HU188108B - Process for preparing alkane-carboxylic acids and esters thereof substituted with alpha-aromatic group - Google Patents

Abstract

The present invention relates to a process for the preparation of substituted carboxylic acid derivatives of the formula (I) having an aromatic group at the α-position and the esters thereof, wherein Ar is optionally halogen, C1-C6-alkyl, C1-C4-alkoxy, phenyl or naphthyl substituted with C1-4 alkylcarbonylamino or 1-3 carbon atoms substituted with 1-3 halogen atoms, or naphthyl, or 5-6 membered sulfur atoms heterocyclic group, or optionally substituted oxo-substituted phenyl or naphthyl substituted with 8 to 10 carbon atoms having two ring members nitrogen atoms, R 'is hydrogen or C1 -C5 alkyl, R1 is a ring attached to the adjacent carbon atom R 2 is hydrogen, C 1-4 alkyl, or hydroxy (1-6C) alkyl. Powder, together with ArésR'egy interrupted alkylene, may form an indan ring. The compounds of the present invention have a favorable anti-inflammatory effect. R1 Ar-CH-COOR2 (I) (II) -1-

Description

The present invention relates to a novel process for the preparation of alkanoic acids substituted at the α-position of formula (I) and esters of these compounds.

In the general formula (I)

Ar is optionally halogen,

C 1 -C 6 alkyl, C 1 -C 4 alkoxy, phenyl or naphthyl, C 1 -C 4 alkylcarbonylamino, or C 1 -C 4 alkoxy-substituted phenyl or naphthyl or a 5-6 membered heterocyclic group containing one sulfur atom as a ring member or a phenyl or naphthyl group optionally substituted with an oxo group and substituted with a C 8 to C10 two membered ring containing a nitrogen atom,

R ¹ is hydrogen or C 1-5 alkyl,

R ¹ may form together with the adjacent carbon atom a fused ring,

R ^{2 is} hydrogen, (C 1 -C 4) alkyl, or hydroxy (C 1 -C 1) alkyl;

Together with Ar and R 'together they can form an indane ring together with a trapped alkylene group.

The process of the present invention is carried out by reacting an alpha-sulfonyloxyketone acetal of formula (II) wherein:

R ³ and R ⁴ each independently represent a C 1-4 alkyl group, or together a C 1-4 alkylene group, or together with the carbon atom to which they are attached form a 5-7 membered heterocyclic ring,

^R5 is C1-4 alkyl or optionally substituted with halogen or C1-4 alkyl substituted by phenyl, naphthyl or camphor,

Ar and R ¹ are as defined above,

(a) hydrolyzed in an inert solvent in the presence of a base at a temperature between 0 ° C and about 250 ° C, or

b) with an oxygen scavenger such as iodine tri (C 1-4) alkylsilane, tri (C 1-4) alkylsilyl perfluoro (C 1-4) alkanesulfonate or Lewis acid at -40 ° C and at about 150 ° C in an aprotic solvent.

Many of the compounds of formula (I) are known. For example, compounds of formula I in which

Ar is isobutylphenyl,

R ¹ is methyl,

R ² is hydrogen; i.e., α- (4-isobutylphenyl) -propionic acid; this compound is marketed as ibuprofen as an anti-inflammatory agent.

The α- (6-methoxy-2-naphthyl) -propionic acid is also represented by the general formula (I), in which case the general formula (I)

Ar is 6-methoxy-2-naphthyl,

R ¹ is methyl,

R ² is hydrogen.

This compound is marketed as Naproxen.

Α- (4-Difluoromethoxyphenyl) isovaleric acid is also represented by the formula (I), in which case

Ar is 4-difluoromethoxyphenyl,

R ¹ is isopropyl,

R ² is hydrogen

This compound can be used for pyrethroid insecticides as an acidic group.

A number of processes are known for the preparation of alkanoic acids containing an aromatic group at the α-position. These procedures are described with respect to α- (4-isobutylphenyl) propionic acid (Ibuprofen).

(1) It is known to process a 4-isobutylphenylacetic acid ester (prepared in two steps starting from 4-isobutylacetone-phenone) with an alkyl carbonate in the presence of a base; In this way, the corresponding malonic ester is obtained by methylation of this compound with methyl iodide, hydrolysis of the methylated product and subsequent thermal decomposition to give the desired propionic acid (see British Patent No. 971,700).

(2) No. 1,167,192. U. S. Patent No. 4,193,125 discloses a process for converting 4-isobutylacetophenone by reaction with potassium cyanide and ammonium carbonate to hydantoin; this compound is hydrolyzed to alkylate the resulting α-amino acid to give a dialkylamino derivative which is reduced to give o- (4-isobutylphenyl) propionic acid.

(3) No. 1,160,725. U. S. Patent No. 4,198,125 describes a process for subjecting a 4-isobutylacetophenone and a monochloroacetic acid ester to a corresponding epoxycarboxylic acid ester by subjecting it to a Darzens reaction. By hydrolyzing the ester compound, the resulting aldehyde can be oxidized to the corresponding propionic acid.

(4) No. 4,242,519. condensing 4-isobutylbenzaldehyde with formaldehyde mercaptal S-oxide using U.S. Pat. yielding ketene mercaptan S-oxide; reacting this compound with thionyl chloride to give α-chloroketene mercaptal; treating this compound with alcohol gives the α- (4-isobutylphenyl) -α-alkylthioacetic acid ester. This ester derivative is methylated, hydrolyzed and subjected to reductive desulfurization to give the desired propionic acid.

Processes (1) and (4) described above have several steps and are therefore not advantageous for industrial use. The disadvantage of process (2) is that it requires the use of a toxic substance (potassium cyanide).

Processes (1) and (3) are uneconomical because the ethoxycarbonyl group introduced in the first step is removed during the final reaction step, decarboxylation.

It is clear from this that a new process which is economically feasible is of great importance for the preparation of compounds of formula (I).

SUMMARY OF THE INVENTION It is an object of the present invention to provide an industrially economical process for preparing the compound of formula (I).

Ar groups of formula (I) and defined herein as pon-2188108 in the broadest sense denote groups containing an aromatic ring; the aromatic nature is related to the delocalized π electrons of the ring; usually a ring containing (4n + 2) conjugated π-electrons has stable and aromatic properties. As used herein, an aromatic group is a group containing a ring having (4n + 2) conjugated π-electrons. A distinction is made between aryl groups having at least one substituent optionally Ar and heteroaromatic groups according to the invention.

(a) Optionally, aryl groups containing one substituent

Aryl groups include monocyclic, polycyclic or fused polycyclic groups such as phenyl or naphthyl.

The aryl groups may be unsubstituted or the aromatic rings may also contain one or more substituents. Among the substituents are halogens, such as chlorine, bromine, fluorine or iodine; lower alkyl groups include methyl, ethyl, npropyl, isopropyl, η-butyl, isobutyl and tert-butyl; lower alkoxy groups include methoxy, ethoxy, n-propoxy and isopropoxy; difluoromethoxy and trifluoromethoxy are mentioned as lower halo (C1-C4) alkoxy; acetylamino and propionylamino as alkylcarbonylamino; 1-2 of these substituents, preferably 1, may be present on the aromatic ring.

Among the aryl groups which carry the aforementioned substituents on the aromatic ring, the following may be mentioned: chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, tolyl, ethylphenyl, isopropylphenyl. , isobutylphenyl, tert-butylphenyl, methoxyphenyl, ethoxyphenyl, isopropoxyphenyl, acetoxyphenyl, tetrafluoroethoxyphenyl, trifluoromethoxyphenyl, difluoromethoxyphenyl , acetylaminophenyl, and methoxynaphthyl.

(b) Heteroaromatic groups:

Among the heteroaromatic groups, the Ar groups of the present invention include thienyl or indolyl.

Among the linear or branched saturated alkyl groups having 1 to 4 carbon atoms, the following are mentioned: methyl, ethyl, η-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

Alkyl refers to straight or branched groups; alkylene groups are lower alkylenes such as ethylene.

It has been found that the hydrolysis of the compound of formula (II) results in a specific reaction in which the sulfonyloxy group at the 2-position is cleaved and the aromatic group at the 1-position is converted to the 2-position; In this way, an alkanoic acid substituted by an aromatic group of formula (I) is obtained.

The hydrolysis may be carried out in the absence of a solvent, but it is preferable to carry out the reaction in an inert solvent. Inert solvents include proton-free polar solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI), 1,4-dioxane, tetrahydrofuran (THF), diethylene glycol'-dimethyl- ether (diglyme), hexamethylphosphoric triazinide (HMPA), 1,2-dimethoxyethane and pyridine; polar solvents include methanol, ethanol, ethylene glycol and acetic acid. The solvents are used singly or in combination.

