of 73-75 ° C is obtained.

Yield: 84%

This product is in full agreement with the standard by IR and NMR spectrum data.

Example 19

2.12 g of α- (p-toluenesulfonyloxy) -p-methoxy-propiophenone dimethylacetal and 0.560 g of calcium carbonate are refluxed in 20 ml of a mixture of water and methanol (weight ratio 3: 7) for 13 hours.

When the crude product as in Example 2 is subjected to an alkaline hydrolysis and then subjected to a conventional method, 0.714 g of a pale yellow crystalline α- (4-methoxyphenyl) propionic acid having a melting point of 47-50 占 폚 is obtained.

Yield: 57%

Example 20

0.735 g of α- (methanesulfonyloxy) -p- (t-butyl) isovalerophenone dimethylacetal and 0.200 g of calcium carbonate are refluxed in 10 ml of a mixture of water and methanol (weight ratio 3: 7) for 72 hours. . Normal operation as in Example 16 and separation by column chromatography (silica gel, methylene chloride) afforded a colorless oily methyl?-[4- (t-butyl) phenyl] isovalerate.

IR (neat): 2965, 1745, 1165, 1025cm ^-1

NMR (CDCl ₃ ): δ

0.71 (3H, d, J = 7 Hz), 1.2 (3H, d, J = 7 Hz), 1.32 (9H, s), 2.1-2.6 (1H, m), 3.10 (1H, d, J = 11 Hz) , 3.60 (3H, s), 7.1-7.4 (4H, m).

For C ₁₆ H ₂₄ O ₂ :

Calculated Value: C 77.37 H 9.74%

Found: C 77.26 H 9.62%

Example 21

0.668 g of α- (p-toluenesulfonyloxy) acetophenoneethyleneacetal is dissolved in 8 ml of 1,3-dimethyl-2-imidazolidinone (DMI) and 200 ml of calcium carbonate 0.2 ml of water is added. . The mixture is heated at 180 ° C. for 22 hours with stirring. After cooling 30 ml of water are added and the mixture is extracted three times with 20 ml of diethyl ether.

The extract is washed twice with 10 ml of water and dehydrated with anhydrous magnesium sulfate. The aqueous layer is combined and 4 ml of concentrated hydrochloric acid is added.

The mixture is extracted three times with 20 ml of diethyl ether.

The extract is washed twice with 10 ml of water and dehydrated with anhydrous magnesium sulfate. The aqueous layer is mixed and 4 ml of concentrated hydrochloric acid is added. The mixture is extracted three times with 20 ml of diethyl ether.

The extract is washed twice with 10 ml of water and dehydrated with anhydrous magnesium sulfate. The aqueous layer is mixed and 4 ml of concentrated hydrochloric acid is added. The mixture is extracted three times with 20 ml of diethyl ether. The extract is washed twice with 10 ml of water and dehydrated with anhydrous magnesium sulfate.

The neutralized and acidic extracts were concentrated under reduced pressure, respectively, and the resulting residue was mixed and 400 ml of potassium hydroxide was added. The mixture is refluxed for 16 h in a mixture of 6 ml methanol and 2 ml water.

After cooling, 30 ml of water are added and the mixture is washed three times with 20 ml of diethyl ether. The aqueous layer was acidified to pH about 2 by adding 7 ml of 3.5% hydrochloric acid, and extracted three times with 20 ml of diethyl ether. The extract is washed with 10 ml of water, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to give 92 mg of residue.

The residue was treated with diazomethane to reveal a mixture of benzoic acid and phenylacetic acid by NMR and GLC of its methyl ester.

From the NMR spectral data, it can be seen that 65 mg (27% yield) of benzoic acid and 27 mg (10% yield) of phenylacetic acid are included.

Example 22

0.798 α- (p-bromobenzenesulfonyloxy) acetophenoneethylene acetal is dissolved in 8 ml of DMI, 200 mg of calcium carbonate and 0.5 ml of water are added.

The mixture is heated at 160 ° C. for 18 hours with stirring.

Operating the reaction mixture in a similar manner to Example 21 and alkali hydrolysis of the crude product yielded 84 mg of semisolid. The semisolid is found by NMR to be a mixture of benzoic acid phenylacetic acid (molar ratio 7.0: 4.5).

Thus, the mixture comprises 49 mg (20% yield) of benzoic acid and 35 mg (13% yield) of phenylacetic acid.

Example 23

0.560 g of 1- (2-thienyl) -2- (methanesulfonyloxy) -1-propaneone dimethylacetal and 0.200 g of calcium carbonate were refluxed in a mixture of water and methanol (weight ratio 3: 7) for 42 hours. do.

Water (30 ml) is added and the mixture is extracted three times with 30 ml of diethyl ether. The extract was washed twice with 10 ml of water, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to yield 316 mg of colorless oily methyl α- (2-thienyl) propionate. This product is in full agreement with the standard by IR and NMR specification data.

Yield 93% (before tablet).

Distillation of the oil before purification at 130 ° C. and 17 Torr yields a pure 279 mg product. Yield 82% (after purification) The aqueous layer obtained by extraction is mix | blended, and 6 ml of concentrated hydrochloric acid is added. Extract three times with 15 ml of diethyl ether. The extract was washed twice with 10 ml of water, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to yield 20 mg of a colorless oily α- (2-thienyl) -propionic acid.

Yield: 6%

This product is in full agreement with the standard by IR and NMR spectral data.

Example 24

0.565 g of 1- (2-thienyl) -2- (methanesulfonyloxy) -1-propaneone dimethylacetal and 0.202 g of calcium carbohydrate were mixed in 6 ml of a mixture of water and methanol (weight ratio 3: 7) for 21 hours. Reflux. 0.420 g of sodium hydroxide is added to the reaction mixture, and the mixture is stirred at room temperature for 15 hours and then refluxed for 2 hours.

Water (30 ml) is added and the mixture is washed with 20 ml of diethyl ether. Concentrated hydrochloric acid (4 ml) is added to the aqueous layer and the mixture is extracted three times with 20 ml of diethyl ether.

The extract was washed with 10 ml of water, dehydrated anhydrous magnesium sulfate and concentrated under reduced pressure to yield 0.299 g of a colorless oily α- (2-thienyl) propionic acid.

Yield: 95%

Example 25

Sodium hydroxide (0.420 g) was dissolved in 6 ml of a mixture of water and methanol (weight ratio 3: 7), and 0.574 g of 1- (2-thienyl) -2- (methanesulfonyloxy) -1-propanone dimethylacetal Add. The mixture is refluxed for 21 hours.

Water (40 ml) is added and the mixture is washed with 20 ml of tetethylether. Concentrated hydrochloric acid (3 ml) is added to the aqueous layer and the mixture is extracted three times with 20 ml of diethyl ether.

The extract was washed with 5 ml of water, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to yield 0.291 g of a colorless oily α- (2-thienyl) propionic acid.

Yield: 91%

Example 26

0.674 g of 1- (2-thienyl) -2- (p-toluenesulfonyloxy) -1-propaneone dimethylacetal and 0.200 g of calcium carbonate were added in 10 ml of a mixture of water and methanol (weight ratio 3: 7). Reflux for time.

Operation as in Example 16 yields an oily crude product, which is distilled at 110-120 ° C. (bath temperature) and 17 Torr to yield 0.253 g of colorless oily methyl α- (2-thienyl) propionate.

Yield: 79%

Example 27

0.684 g of 1- (2-thienyl) -2- (benzenesulfonyloxy) -1-propaneone dimethylacetal and 0.200 g of calcium carbonate in 10 ml of a mixture of water and methanol (weight ratio 3: 7) for 8 hours Reflux. An oily crude product was obtained in the same manner as in Example 16, but distillation at 110 ° C. (bath temperature) and 15 Torr yielded 0.277 g of methyl α- (2-thienyl) propionate as a colorless oil.

Yield: 81%

Example 28

0.299 g of α- (methanesulfonyloxy) -p-acetylaminofliophenone dimethylacetal and 0.090 g of calcium carbonate are refluxed in 3 ml of a mixture of water and methanol (weight ratio 3: 7) for 21 hours.