The reaction temperature is not critical and may vary widely depending on the nature of the starting material. In general, the reaction is carried out at 0 to 250 ° C, preferably at room temperature to 200 ° C. It is advisable to choose a higher temperature to facilitate the reaction, generally between 40 ° C and the boiling point, preferably between 50 ° and 180 ° C. The reaction may be carried out at atmospheric pressure or at elevated pressure.

The water required for the hydrolysis of the compounds of formula (II) is introduced at the beginning of the operation by mixing with the solvent and adding the compound (II) to the solvent. Alternatively, the process may be reversed by adding the compound of formula (II) to the solvent and then adding the required amount of water to the solution.

Alternatively, the compound of formula (II) is heated to the desired temperature in the presence of anhydrous solvent and then the required amount of water is added (Examples 31 and 35).

The simplest solution is to add the compound of formula II to a mixture of water and a polar solvent.

The amount of water required for hydrolysis is not critical and will depend upon the nature of the compound of formula II, the reaction conditions, and the like. Generally, at least 1 mol of water, preferably at least 5 mol, of water is used per compound of formula (II). If the amount of water used is too high, the solubility of the compound of formula II will decrease. Therefore, it is advisable to keep the amount of water within limits.

Hydrolysis is generally carried out under neutral or basic conditions at a pH of 7 to 14 to prevent an undesired acid break of the acetal group on the compound of formula (II).

Since the sulfonyloxy group (-OSO ₂ -R ⁵ ) at the 2-position is cleaved as the sulfonic acid (R ⁵ SO ₃ H) by hydrolysis, it is preferable to carry out the reaction in the presence of an alkali and thus to neutralize the pH of the reaction mixture. in the alkaline range. Useful bases include alkali metal hydroxides such as potassium or 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 and calcium carbonate; alkali metal bicarbonates such as potassium and sodium bicarbonate; alkali metal carboxylates such as formic acid sodium, sodium acetate, potassium acetate, sodium propionate; alkali metal phosphates such as sodium and potassium phosphate; organic tertiary amines such as pyridine, triethylamine, tributylamine. These

Suitably, the inorganic or organic bases are used in an amount of at least one equivalent, preferably from 1 to 10 equivalents, per mole of compound (II).

The hydrolysis is generally carried out over a period of from 1 to 250 hours, but the reaction time is highly dependent on the nature of the compounds of formula II and the reaction conditions.

During hydrolysis, the sulfonyloxy group at position 2 is removed from the compound of formula II, while the aromatic group at position 1 moves to position 2. However, one of the acetal groups OR ³ and OR ⁴ is separated, and the remaining acetal group will form the OR ² group (where R ² is an alkyl group) in the resulting compound of formula (I). Depending on the conditions of hydrolysis, especially under strongly basic conditions, the resulting ester compound of formula I (where R ² is alkyl) may be further hydrolyzed to give compounds of formula I wherein R ² is hydrogen.

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

In another embodiment of the present invention, compounds of formula II are treated with an agent that is capable of binding oxygen. It has now been found that the compound of formula (II) is cleaved at the 2-position (-OSO ₂ -R ⁵ ) and the aromatic at the 1-position is shifted to the 2-position. The reaction gives a compound of formula (I). One of the groups OR ³ and OR ⁴ will form OR ^{2 in} the compound of formula (I). When R ² is alkyl in formula I, the reaction product is an ester.

The term "oxygen scavenger compound" refers to a derivative capable of binding a free electron pair of an oxygen atom. Among the compounds capable of oxygen scavenging are the following:

(a) The iodo-trialkylsilanes of formula (III) wherein A ¹ , A ² and A ³ are the same or different C 1 -C 4 alkyl groups, e.g. iodine trimethylsilane or iodine triethylsilane.

(b) The trialkylsilyl perfluoroalkylsulfonates of formula IV wherein A ⁴ is a perfluoro (C 1 -C 4) alkyl group and A ¹ , A ² and A ³ are upper; such as. trimethylsilyl trifluoromethane sulfonate, trimethylsilyl pentafluoroethane sulfonate.

(c) Lewis acids, e.g. aluminum chloride, aluminum bromide, zinc chloride, lead chloride, titanium chloride, boron fluoride and ferric chloride.

These compounds are capable of binding oxygen, individually or in combination. Particularly preferred are iodine trimethylsilane, trimethylsilyl trifluoromethanesulfonate, ferric chloride, aluminum chloride and tin chloride.

The amount of oxygen scavenger used is not strictly determined and may vary according to the type of compound of formula II and the type of oxygen scavenger. Generally, at least 0.1 mol, preferably 0.2-5.0 mol, more preferably 1.0-2.0 mol, are used per mol of compound (II).

The compound of formula II can also be treated with an oxygen scavenger in the absence of a solvent. In general, however, the operation is carried out in the presence of a solvent, in particular a proton-free solvent. When a Lewis acid or an iodo-trialkylsilane is used as an oxygen scavenger, the solvent used is a halogenated hydrocarbon such as methylene chloride, chloroform, 1-2-difluoroethane, with good results.

When trialkylsilyl perfluoroalkane sulfonate is used as the oxygen scavenger, it is preferable to use acetonitrile or ortho-formic acid ester.

Under mild conditions, the reaction proceeds smoothly. The treatment temperature is -40 ° C to 150 ° C, preferably -20 ° C to 100 ° C, preferably -10 ° C to 90 ° C.

Treatment of the compounds of formula (II) with an oxygen scavenger under the above conditions gives the compounds of formula (I). In the case where the oxygen scavenger is a Lewis acid _% and the product may form a complex. In this case, the product may be isolated by adding water; in this way, the complex is decomposed and the target compound can then be isolated in a known manner.

The compound of formula (I) of the present invention is isolated from the reaction mixture in a known manner, e.g. extraction, chromatography, distillation, crystallization.

The compounds of formula II are novel compounds.

Examples of groups in the compounds of formula II include:

(1) An aromatic group of formula Ar optionally has at least one substituent! an aryl group; Ar is preferably an R ⁶ -Ar 'moiety wherein Ar ¹ represents a phenylene or naphthylene group, R ⁶ is hydrogen, halogen, lower alkyl, lower alkoxy, lower haloalkoxy groups, lower alkanoylamino, oxo an isoindolyl group or a phenyl group. Suitable instances of the Ar group include the thienyl group.

(2) Examples of lower alkyl groups include methyl, ethyl, η-propyl, isopropyl, butyl, which may be used as saturated aliphatic R 'groups. R ¹ is hydrogen or lower alkyl.

(3) Lower alkyl groups are preferably R ³ and R ⁴ . As lower alkylene, ethylene, propylene, trimethylene may be mentioned, which may be taken together as R ³ and R ⁴ .

(4) R ⁵ is lower alkyl, such as methyl, ethyl or butyl c; and d- or 1-10-camphoryl. R ⁵ may be substituted as aromatic, optionally substituted phenyl of formula (1) wherein R ⁷ is hydro-41

188 108 genes, halogen, lower alkyl.

Among the compounds of formula (II), the compounds of formula (I-1) are particularly preferred, wherein Ar ² is R ⁶ -Ar * or a thienyl group; R ¹ is hydrogen or lower alkyl; R ³ and R ⁴ are each independently lower alkyl; R ³ and R ⁴ are each independently lower alkyl; R ³ 'and R ⁴ ' together may form a lower alkylene group; ^R5 is lower alkyl, lower haloalkyl, d- or 1-10-camphoryl group or a (1) wherein; R ¹ , R ⁶ and R ⁷ and Ar ¹ are as defined above.

In formula (II) wherein Ar and R ¹ together with the adjacent carbon atom to form a condensed ring. Examples of compounds of formula II containing a ring fused to Ar and R ¹ include compounds of formula II-1 and II-2.

These compounds are hydrolyzed or treated with an oxygen scavenger to give compounds of formula (3) and (4).

The compounds of formula (II) may be prepared starting from the α-halo ketone of formula (V); wherein X is halogen, Ar and R ¹ are as defined above. The reaction is illustrated in Scheme A.

In the reaction scheme, M is an alkali metal, Hal is halogen, preferably chlorine, Ar, R ¹ , R ³ , R ⁴ , R ⁵ and X are as defined above.

Compounds of formula (V) may be prepared by subjecting a compound of formula (VIII) wherein R ¹ and X are as defined above to a Friedel-Crafts reaction in the presence of a compound of formula (IX); Ar in Formula IX is as defined above; alternatively, a compound of formula (X) wherein Ar and R 'are as defined above is halogenated in a manner known per se.

The reaction scheme described below is detailed below.