Water (30 ml) is added and the mixture is extracted three times with 20 ml of methylene chloride. The extract is washed with 10 ml of water, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to give a crystalline residue.

Purification of the residue by column chromatography (silica gel, methylene-diethyl ether) afforded 0.186 g of colorless crystalline methyl α- (4-acetylaminophenyl) propionate.

Yield: 93%

Melting point: 107-109 ° C. (from ethanol-hexane)

IR (KBr):

1740, 1665, 1610, 1555, 1515, 1415, 1330, 1160, 860, 840 cm ^-1

NMR (CDCI ₃ ):

δ 1.46 (3H, d, J = 7 Hz), 2.11 (3H, s), 3.64 (3H, s), 3.67 (1H, q, J = 7 Hz), 7.17 (2H, d, J = 8 Hz), 7.53 (2H, doublet, J = 8 Hz), 8.17 (1H, broads).

For C ₁₂ H ₁₅ NO ₃ :

Calculated Value: C 65.14 H 6.83 N 6.33%

Found: C 64.94 H 7.00 N 6.27%

Example 29

0.329 g of α- (benzenesulfonyloxy) -p-isobutylpropiophenone dimethylacetal and 0.10 g of calcium carbonate are refluxed in 10 ml of a mixture of water and methanol (weight ratio 3: 7) for 10 hours. Operation similar to Example 28 and purification by column chromatography (silica gel, methylene chloride) yielded 0.181 g of methyl α- (4-isobutylphenyl) propionate as a colorless oil.

Yield: 82%

Example 30

0.392 g of α- (benzenesulfonyloxy) -p-isobutylpropiophenone dimethylacetal is heated in a 40 ml mixture of water and pyridine (weight ratio 1: 3) for 19 hours on an oil bath surface at 100 ° C. Operation as in Example 28 and purification by column chromatography (silica gel, methylene chloride) yielded 0.164 g of methyl α- (4-isobutylphenyl) propionate as a colorless oil.

Yield: 74%

Example 31

0.392 g of α- (benzenesulfonyloxy) -p-isobutylpropiophenone dimethylacetal is mixed with 10 ml of a mixture of water and methanol (weight ratio 3: 7) and 2 ml of 10% aqueous potassium hydroxide solution, and the mixture is mixed for 9 hours. Reflux.

Water (30 ml) is added and the mixture is washed four times with 15 ml of methylene chloride. Concentrated hydrochloric acid was added to the aqueous layer to adjust the pH to 1, and extracted four times with 15 ml of methylene chloride. The extract was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to yield 0.138 g of colorless crystalline α- (4-isobutylphenyl) propionic acid having a melting point of 73-75 占 폚.

Yield 67%.

Example 32

0.150 g of α- (p-toluenesulfonyloxy) propiophenone diethyl ether and 0.05 g of calcium carbonate are refluxed in 10 ml of a mixture of water and methanol (weight ratio 3: 7) for 72 hours.

Water (20 ml) is added and the mixture is extracted four times with 5 ml of diethyl ether to dehydrate anhydrous magnesium sulfate. Quantitative analysis of the product by gas chromatography (internal standard method) indicates that 23 mg of ethyl α-phenyl propionate is included.

Yield 32%.

Example 33

0.978 g of α- (methanesulfonyloxy) -p-fluoropropiophenone dimethylacetal and 0.33 g of calcium carbonate are refluxed in 15 ml of a mixture of water and methanol (weight ratio 3: 7) for 24 hours. Performing and purifying as in Example 29 yielded 0.454 g of colorless oily methyl α- (4-fluorophenyl) propionate.

Yield: 76%

R (neat): 1744,1607,1513, 1460, 1439, 1340, 1230, 1210, 1170, 1160, 840, 796cm ^-1

NMR (CDCI ₃ ): δ 1.46 (3H, d, J = 7 Hz), 3.60 (3H, s), 3.67 (1H, q, J = 7 Hz), 6.8-7.4 (4H, m).