Step One: (V) -> (VI)

In this step, the compounds of formula (V) are treated with an alkali metal alkoxide of formula (R'OM). The reaction is carried out in the presence of the corresponding alcohol R'OH; In this way, a-hydroxy ketone acetal of formula (VI) is obtained. In the resulting compound of formula VI, R ⁴ is then R ³ . The alkali metal alkoxide is preferably lithium alkoxide, sodium alkoxide or potassium alkoxide. Due to its low price, it is preferable to use sodium alkoxide. Generally, at least 1 mol of alkali metal alkoxide is used per mole of the compound of formula (V). The reaction proceeds faster when the amount of alkoxide is between 1.5 and 3 moles. The amount of alcohol also present is at least 1 mol per liter of the compound of formula (V). It is advisable to take excess alcohol so that it can also act as a solvent. It is also advantageous to use a proton-free solvent which does not participate in the reaction. The proton-free solvent may be diethyl ether, tetrahydrofuran, DMF (dimethylformamide) or 1,2-dimethoxyethane. The reaction proceeds smoothly at temperatures between -20 ° C and 120 ° C. To simplify the operation, the reaction is carried out at room temperature to 60 ° C.

Alternatively, this step is carried out by reacting a compound of formula (V) with an alkali metal alkoxide of formula R'OM in a proton-free solvent; as a solvent, diethyl ester, tetrahydrofuran or 1,2-dimethoxyethane; This yields the epoxy compounds of formula VII. The resultant compound is treated with a catalytic amount of an alkali metal alkoxy of the formula R ⁴ OM to form an alcohol of the formula R ⁴ O 1 to give an alpha-hydroxy ketone acetal compound of formula VI (Examples 1, 8 and 9). ).

This procedure provides a compound of formula VI wherein R ³ and R ⁴ are different.

The reaction of the compound of formula (V) with an alkali metal alkoxide R'OM is generally carried out at a temperature of from 0 ° C to 60 ° C; from 1 to 3 moles of alkali metal alkoxide per mole of compound (V). The reaction of the compound of formula VII with the alcohol of the formula R ⁴ OH is generally carried out at a temperature between 0 'and 100'C; at least 1 mol of alcohol is used per mole of compound (VII). Preferably, the alcohol is taken in excess and is thus used as a solvent.

Alternatively, the α-halo ketone of formula (V) is reacted in the presence of a divalent alcohol (such as ethylene glycol, propylene glycol, or 1,3-propanediol) with the mono-alkali metal salt of a divalent alcohol. The u-hydroxy ketone acetal of formula VI is obtained. This process results in a compound of formula VI wherein R ³ and R ^{4 are taken} together to form an alkylene group, e.g. forms an ethylene, propylene or trimethylene group (Example 1 a, 111).

This reaction is generally carried out at a temperature between 0 ° C and 100 ° C; at least 1 mol, preferably 1.5-3 mol, of a divalent alcohol mono-alkali metal salt; 0.5 moles, preferably 2-10 moles, of the divalent alcohol are taken. A proton-free solvent which is not involved in the reaction is also added to the reaction mixture. The solvent may be diethyl ester, tetrahydrofuran or 1,2-dimethoxyethane.

Compounds of formula (VI) obtained in the above reaction wherein Ar is other than phenyl and 4-chlorophenyl and wherein R 'is other than hydrogen are new compounds are not reported in the literature.

Among the compounds of formula VI, the following are mentioned: compounds of formula VI wherein

Ar means R ¹ means:

4-prenylphenyl, methyl,

N-methylphenothiazinyl, hydrogen or methyl,

-5188108

1-methylpyrrolyl,

2-fluoro-4-biphenylyl, 2-acetylamino-4-biphenylyl, 4-chlorophenyl,

3-chloro-4- (3-pyrrolidin-1-yl) phenyl hydrogen or methyl, methyl, methyl, isopropyl and methyl.

Step Two: (VI) (II)

In this step, a-hydroxy ketone acetal compound of formula (VI) is treated with an O-sulfonating agent of the formula R ⁵ -SO ² Hal or (R ⁵ SO ₂ ) ₂ O; In this way, the compounds of formula II are obtained.

Among the O-sulfonating agents, the following are mentioned; benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-nitrobenzoylthiolyl chloride and naphthalenesulfonyl chloride; Lwibba. ^,, k.ín sulfonyl halides or alkénsrulfon. ..hydrides such as methanesulfonyl chloride, bu! sulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, d-10-camphorsulfonyl chloride and 1-10-camphorsulfonyl chloride.

The reaction is conveniently carried out under neutral or basic conditions, with 1 mol of tertiary amine, e.g. triethylamine, pyridine or 4-dimethylaminopyridine are used per mole of compound (VI). In this way, the reaction proceeds at a relatively low temperature, between 0 ° and room temperature. The operation may also be carried out in the presence of a proton-free solvent which does not participate in the reaction. The solvent may be methylene chloride or diethyl ether.

The starting compound (II) can be prepared in two steps starting from the α-halo ketone (V). This compound can also be prepared by other methods, e.g. a compound of formula (XI) starting from a 1-alkoxy-1-alkene derivative containing an aromatic group in the 1-position. Ar, R 'and R ³ are as defined above. This compound is oxidized to give an epoxy compound of formula VII, the epoxy compound is converted to a-hydroxy ketone acetal compound of formula VI, and the compound of formula VI is converted into a compound of formula II. Alternatively, the corresponding α-sulfonyloxyketone can be converted to the compound of formula II by acetalization. Alternatively, the α-oxo-ketone acetal of formula (XII) wherein Ar, R ¹ , R ³ and R ⁴ are as defined above is reduced; In this way, an alpha-hydroxy ketone acetal of formula (VI) is obtained and the compound of formula (VI) is converted to the compound of formula (II).

Thus, the α-sulfonyloxyketone acetal of formula (II) can be readily prepared in various ways.

The compounds of the formula I have a beneficial therapeutic effect and are also useful in agriculture. Among these compounds, the following are mentioned; Ibuprofen, Naproxen and α- [4- (1-oxo-2-isoindolinyl) phenyl] propionic acid (anti-inflammatory agent, Indoprofen). Further, methyl ester of α- (2-thienyl) propionic acid, α- [4- (tert-butyl) phenyl] isovaleric acid, methyl α- (4-alkoxyphenyl) isovaleric acid, α- (4-biphenyl) propionic acid , α- (4-difluoromethoxyphenyl) -isovalerianeave methyl ester, α- (4-alkoxyphenyl) propionic acid methyl) ester.

⁵ These compounds are useful as intermediates for anti-inflammatory agents and in the preparation of insecticides.

The following examples illustrate the invention;

Example 7

9.81 g of p-toluenesulfonyl chloride are dissolved in 10 ml of anhydrous pyridine and the mixture is stirred at room temperature. Anhydrous pyridine solution (10 ml) containing 6.65 g of α-hydroxypropiophenone dimethylacetal was added dropwise over 10 minutes. The mixture was then stirred for 48 hours. The reaction mixture was poured into 200 ml of ice water and stirred for 2 hours. The resulting precipitate was filtered, washed, and dried over potassium hydroxide in vacuo. This gives 10.91 g of α- (p-toluenesulfonyloxy) -propiophenone dimethylacetal as colorless crystals.

Yield: 92%

Mp .: 62-63 'C (from ligroin)

Infrared spectrum:

1360, 1190, 1175, 1090, 1060, 1040, 910, 710 ^cm-1

MMR (CDCl3):

1.07 (3H, d, J = 6Hz), 2.73 (3H, s), 3.08 (3H, s), 3.15 (3H, s), 4.95 (1H, q, J = 6Hz), 7.33 (7H, m), 7.77 (2H, d, J = 9Hz)

Anal (C ₈ H ₂₂ O ₅ S) Calcd:

³⁵ Calculated: C, 61.70; H, 6.33; S, 9.15% Found; C: 61.72; H, 6.26; S, 9.19%

Example 2

19.0 g of p-isobutylpropiophenone are dissolved in 15 ml of anhydrous diethyl ether and 5 ml of anhydrous dioxane. The solution was stirred at room temperature. 17.6 g of bromine are added dropwise to the lead ⁴⁵ over 25 minutes and the mixture is stirred for 2.5 hours. After addition of 50 ml of water, the mixture was extracted three times with 20 ml of diethyl ether. The extract was washed four times with 50-50 ml of water, the organic layer was dried over anhydrous magnesium sulphate and concentrated ⁵⁰ under reduced pressure. The residue was dissolved in hot methanol (30 mL) and cooled to -40 ° C. The precipitate was collected by filtration and washed with cold methanol; this way

21.88 g of α-bromo-p-isobutylpropiophenone are obtained in the form of colorless crystals.