Example 34

0.490 g of 1- (6-methoxy-2-naphthyl) -2- (methanesulfonyloxy) -1-propaneone dimethylacetal and 0.140 g of calcium carbonate were mixed with water and dimethylformamide (weight ratio 1: 4). Reflux in 10 ml of a mixture for 5 hours.

Water (20 ml) is added and the mixture is extracted four times with 7 ml of methylene chloride. The extract is washed four times with 10 ml of water, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, methylene chloride) yielded 0.323 g of colorless crystalline methyl α- (6-methoxy-2-naphthyl) propionate having a melting point of 65-68 ° C.

Yield: 94%

This product is fully consistent with the standard by IR and NMR spectral data.

Example 35

0.354 g of 1- (6-methoxy-2-naphthyl) -2-methanesulfonyloxy-1-propaneone dimethylacetal and 0.10 g of calcium carbonate in 8 ml of a mixture of water and methanol (weight ratio 3: 7) Reflux for 28 hours. Water (20 ml) is added and the mixture is extracted three times with 10 ml of methylene chloride.

The extract was washed with 20 ml of water, dehydrated with magnesium sulfate and concentrated under reduced pressure to yield 0.178 g of colorless crystalline methyl α- (6-methoxy-2-naphthyl) propionate.

Yield: 73%

Example 36

Prepare one of two possible diastereomers of 1- (6-methoxy-2-naphthyl) -2- (d-10-camphorsulfonyloxy) -1-propaneone dimethylacetal (melting point 102-) 105 ° C. [α _D ²⁵ + 32.5 ° (c = 1, chloroform)).

170 mg of this diastereomer and 40 mg of calcium carbonate are heated in a 110 ml bath for 14 hours in 5 ml of a mixture of water and dimethylformamide (weight ratio 1: 4).

Water (20 ml) is added and the mixture is extracted four times with 10 ml of diethyl ether. The extract is washed four times with 10 ml of water, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure.

Purification of the residue by column chromatography (silica gel, methylene chloride) afforded 68 mg of methyl (-)-α- (6-methoxy-2-naphthyl) propionate as a colorless crystalline phase.

Yield: 80.2%.

Melting point: 94.5-95 ° C.

[α] _D ²⁰ : -78.2 ° (c = 1.chloroform)

IR (KBr): 2970, 1739, 1602, 1450, 1334, 1270, 1231, 1205, 1172, 1158, 1028, 893, 856, 823 cm ^-1

This product is consistent with the methyl α- (6-methoxy-2-naphthyl) propionate obtained in Example 34 in NMR spectral data.

Example 37

1.007 g (3.308 mmol) of 1- (4-methoxyphenyl) -2-methanesulfonyloxy-1-propaneone dimethylacetal and 330 mg (3.30 mmol) of calcium carbonate were dissolved in water and methanol (weight ratio 3: 7). It is refluxed for 20 hours with stirring in 10 ml of the mixture. 597 mg of methyl α- (4-methoxyphenyl) propionate as colorless oil was obtained by the same operation and purification as in Example 29.

Yield: 92.2%

NMR (CDCI ₃ ):

δ 1.47 (3H, d, J = 7 Hz), 3.61 (3H, s), 3.67 (1H, q, J = 7 Hz), 3.73 (3H, s), 6.83 (2H, d, J = 9 Hz), 7.19 (2H, d, J = 9 Hz).

Example 38

1.922 g (5,000 mmol) of 1- (4-chlorophenyl) -2- (p-toluenesulfonyloxy) -1-propaneone dimethylacetal and 500 mg (5.00 mmol) of calcium carbonate were converted to dimethylformamide and water (weight ratio). It is stirred and heated at 110 degreeC (bath temperature) for 3 days in the mixture of 4: 1). Operation as in Example 16 gave 337 mg of a colorless oil. It can be seen that the oil contains 238 mg of methyl α- (4-chlorophenyl) propionate by NMR spectrum.

Yield: 12.0%

Example 39

In the same manner as in Example 28, the colorless crystalline methyl α- [4- (from 1- [4- (1-oxo-2-isoyldolynyl) phenyl] -methanesulfonyloxy-1-propaneone dimethylacetal 1-oxo-2-isoindolinyl] propionate is obtained as yield 86%.

Example 40

In the same manner as in Example 21, methyl α- (4-biphenylyl on colorless oil from 1- (4-biphenylyl) -2-methanesulfonyloxy-1-propaneone dimethylacetal obtained in Example 89 was obtained. ) Propionate is obtained.

Yield: from 80.5% 1- (4-biphenylyl) -2-hydroxy-1-propaneone dimethylacetal].

NMR (CDCI ₃ ):

δ 1.47 (3H, d, J = 7 Hz), 3.55 (3H, s), 3.68 (1H, q, J = 7 Hz), 7.1-7.56 (9H, m).

IR (neat): 1741, 1490, 1215, 1167, 765, 701cm ^-1

Example 41

Methyl α- (4-biphenylyl) propio from 1- (4-biphenylyl) -2-methanesulfonyloxy-1-propaneone dimethylacetal obtained in example 89 by an operation similar to Example 57 Nates are prepared.

Yield: 68% [from 1- (4-biphenylyl) -2-hydroxy-1-propanonedimethylacetal].

Example 42

By a similar operation as in Example 34, methylindan-1-carboxylate is prepared from 1,1-dimethoxy-2-methanesulfonyloxy-1,2,3,4-tetrahydronaphthalene.

Yield: 4%.

Example 43

Methyl α- (4-difluoromethoxyphenyl) propionate was converted from 1- (4-difluoromethoxyphenyl) -2-methanesulfonyloxy-1-propaneone dimethylacetal by a similar operation as in Example 34. Yield 51%.

IR (neat): 1745, 1515, 1385, 1230, 1160, 1130, 1050cm ^-1

NMR (CDCI ₃ ):

δ 1.46 (3H, d, J = 7 Hz), 3.61 (3H, s), 3.67 (1H, q, J = 7 Hz), 6.43 (1H, t, J = 74 Hz), 7.02 (2H, J = 9 Hz) , 7.26 (2H, J = 9 Hz).

Example 44

0.368 gdml 1- (4-difluoromethoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone dimethylacetal and 0.100 g of calcium carbonate were mixed with 3 ml of water and ethanol (weight ratio 3: 7) Reflux for 18 days. Normal operation and separation by chromatography give 0.132 g of methyl α- (4-difluoromethoxyphenyl) isovalerate as colorless oil.

Yield 51%.

NMR (CDCI ₃ ):

δ 0.71 (3H, d, J = 7 Hz), 1.02 (3H, d, J = 7 Hz), 2.0-2.5 (1H, m), 3.14 (1H, d, J = 1 Hz), 3.63 (3H, s) , 6.47 (1H, t, J = 74 Hz), 7.02 (2H, J = 9 Hz), 7.31 (2H, d, J = 9 Hz).

Example 45

0.368 g of 1- (4-difluoromethoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone and 0.100 g of calcium carbonate in 3 ml of a mixed solvent of water and DMF (weight ratio 1: 4) Heated at 110 ° C. for 12 days and then refluxed for 3 days.

Under normal operation and separation, 78 mg of methyl α- (4-difluoro methoxyphenyl) isovalerate are obtained.

Yield: 30%.

Example 46

In 7 ml of a mixture of water and methanol (weight ratio 3: 7), 724 mg of 1- (4-ethoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone dimethylacetal and 200 mg of calcium carbonate were added for 11 hours. Reflux for a while.

The usual operation and purification give 467 mg of methyl α- (4-ethoxyphenyl) isovalerate as a colorless oil.

Yield: 9%

Boiling Point: 160 ° C. (bath temperature) / 17 Torr.

NMR (CDCI ₃ ):

δ 0.70 (3H, d, J = 6 Hz), 1.01 (3H, d, J = 6 Hz), 1.38 (3H, t, J = 7 Hz), 2.0-2.6 (1H, m), 3.07 (1H, d, J = 10 Hz), 3.30 (3H, s), 6.80 (1H, q, J = 7 Hz), 6.80 (2H, d, J = 9 Hz), 7.20 (2H, d, J = 9 Hz),

For C ₁₄ H ₂₀ O ₃ :

Calculation: C 71.16 H 8.53%

Found: C 70.93 H 8.52%

Example 47

In a similar manner as in Example 46, methyl α- (4-methoxyphenyl) iso in colorless oil from 1- (4-methoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone dimethylacetal Valerate is obtained.