Yield: 81%

O.p .: 63-66'C Infrared spectrum;

2950, 1680, 1608, 1419, 1260, 1250, 1167, 955, «0 862 cm ¹

NMR (CDC1 _3);

Δ 0.91 (6H, d, J = 7Hz), 1.87 (3H, d, J = 7Hz),

1.8-2.2 (1H, m), 2.52 (2H, d, J = 7Hz), 5.25 (1H, q, J = 7Hz), 7.22 (2H, d, J = 9Hz) ), 7.92 (2H, d,

J = 9Hz)

188 108

Analysis calculated for C ₁₃ H ₁₇ OBr: C, 58.00; H, 6.37; Br, 29.69; Found: C, 57.80; H, 6.27; Br: 29.42%

Example 3

Sodium methoxide (1.134 g) was dissolved in methanol (20 ml) and the solution was stirred at room temperature under argon. To this solution was added a solution of? -Bromo-p-isobutylpropiophenone (2.692 g) in dry methanol (20 mL) at room temperature over 30 minutes. After the addition was complete, water (50 mL) was added and the mixture was extracted with diethyl ether (3 x 20 mL). The extract was washed with water (20 mL), dried over anhydrous magnesium sulfate and potassium carbonate, and concentrated under reduced pressure in the presence of a small amount of potassium carbonate; This gives 2.370 g of α-hydroxy-isobutylpropiophenone dimethylacetal as a colorless oily product. Yield: 94%. For analysis, the product was purified by column chromatography (Florisil; methylene chloride). Infrared spectrum:

3500, 2950, 1460, 1100, 1050, 980, 850, 800, 740 cm ^-1

NMR (CDC1 _3): δ 0.91 (6H, d, J = 7Hz), 0.96 (3H, d, J = 7Hz),

1.6-2.1 (1H, m), 2.43 (2H, d, J = 7Hz), 2.57 (1H, broad s), 3.20 (3H, s), 3.30 (3H) , s), 4.06 (1H, q, J = 7Hz), 7.08 (2H, d, J = 9Hz), 7.33 (2H, d, J = 9Hz)

Analysis for C ₁₅ H ₂₄ O ₃ :

Calculated: C, 71.39; H, 9.59; Found: C, 71.39; H: 9.48%

Example 4

26.84 g of isobutylbenzene, 29.34 g of aluminum chloride are mixed with 20 ml of carbon disulfide under ice-cooling. To the mixture was added 40.63 g of chloropropionyl chloride over 30 minutes, and the mixture was stirred under ice-cooling for 1.5 hours. The mixture was stirred for an additional 30 minutes at room temperature. The reaction mixture was poured into 200 mL of ice water and 100 mL of concentrated hydrochloric acid was added. The mixture was extracted with diethyl ether (4 x 100 mL). The extract was washed with water (100 mL), then with saturated aqueous sodium bicarbonate (50 mL, 4 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was dissolved in methanol (40 mL) with heating, treated with charcoal and cooled to -40 ° C. The precipitated crystals were collected by filtration and washed with cooled methanol; 17.83 g of chloro-p-isobutylpropiophenone are obtained in the form of colorless crystals. Melting point: 51-53 ° C. Yield: 40%

Infrared spectrum:

2950, 1690, 1608, 1419, 1357, 1266, 1180, 956, 861 cm '

NMR (CDC1 _3):

δ 0.91 (6H, d, J = 7Hz), 1.71 (3H, d, J = 7Hz), 1.5-2.2 (1H, m), 2.52 (2H, d, J = 7Hz), 5.20 ΠΗ, q, J = 7Hz), 7.23 (2H, d, J = 9Hz), 7.91 (2H, d, J = 9Hz).

Analysis (C, H, _{I3 I7} OC1) Found:

Calculated: C, 69.47; H, 7.63; Cl, 15.78; Found: C, 69.56; H, 7.44; Cl: 15.76%

Example 5

Dissolve 0.979 g of sodium methoxide in 10 ml of anhydrous methanol and stir at room temperature under argon. A solution of a-chloro-p-isobutylpropiophenone (2.036 g) in anhydrous methanol (10 mL) was added dropwise over 20 minutes and the mixture was stirred at room temperature for 4 hours. Usual work up of the reaction mixture gave 2.158 g (95% yield) of α-hydroxy-isobutylpropiophenone dimethylacetal as a pale yellow oily product.

Example 6

As described in Example 1, a- (p-toluenesulfonyloxy) -P-isobutylpropiophenone-dimethyl acellal was prepared as a colorless crystalline product starting from a-hydroxy-p-isobutylpropiophenone dimethylacetal. used.

Yield: 89%

M.p .: 64-65 ° C (from hexane)

Infrared spectrum:

2960, 1360, 1185, 1090, 1050, 930, 915, 780 cm⁻¹ NMR (CDC1 _3):

δ 0.88 (6H, d, J = 7Hz), 1.09 (3H, d, J = 7Hz), 1.5-2.1 (1H, m), 2.40 (3H, s), 2, 42 (2H, d, J = 7Hz), 3.07 (3H, s), 3.15 (3H, s), 4.93 (1H, q, J = 7Hz), 6.9-7.4 ( 6H, m), 7.72 (2H, d, J = 9Hz) Analysis for C ₂₂ H ₃₀ O ₅ S):

Calculated: C, 64.99; Η: 7.44; S, 7.89. Found: C, 64.78; H, 7.26; S: 7.93%

Example 7

Dissolve 2.94 g of methanesulfonyl chloride in 5 ml of anhydrous pyridine. The solution was stirred under ice-cooling. Add the solution in about 15 minutes

A solution of 3.23 g of α-hydroxy-p-isobutylpropiophenone dimethylacetal in 10 ml of anhydrous pyridine is added. The mixture was stirred under ice-cooling for 1 hour and then at room temperature for 30 minutes. Water (30 mL) was added and the mixture was stirred for 1 hour. The mixture was extracted with methylene chloride (3 x 10 mL), washed with water (3 x 10 mL) and dried over anhydrous magnesium sulfate. The organic phase is concentrated in the presence of a small amount of anhydrous potassium carbonate. An oily product is obtained which is purified by column chromatography (Florisil; methylene chloride). This gives 3.477 g of α- (methanesulfonyloxy) -p-isobutylpropiophenone dimethylacetal as a colorless oily product. Yield: 79%

188 108

Infrared spectrum:

2960, 1175, 1095, 1065, 1350, 1040, 915 cm -1 ¹ H NMR (CDCl ₃ ):

δ 0.88 (6H, d, J = 7Hz), 1.16 (3H, d, J = 7Hz),

1.6-2.1 (1H, m), 2.44 (2H, d, J = 7Hz), 3.06 (3H, s), 3.18 (3H, s), 3.26 (3H, s), 4.95 (1H, q, J = 7Hz), 7.10 (2H, d, J = 8Hz), 7.32 (2H, d, J = 8Hz) Analysis (C _I6 H ₂₆ O ₅ s ):

Calculated: C, 58.16; H, 7.93; S, 9.69. Found: C, 58.06; H, 7.80; S: 9.60%

Example 8

9.20 g of sodium methoxide are suspended in 10 ml of anhydrous diethyl ether and under argon, and the solution is stirred under ice-cooling. Then, a solution of 15.0 g of α-bromo-p-methoxypropylphenone in 80 ml of anhydrous diethyl ether is added dropwise over 40 minutes. At the end of the addition, the insolubles were removed by filtration under argon. The filtrate was concentrated under reduced pressure to give 1- (4-methoxyphenyl) -1-methoxy-1,2-epoxypropane (7.88 g) as a pale yellow oil.

Yield: 68%

NMR (CDC1 _3): δ 1.00 (3H, d, J = 6Hz), 3.23 (3H, s), 3.52 (1H, q, J = 6Hz), 3.82 (3H, s ), 6.92 (2H, d, J = 7Hz), 7.38 (2H, d, J = 7Hz)

Example 9

1- (4-Methoxyphenyl) -1-methoxy-1,2-epoxypropane (7.88 g) and sodium methoxide (200 mg) in anhydrous methanol (30 ml) were stirred at room temperature for 15 hours. Water (50 mL) was added and the mixture was extracted with diethyl ether (3 x 20 mL). The extract was dried over anhydrous magnesium sulfate and potassium carbonate and then concentrated under reduced pressure in the presence of a small amount of anhydrous potassium carbonate. 8.26 g of a-hydroxy-p-methoxypropiophenone-dimethylacetal are thus obtained in the form of a colorless oily product. The resulting material was subjected to column chromatography (Florisil; methylene chloride) for analysis.

Yield: 61%

Infrared Spectrum: 3520, 1050 cm ^-1 MMR Spectrum (CDCl ₃ ):

δ 0.94 (3H, d, J = 7Hz), 2.35 (1H, d, J = 4Hz), 3.20 (3H, s), 3.33 (3H, s), 3.78 (3H) , s), 4.05 (1H, dq, J = 4 and 7Hz), 6.18 (2H, d, J = 9Hz), 7.35 (2H, d, J = 9Hz)

Analysis for (ϋ ^ Η ^ Ο ^):

Calculated: C, 63.70; H, 8.02; Found: C, 63.98; H: 8.08%

Example 10

Dissolve 2.67 g of p-toluenesulfonyl chloride in 5 ml of anhydrous pyridine and stir at room temperature. Add a solution of 1.58 g of α-hydroxy-p-methoxypropiophenone dimethylacetal in 5 ml of anhydrous pyridine over a period of 10 minutes. After stirring for 72 hours, ice water (20 g) was added and the mixture was extracted with diethyl ether (3 x 20 mL). The extract was washed with water (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure in the presence of a small amount of anhydrous potassium carbonate. This gives 2.12 g of α- (p-toluenesulfonyloxy) p-methoxypropiophenone dimethylacetal as a pale yellow oily product.

Yield: 80%

Infrared spectrum:

1600, 1510, 1350, 1245, 1170, 1090, 1055, 1035, 905 ^cm-1

NMR (CDC1 ₃₎ δ 1.07 (3H, d, J = 7Hz), 2.40 (3H, s), 3.07 (3H,

s), 3.12 (3H, s), 3.75 (3H, s), 4.92 (1H, q, J = 7Hz),

6.7-7.0 (2H, m), 7.1-7.4 (4H, m), 7.73 (2H, d, J = 8Hz)

Example 11

As described in Example 2, α-bromo-β-tert-butyl isovalerophenone was prepared as a colorless liquid; p-tert-butyl isovalerophenone is used as starting material.

Yield: 72%

Boiling point: 128-140 ° C (1 torr)

Infrared spectrum:

2960, 1680, 1600 cmMMR spectrum (CDC1 _3):

δ 1.00 (3H, d, J = 7Hz, 1.20 (3H, d, J = 7Hz),

1.35 (9H, s), 2.2-2.7 (1H, m), 4.90 (1H, d, J = 9Hz), 7.47 (2H, d, J = 10Hz), 7, 90 (2H, d, J = 10Hz)

Analysis for C ₁₅ H ₂₁ OBr:

Calculated: C, 60.61; H, 7.12; Br, 26.89; Found: C, 60.71; H, 7.11; Br: 26.58%

Example 12

1.62 g of sodium methoxide are dissolved in 20 ml of anhydrous methanol and the solution is stirred at room temperature under argon. A solution of 2.64 g of α-bromo-p-tert-butyl isovalerophenone in 20 ml of anhydrous methanol is added to the above solution over about 15 minutes and the mixture is stirred at room temperature for 18 hours.

Workup of the reaction mixture as in Example 3 gave 2.44 g of α-hydroxy-β-tert-butyl-isovalerophenone dimethyl-acetal as a pale yellow oily product.

Yield: 98%

Infrared spectrum:

2950, 1110, 1040 cmMMR spectrum (CDC1 _3):

δ 0.70 (3H, d, J = 7Hz), 0.90 (3H, d, J = 7Hz),

1.32 (9H, s), 1.0-1.6 (1H, m), 2.45 (1H, broad s), 3.22 (3H, s), 3.25 (3H, s), 3, 67 (1H, d, J = 6Hz),

7.33 (4H, s)

188 108

Example 13

Methanesulfonyl chloride (1.90 g) was dissolved in dry pyridine (5 mL) and stirred at room temperature; a solution of 2.34 g of? -hydroxy -? - t -butyl) isovalerophenone dimethylacetal in 5 ml of anhydrous pyridine is added dropwise over 10 minutes. The mixture was stirred at this temperature for a further 24 hours. The mixture was worked up as described in Example 7; 1.63 g of (methanesulfonyloxy) -? - tert -butyl) -isovalerophenone-dimethylacetal are obtained in the form of a colorless oily product (the mixture is left at room temperature and the compound crystallizes).

Yield: 55%

Mp .: 80-86 ° C

Infrared spectrum:

2960, 1357, 1176, 1060, 955 cm -1 ¹ H NMR (CDCl ₃ ):

δ 0.70 (3H, d, J = 7Hz), 0.90 (3H, d, J = 7Hz),

1.32 (9H, s), 1.4-1.9 (1H, m), 3.17 (3H, s), 3.20 (3H, s), 3.26 (3H, s), 4 76 (1H, d, J = 4Hz), 7.37 (4H, s) Elemental Analysis (C | ₈ H ₃₀ O ₅ s) Calcd:

Calculated: C, 60.30; H, 8.44; S, 8.95. Found: C, 60.07; H, 8.23; S: 9.07%

Example 14

To a mixture of 7.12 g of? -Acetoxyacetophenone in 7.44 g of ethylene glycol and 0.200 g of p-toluenesulfonic acid monohydrate is added 100 ml of benzene and the mixture is heated under reflux. The resulting water is removed using a Dean-Stark pad. The mixture was refluxed for 21 hours and ethylene glycol (4.00 g) was added. The mixture was refluxed for a further 6 hours. The resulting water is distilled off. After cooling, 30 ml of saturated aqueous sodium bicarbonate solution and 20 ml of water are added and the mixture is extracted twice with 30 ml of diethyl ether. The combined extracts were washed with water (10 mL), dried over magnesium sulfate and concentrated under reduced pressure. 7.874 g of product are obtained. The product was found to be a mixture of α-acetoxyacetophenone ethylene acetal and α-hydroxyacetophenone ethylene acetal, based on the MMR spectrum and gas chromatography. The mixture was dissolved in methanol (20 mL) and potassium carbonate (0.300 g) was added, followed by stirring at room temperature for 4 hours. After addition of 200 ml of water, colorless crystals precipitated and were filtered, dried over potassium hydroxide in vacuo overnight to give 4.79 g of α-hydroxyacetophenone ethylene acetal.

Yield: 67%

NMR (CDC1 _3): δ 2.10 (1H, br s), 3.70 (2H, br s), 3.7-4.0 (2H, m), 4.0-4.2 (2H , m), 7.2-7.6 (5H, m)

Example 75

To 0.900 g of α-hydroxyacetophenone ethylene acetal was added 5 ml of pyridine. After stirring under ice-cooling, 1.08 g of p-toluenesulfonyl chloride was added. The mixture was ice-cooled for 2 hours and then at room temperature for 1 hour. The reaction mixture was again cooled with ice. After adding 10 ml of water, the mixture was stirred for 1 hour and extracted with diethyl ether (3 x 20 ml). The combined extracts were washed with water (10-10 mL), dried over anhydrous magnesium sulfate, to give 1.584 g of crystalline product under reduced pressure. The residue was washed with a small amount of hexane to give 1.330 g of α- (p-toluenesulfonyloxy) -acetophenone-ethylene-acetal as colorless crystals.

Yield: 80%

NMR (CDC1 _3): δ 2.40 (3H, s), 3.7-3.9 (2H, m), 3.9 ^ 1.1 (2H, m);

4.11 (2H, s), 7.1-7.5 (5H, m), 7.55 (2H, d, J = 8Hz)

Example 16

As in Example 15, α- (p-bromobenzenesulfonyloxy) -acetophenone-ethylene-acetal was prepared as colorless crystals. Starting material is c-hydroxyacetophenone ethylene acetal.

Yield: 86%

MMR (CDCl3): δ 3.7-3.9 (2H, m), 3.9-4.1 (2H, m), 4.16 (2H, s),

7.2-7.5 (5H, m), 7.63 (4H, s)

Example 77

0.46 g of metallic sodium are dissolved in 10 ml of anhydrous methanol and the solution is stirred at room temperature. The solution was added dropwise over 10 minutes to a solution of 2.19 g of 1- (2-thienyl) -2-bromo-1-propanone in 10 ml of anhydrous methanol, and the mixture was stirred for an additional 3.5 hours at room temperature. Work up as in Example 3 to give 1.900 g of 1- (2-thienyl) -2-hydroxy-1-propane-dimethylacetal as a colorless oily product.