Yield: 94%

IR (neat): 1740, 1515, 1255, 1160, 1040, 830cm ^-1

NMR (CDCI ₃ ):

δ 0.70 (3H, d, J = 6 Hz), 1.00 (3H, d, J = 7 Hz), 2.0-2.6 (1H, m), 3.08 (1H, d, J = 10 Hz), 3.63 (3H, s) , 3.78 (1H, s), 6.80 (2H, d, J = 9 Hz), 7.21 (2H, d, J = 9 Hz),

Example 48

495 mg of 1- (4-methoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone ethylene acetal and 150 mg of calcium carbonate in 5 ml of a mixture of water and methanol (weight ratio 3: 7) were 148 hours. Reflux for a while. Purification by column chromatography after usual operation affords 307 mg of 2-hydroxyethyl α- (4-methoxyphenyl) isovalerate as a colorless oil.

Yield 81%.

IR (neat): 3600-3200, 1735, 1610, 1510, 1255, 1170, 1160, 1035, 830cm ^-1

NMR (CDCI ₃ ):

δ 0.70 (3H, d, J = 7 Hz), 1.03 (3H, d, J = 7 Hz), 2.0-2.5 (1H, m), 2.27 (1H, broad s), 3.13 (1H, d, J = 10 Hz ), 3.5-3.8 (2H, m), 3.76 (3H, s), 4.0-4.3 (2H, m), 6.81 (2H, d, J = 9 Hz), 7.21 (2H, d, J = 9 Hz).

Claims (17)

Α-aromatic group substituted alkanoic acid of the general formula (I) and esters thereof, characterized by hydrolysis of α-sulfonyloxyketone acetal of the following general formula (II).

Wherein Ar represents an aromatic group, R ¹ represents a hydrogen atom or a saturated aliphatic group, or Ar and R ¹ together may form a condensed ring, R ² represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, and R ³ and R ⁴ are each an alkyl group, or may form an alkylene group with each other, and R ⁵ represents a substituted or unsubstituted alkyl group or an aromatic group. The method of claim 1 wherein the hydrolysis is performed at a temperature of about 0 ° C.-250 ° C. The method of claim 2, wherein the hydrolysis is performed at a temperature of about 50 ° C. to 180 ° C. 4. The method of claim 1 wherein the hydrolysis is carried out in a protic or aprotic polar solvent. The method of claim 1 wherein the hydrolysis is performed under neutral or basic conditions. The method of claim 1 wherein the hydrolysis is performed in the presence of a base. 7. A process according to claim 6 wherein the base is at least 1 equivalent per mole of compound of formula (II). The method of claim 1 wherein Ar is a 6-methoxy-2-naphthal group and R ¹ is a methyl group. The method according to claim 1, wherein Ar is a 4-isobutylphenyl group and R ¹ is a methyl group. The method of claim 1 wherein Ar is a 4-lower alkoxyphenyl group and R ¹ is an isopropyl group. The method of claim 1 wherein Ar is a 4-lower alkoxyphenyl group and R ¹ is a methyl group. The method of claim 1 wherein Ar is a 4-difluoromethoxyphenyl group and R ¹ is an isopropyl group. The method of claim 1 wherein Ar is a 2-dienyl group and R ¹ is a methyl group. The method of claim 1 wherein Ar is a 4-acetylaminophenyl group and R ¹ is a methyl group. The method of claim 1 wherein Ar is a 4- (1-oxo-2-isoindolinyl) phenyl group and R ¹ is a methyl group. The method according to claim 1, wherein Ar is a 4-biphenylyl group and R ¹ is a methyl group. The method of claim 1 wherein Ar is a 4- (t-butyl) phenyl group and R ¹ is an isopropyl group.