Yield: 94%

Infrared spectrum:

3450, 1110, 1055, 980, 855, 710 cm -1 ¹ H NMR (CDCl ₃ ):

δ 1.05 (3H, d, J = 7Hz), 2.54 (1H, broad s), 3.26 (3H, s), 3.30 (3H, s), 4.16 (1H, broad q , J = 7Hz), 6.9-7.2 (2H, m), 7.2-7.4 (1H, m)

Example 18

1- (2-Thienyl) -2-hydroxy-1-propanone dimethylacetal (0.606 g) was dissolved in pyridine (5 mL) and the solution was stirred under ice-cooling. After more than 1 minute, methanesulfonyl chloride (0.30 mL) was added and the mixture was stirred under ice-cooling for 5 minutes and then at room temperature for 5 hours. After the addition of 30 ml of water, the mixture was stirred at room temperature for 30 minutes and then extracted three times with 30 ml of diethyl ether. The extract was washed twice with 10 ml of water, anhydrous

188 108 dried over magnesium sulfate and potassium carbonate and concentrated under reduced pressure. The residue was purified by column chromatography (Florisil; methylene chloride). 0.788 g of 1- (2-thienyl) -2-methanesulfonyloxy-1-propanone dimethylacetal are obtained in the form of a colorless oily product. Yield: 94%

Infrared spectrum:

1360, 1180, 1120, 1055, 990, 975, 930, 905, 855, 810, 715, 540, 525 cm -1 ¹ H NMR (CDCl ₃ ):

δ 1.27 (3H, d, J = 7Hz), 3.09 (3H, s), 3.27 (6H, s), 5.02 (1H, q, J = 7Hz), 6.9-7 , 1 (2H, m), 7.2-7.4 (1H, m)

Analysis for C ^ HH ^ OOjSj:

Calculated: C, 42.84; H, 5.75; S, 22.87. Found: C, 42.64; H, 5.64; S: 22.90%

Example 19

Benzenesulfonyl chloride (2.01 g) was dissolved in anhydrous pyridine (10 mL) and the solution was stirred at room temperature. A solution of 1.93 g of α-hydroxy-p-isobutylpropiophenone dimethylacetal in 10 ml of anhydrous pyridine is added dropwise over 15 minutes. The mixture was stirred for 72 hours. Work up as in Example 1 to give 2.62 g of (benzenesulfonyloxy) -? - isobutylpropiophenone dimethylacetal as colorless crystals. Yield: 88%

O. p .: 79-82 'C

Infrared spectrum:

2950, 1362, 1195, 1097, 1043, 990, 921, 813, 594 cm ^-1

NMR (CDC1 _3): δ 0.86 (6H, d, J = 7Hz), 1.08 (3H, d, J = 7Hz),

1.6-2.1 (1H, m), 2.41 (2H, d, J = 7Hz), 3.02 (3H, s), 3.10 (3H, s), 4.94 (1H, q, J = 7Hz), 7.04 (2H, d, J = 9Hz), 7.19 (2H, d, J = 9Hz), 7.36-7.70 (3H, m), 7.84-. 8.02 (2 H, m)

Example 20

1.91 g of p-toluenesulfonyl chloride is dissolved in 10 ml of anhydrous pyridine and the solution is stirred at room temperature. A solution of 1.13 g of α-hydroxypropiophenone diethyl acetal in 10 ml of anhydrous pyridine is added dropwise over about 10 minutes. The mixture was then stirred for 72 hours. After standard work-up and purification by column chromatography (Florisil; methylene chloride), 1.16 g of α- (p-toluenesulfonyloxy) -propiophenone diethyl acetal are obtained as a colorless oily product. Yield: 85%

Infrared spectrum:

2980, 1360, 1192, 1178, 1087, 1055, 1042, 920 ^cm-1

NMR (CDC1 _3): δ 0.8-1.3 (9H, m), 2.38 (3H, s), 3.1-3.6 (4H, m);

4.89 (1H, q, J = 7Hz), 7.1-7.5 (7H, m), 7.80 (2H, d, J = 9Hz)

Analysis for (C _M H ₂₆ O ₅ S):

Calculated: C, 63.46; H, 6.93; S, 8.47. Found: C, 63.54; H, 6.90; S: 8.35%

Example 21

0.526 g of α- (p-toluenesulfonyloxy) -propiophenone-dimethylacetal and 0.150 g of calcium carbonate are refluxed for 72 hours, then 10 ml of water-methanol (3: 7 w / w) are added, followed by 10-10 It is extracted three times with 3 ml of diethyl ether each time. The combined extracts were washed with water (10 mL) and dried over anhydrous magnesium sulfate. The product was analyzed by gas chromatography (internal standard method) to give 0.162 g of methyl a-phenylpropionic acid. Yield: 66%

Example 22

1.75 g of α- (p-toluenesulfonyloxy) propiophenone dimethylacetal and 0.500 g of calcium carbonate are refluxed for 72 hours in a mixture of 33 ml of water and ethanol (3: 7 weight ratio of water to methanol). Water (50 mL) was added and the mixture was extracted with diethyl ether (3 x 30 mL). The combined extracts were washed with water (30 mL) and concentrated to about 5 mL under reduced pressure. To the residue were added 12 ml of methanol, 5 ml of water, 7 ml of 10% aqueous potassium hydroxide solution, and the mixture was refluxed for 5 hours. Water (30 mL) was then added and the mixture was washed with diethyl ether (5 x 20 mL). The aqueous phase was adjusted to pH 1 with concentrated hydrochloric acid and extracted with diethyl ether (4 x 20 mL). The combined extracts were washed with water (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 0.358 g of α-phenylpropionic acid as a colorless oily product. Yield: 48%, identified by IR and MMR spectra.

23rd-35th examples

An equimolar amount of base is taken from 0.526 g of α- (p-toluenesulfonyloxy) -propiophenone-dimethylacetal as shown in Table 1. The mixture was heated in an oil bath in 10 mL of the solvent shown in Table 1. Water (10 mL) was added and the mixture was extracted with diethyl ether (3 x 10 mL). The combined extracts were washed with water (10 mL) and dried over anhydrous magnesium sulfate.

The content of the methyl a-phenylpropionic acid ester of the obtained product was analyzed by gas chromatography according to Example 21.

The results are shown in 'l. Table.

-101

188 108

Table 1

Example number Solvent (mixture ratio) Base Bath temperature CC) Reaction- time (Hours) the-butenyl propionic acid methyl -ester return (%) 23 dioxane: water (9: 1) CH, COOK 110 216 54.3 24 dioxane: water (6: 4) CaCO ₃ 110 64 56.6 25 DMF: water (9: 1) CH ₃ COOK 150 14 40.3 26 DMF: water (6; 4) CH, COOK 150 14 55.6 27 DMF: water (6: 4) CaCOj 100 94 54.6 28 DMF: water (6: 4) CaCO ₃ 100 72 54.4 29 DMSO: water (6: 4) CaCO ₃ 100 94 54.3 30 DMSO: water (4: 6) CaCOj 100 72 58.5 31 anhydrous methanol - 150 (+) 7 34.2 32 methanol: water (7: 3) CH, COOK 110 72 60.8 33 methanol: water (6: 4) CaCO ₃ 110 64 63.0 34 methanol: water (4: 6) CaCO ₃ 110 72 33.3 35 acetic acid CH, COOK 130 14 39.0

(+) = 30 ml in a sealed container

Example 36

0.410 g of α- (p-toluenesulfonyloxy) -p-isobutylpropiophenone dimethylacetal was heated to reflux for 22 hours with 0.100 g of calcium carbonate in a 3: 7 mixture of water and methanol. Water (15 mL) was added and the mixture was extracted with diethyl ether (3 x 10 mL). The combined extracts were washed with water (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (silica gel, methylene chloride). This gives 0.180 g of methyl α- (4-isobutylphenyl) propionic acid as a colorless product. Yield: 81%; the product was identified by infrared and MMR spectra.

Example 37

0.910 g of α- (p-toluenesulfonyloxy) -p-isobutylpropiophenone dimethylacetal and 1.25 g of potassium carbonate in a 3: 7 weight ratio of water to methanol are refluxed for 20 hours. After addition of 30 ml of water, the mixture was extracted four times with 10 ml of methylene chloride. The aqueous phase was adjusted to pH 2 with dilute hydrochloric acid and extracted four times with 20 ml of methylene chloride. The combined extracts were washed with water (30 mL), dried over anhydrous magnesium sulfate to give 0.335 g of α- (4-isobutylphenyl) propionic acid as colorless crystals. O. p .: 71-75 'C. Yield: 73%. The product was identified by infrared and MMR spectra.

Example 38

0.991 g of α- (methanesulfonyloxy) -? - isobutylpropiophenone dimethylacetal and 0.300 g of calcium carbonate are refluxed in a 3: 7 weight ratio of 10 ml of water and methanol for 72 hours. The crude product was subjected to alkaline hydrolysis and worked up as described in Example 22; 0.519 of α- (4-isobutylphenyl) propionic acid is obtained in the form of colorless crystals. O. p .: 73-74 'C. Yield: 84%. The material was identified by infrared and MMR spectra.

Example 39 45

2.12 g of α- (p-toluenesulfonyloxy) -p-methoxypropiophenone dimethylacetal and 0.560 g of calcium carbonate are refluxed in 20 ml of methanol: water (3: 7) for 13 hours. The crude product obtained was subjected to alkaline hydrolysis as in Example 22 and worked up in the usual manner. 0.714 g of α- (4-methoxyphenyl) propionate are obtained. (). m.p .:

47-50 'C. Yield: 577 ,,.

Example 40

0.735 g of α-methanesulfonyloxy-β-tert-butyl 60 isovalerophenone dimethylacetal and 0.200 g of calcium carbonate are refluxed with 10 ml of water-methanol (3: 7) for 72 hours. The resulting material was worked up as in Example 36. Purify by column chromatography 65 g (silica gel, methylene chloride)

-111

188 108 materials. This gives the methyl 4- (4-tert-butylphenyl) -isovaleric acid as a colorless oil. Infrared spectrum:

2965, 1745, 1165, 1025 cm -1 ¹ H NMR (CDCl ₃ ):

δ 0.71 (3H, d, J = 7Hz), 1.02 (3H, d, J = 7Hz),

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

Analysis for C ^ HH ^ OO::

Calculated: C, 77.37; H, 9.74; Found: C, 77.26; H: 9.62%

Example 41

0.668 g of α- (p-toluenesulfonyloxy) -acetophenone-ethylene-acetal is dissolved in 8 ml of 1,3-dimethyl-2-imidazolidinol (DMI), 200 mg of calcium carbonate and 0.7 ml of water are added. The mixture was heated at 180 ° C for 22 hours with stirring. After cooling, water (30 ml) was added and the mixture was extracted with diethyl ether (3 x 20 ml). The combined extracts were washed with water (2 x 10 mL), dried over anhydrous magnesium sulfate. The aqueous layers were combined and acidified with 4 mL of concentrated hydrochloric acid. The mixture was extracted with diethyl ether (3 x 20 mL). The combined extracts were washed with water (10-10 mL) and dried over anhydrous magnesium sulfate. The organic phase is concentrated under reduced pressure and 400 ml of potassium hydroxide are added to the residue. The mixture was refluxed with methanol (6 mL) and water (2 mL) and refluxed for 16 hours. After cooling, water (30 ml) was added and the mixture was washed with diethyl ether (3 x 20 ml). The aqueous phase is acidified to pH 2 by the addition of about 7 ml of 3.5% hydrochloric acid and extracted with 3 times 20 ml of diethyl ether. The combined extracts were washed with water (10 mL, 10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 92 mg of a residue are obtained. The residue is benzoic acid and phenylacetic acid, as determined by the MMR spectrum. The resulting material was treated with diazomethane to afford the methyl ester. The MMR spectrum data showed that the mixture contained 61 mg (27% yield) benzoic acid, 27 mg (10% yield) phenylacetic acid.

Example 42

Dissolve 0.798 g of α- (p-bromobenzenesulfonyloxy) -acetophenone-ethylene-acetal in 8 ml of DMI and add 200 mg of calcium carbonate and 0.5 ml of water. The mixture was stirred at 160 ° C for 18 hours. The reaction mixture was worked up as described in Example 41 and the crude product was subjected to alkaline hydrolysis. 84 mg of the semi-solid product are thus obtained. The semi-solid product was found to be a 7.0: 4.5 molar mixture of benzoic acid and phenylacetic acid in the MMR spectrum. Accordingly, the reaction mixture contained 49 mg (20% yield) benzoic acid and 35 mg (13% yield) phenylacetic acid.

Example 43

1- (2-Thienyl) -2- (methanesulfonyloxy) -1-propanone dimethylacetal (0.560 g) and calcium carbonate (0.200 g) were refluxed with water / methanol (3: 7) for 42 hours. Water (30 mL) was added and the mixture was extracted with diethyl ether (3 x 30 mL). The combined extracts were washed with water (2 x 10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 316 mg of methyl α- (2-thienyl) propionate as a colorless oily product. The structure was confirmed by infrared and MMR spectra. Yield: 93% of crude product.

The crude product was distilled at 130 ° C (bath temperature) and 17 torr to give 279 mg of pure product. After purification, the yield is 82%.

The aqueous phases obtained during extraction are combined and acidified with 6 ml of concentrated hydrochloric acid and extracted 3 times with 15 ml of diethyl ether. The extract was washed with water (2 x 10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This gives 20 mg of α- (2-thienyl) propionic acid as a colorless oily product. Yield: 6%. The structure of the resulting material was verified by infrared and MMR spectra.

Example 44

0.565 g of 1- (2-thienyl) -2- (methanesulfonyloxy) -1-propanone dimethylacetal and 0.202 g of calcium carbonate are refluxed in 6 ml of water-methanol (3: 7) for 21 hours. Sodium hydroxide (0.420 g) was added to the reaction mixture, which was stirred at room temperature for 15 hours, then refluxed for 2 hours with stirring. Water (30 ml) was added and the mixture was washed with diethyl ether (20 ml). Concentrated hydrochloric acid (4 mL) was added to the aqueous phase and the mixture was extracted with diethyl ether (3 x 20 mL). The combined extracts were washed with water (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This gives 0.299 α- (2-thienyl) propionic acid as a colorless oily product. Yield: 95%.

Example 45

Sodium hydroxide (0.420 g) was dissolved in a 3: 7 mixture of water-methanol (6 mL) and 0.574 g of 1- (2-thienyl) -2- (methanesulfonyloxy) -1-propanone dimethylacetal was added. The mixture was refluxed for 21 hours, water (40 mL) was added and the mixture was washed with diethyl ether (20 mL). The aqueous phase was acidified with 3 ml of concentrated hydrochloric acid and extracted three times with 20 ml of diethyl ether. The combined extracts were washed with water (5 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

188,108 lbs. 0.291 g of a- (2-thienyl) propionic acid are thus obtained in the form of a colorless oily product. Yield: 91% '

Example 46

0.674 g of 1- (2-thienyl) -2- (p-toluenesulfonyloxy) -1-propanone dimethylacetal and 0.200 g of calcium carbonate are heated at reflux for 12 hours with 10 ml of water-methanol (3: 7). The mixture was worked up as described in Example 36. This gives an oily crude product which is distilled from an oil bath at 110-120 ° C at 17 torr. 0.253 g of methyl α- (2-thienyl) propionic acid is obtained in the form of a colorless oily product. Yield: 79%.

Example 47

1- (2-Thienyl) -2- (benzenesulfonyloxy) -1-propanone-dimethylacetal (0.684 g) and calcium carbonate (0.200 g) were heated at reflux in 10 ml water: methanol (3: 7) for 8 hours. Conventional work-up (Example 36) yields an oily crude product which is distilled from a 110 ° C oil bath at 15 torr. 0.277 g of methyl α- (2-thienyl) propionic acid are obtained in the form of a colorless oily product. Yield: 81%.

Example 48

0.299 g of α-methanesulfonyloxy-β-acetylamine propiophenone dimethylacetal and 0.090 g of calcium carbonate are refluxed in 3 ml of water-methanol (3: 7) for 21 hours. Water (30 mL) was added and the mixture was extracted with methylene chloride (3 x 20 mL). The extract was washed with water (10 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure; a crystalline residue is obtained. The residue was purified by column chromatography (silica gel, methylene chloride and diethyl ether). 0.186 g of methyl α- (4-acetylaminophenyl) -propionic acid are obtained in the form of colorless crystals.

Yield: 93%

O.p .: 107-109 C (from ethanol-hexane) Infrared spectrum:

1740, 1665, 1610, 1555, 1515, 1415, 1330, 1160, 860, 840 cm ^-1 MMR (CDCl ₃ ):

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

Analysis for C ₁₂ H ₁₅ NO 3:

Calculated: C, 65.14; H, 6.83; N, 6.33. Found: H, 64.94; H, 7.00; N: 6.27%

Example 49

A solution of 0.329 g of α- (benzenesulfonyloxy) -? - isobutylpropiophenone dimethylacetal and 0.10 g of calcium carbonate was refluxed in 10 ml of water methanol (3: 7) for 10 hours. Work up as in Example 48 and purify the product by column chromatography (silica gel, methylene chloride) to give methyl α- (4-isobutylphenyl) propionate.

Yield: 82%

Example 50

0.392 g of α- (benzenesulfonyloxy) -? - isobutylpropiophenone dimethylacetal in 4 ml of water-pyridine (1: 3) was heated in an oil bath at 100 ° C for 19 hours. Work up as in Example 48 and purify the resulting material by column chromatography (silica gel, methylene chloride). 0.164 g of methyl methyl ester of α- (4-isobutylphenyl) propionic acid are obtained in the form of a colorless oily product. Yield: 74%.

Example 57

0.39 g of α- (benzenesulfonyloxy) -? - isobutylpropiophenone dimethylacetal was added to a mixture of 10 ml of water-methanol (3: 7) and 2 ml of 10% aqueous potassium hydroxide and refluxed for 9 hours. boil for a long time. After addition of 30 ml of water, the mixture was washed four times with 15 ml of methylene chloride. The pH of the aqueous phase was adjusted to less than 1 with concentrated hydrochloric acid and extracted with methylene chloride (4 x 15 mL). The combined extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.138 g of α- (4-isobutylphenyl) propionic acid as colorless crystals. O. p .: 73-75 'C. Yield: 67%.

Example 52

0.150 g of α- (p-toluenesulfonyloxy) propiophenone diethyl acetal and 0.05 g of calcium carbonate are refluxed with 10 ml of water-methanol (3: 7) for 72 hours; water (20 mL) was added and the mixture was extracted with diethyl ether (4 x 5 mL). The extract was dried over anhydrous magnesium sulfate. The product was analyzed by gas chromatography (internal standard method) to give 23 mg of ethyl α-phenylpropionic acid. Yield: 32%.

Example 53

0.978 g of α- (methanesulfonyloxy) -p-fluoropropiophenone dimethylacetal and 0.33 g of calcium carbonate are refluxed in 15 ml of water-methanol (3: 7 w / w) for 24 hours. Work up as described in Example 49 to give 0.45 mg of methyl α- (4-fluorophenyl) propionic acid as a colorless oily product.

Yield: 76%

-131

188 108, 2

Infrared spectrum:

1744, 1607, 1513, 1460, 1439, 1340, 1230, 1210, 1170, 1160, 840, 796 cm ^-1 MMR (CDCl 3):

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

Infrared spectrum:

2970, 1739, 1602, 1450, 1334, 1270, 1231, 1205, 1172, 1158, 1028, 893, 856, 823 cm -1. The structure of the product obtained is q- (6-methoxy-2-naphthyl) based on the MMR spectrum. propionic acid methyl esters were found. (Example 54)

Example 54

0.490 g of 1- (6-methoxy-2-naphthyl) -2- (methanesulfonyloxy) -1-propanone dimethylacetal and 0.140 g of calcium carbonate are refluxed in 10 ml of water and dimethylformamide (1: 4) for 5 hours. After adding 20 ml of water, the mixture was extracted four times with 7-7 ml of methylene chloride. The extract was washed with water (4 x 10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, methylene chloride) to give 0.323 g of methyl α- (6-methoxy-2-naphthyl) -propionic acid as a colorless crystalline product. O. p .: 65-68 'C. Yield: 94%. The structure of the obtained material was confirmed by infrared and MMR spectra.

Example 55

1- (6-Methoxy-2-naphthyl) -2-methanesulfonyloxy-1-propanone-dimethylacetal (0.354 g) and calcium carbonate (0.10 g) were refluxed in 3 mL of water (8 mL) and methanol for 28 hours. Water (20 mL) was added and the mixture was extracted with methylene chloride (3 x 10 mL). The extract was washed with water (20-20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This gives 0.178 g of methyl ester of α- (6-methoxy-2-naphthyl) -propionic acid as colorless crystals. Yield: 73%.

Example 56

One of the two possible diastereomers of 1- (6-methoxy-2-naphthyl) -2- (d-10-camphorsulfonyloxy) -1-propanone dimethylacetal was prepared. Mp .: 102-105 ° C; [α] θ ⁵ + 32.5 ° (c = 1, chloroform). 170 mg of this diastereomer are added, 40 mg of calcium carbonate are added and the mixture is refluxed at 110 ° C for 5 hours in 5 ml of water-dimethylformamide (1: 4). Water (200 mL) was then added and the mixture was extracted with diethyl ether (4 x 10 mL). The combined extracts were washed with water (4 x 10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, methylene chloride) to give (-) -? - (6-methoxy-2-naphthyl) -propionic acid methyl ester (68 mg) as colorless crystals.

Yield: 80.2%

Mp: 94.5-95 'C [α] θ: -78.2 ° (c = 1, chloroform)

Example 57

0.31 ml (0.44 g) of iodine trimethylsilane and 2 drops of cyclohexene were stirred in 5 ml of anhydrous methylene chloride at room temperature under argon gas. A solution of 529 mg of 1-phenyl-2- (p-toluenesulfonyloxy) -1-propanone dimethylacetal in 4 ml of methylene chloride was added dropwise. After stirring at room temperature for 3 hours, saturated aqueous sodium bicarbonate (5 mL) was added. The organic phase is then washed with 5 ml of 10% aqueous sodium bicarbonate solution and again with 5 ml of water. The organic layer was dried over anhydrous magnesium sulfate. The product was subjected to gas chromatography (internal standard method) to obtain 226.4 mg of methyl α-phenylpropionic acid. Yield: 91.9%.

58th-62nd examples

176 mg of 1-phenyl-2- (toluenesulfonyloxy) -1-propanone-dimethylacetal and the oxygen scavenger as shown in Table 2 were mixed with 4 ml of anhydrous methylene chloride in the amount indicated therein, and stirring at temperature. Water (5 ml) was then added and the mixture was extracted with methylene chloride (4 x 5 ml). The extract was washed with 1.0 mL of water and dried over anhydrous magnesium sulfate.

The product obtained was subjected to gas chromatography as described in Example 57. The yield of methyl α-phenylpropionic acid ester obtained is shown in Table 2.

Table 2

Example number Oxygen scavenger (molar ratio) Reaction conditions Yield (%) of α-phenylpropionic acid methyl ester Temperature (° C) Time (hours- in) 58 AlCl, (0.6) 0 1 52.5 59 Aid, (0.7) At source temperature 1 63.6 60 AlCl, (1.0) At source temperature 0.7 69.3 61 AlCl, (1,4) 0 1 68.0 62 TiCl, (3.0) At source temperature 10 16.8

-141

188 108

Example 63

1- (4-Chlorophenyl) -2- (p-toluenesulfonyloxy) -1-propanone dimethylacetal (3.849 g) was stirred at room temperature under an argon atmosphere with 10 ml of anhydrous methylene chloride. 1.71 ml (2.40 g) of iodomethylsilane are dissolved in 2 ml of anhydrous methylene chloride with 2 drops of cyclohexene. This solution was added dropwise to the above mixture at room temperature and the mixture was stirred for 30 minutes. Work-up as in Example 57 gave an oily product which, according to the MMR spectrum, contained 1.61 g of methyl α- (p-chlorophenyl) propionic acid. Yield: 81.0%.

Example 64

Iodtrimethylsilane (0.20 mL, 0.28 g) and cyclohexene (1 drop) were stirred in dry methylene chloride (8 mL) at room temperature under argon. Subsequently, 490 mg (1.00 mmol) of 1- (6-methoxy-2-naphthyl) -2- (d10-camphorsulfonyloxy) -1-propanone dimethylacetate was dissolved in 6 ml of anhydrous methylene chloride solution [α] θ + 32.5 ° (c = 1.00, chloroform), this solution was added dropwise to the above mixture and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution (10 ml) was added to the mixture, followed by purification by column chromatography (silica gel, methylene chloride) (230 mg) (R) (-) -? - (6-methoxy-2-naphthyl). Methyl propionic acid methyl ester is obtained in the form of colorless crystals. M.p .: 85-97 ° C. Yield: 94.2%. The product was monitored by MMR; using optically active Eu (TFC) ₃ , the product was found to be optically pure.

Example 65

In the same manner as in Example 17, 1- (4-methoxyphenyl) 2-hydroxy-1-propanone dimethylacetal was prepared as a pale yellow oily product. Starting material is 1- (4-methoxyphenyl) -2-bromo-1-propane. The crude product obtained is used without purification in Example 66.

Example 66

In the same manner as in Example 7, 1- (4-methoxyphenyl) 2-methanesulfonyloxy-1-propanone dimethylacetal was prepared as a pale yellow oil. Starting with 1- (4-methoxyphenyl) -2-hydroxy-1-propanone dimethylacetal (prepared according to Example 65).

Yield: 80.1% [based on 1- (4-methoxyphenyl) -2-bromo-propanone].

Infrared spectrum:

2935, 1615, 1517, 1358, 1257, 1176, 1100, 1065, 145, 915 cm -1 ¹ H NMR (CDCl ₃ ):

δ 1.18 (3H, d, J = 6Hz), 3.09 (3H, s), 3.21 (3H, s), 3.28 (3H, s), 3.80 (3H, s), 4.97 (1H, q, J = 6Hz), 6.87 (2H, d, J = 9Hz), 7.37 (2H, d, J = 9Hz)

Example 67

1- (4-methoxyphenyl) -2-methanesulfonyloxy-1-propanone-dimethylacetal (1.007 g, 3.308 mmol) and calcium carbonate (330 mg, 3.30 mmol) in water (10 mL) were stirred under reflux. and methanol (3: 7) for 20 hours. The product was purified as described in Example 49; 597 mg of methyl α- (4-methoxyphenyl) propionic acid are obtained in the form of a colorless oily product.

Yield: 92.9%

NMR (CDC1 _3):

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

Example 68 i

In the same manner as in Example 20, 1- (2-thienyl) -2- (ptoluenesulfonyloxy) -1-propanone dimethylacetal was prepared as a colorless oily product. 1- (2-thienyl) -2-hydroxy-1-propanone dimethylacetal was used as starting material. Yield: 64%. Infrared spectrum:

1360, 1190, 1180, 1060, 985, 925, 905, 820, 790, 710, 665, 565 cmMMR spectrum (CDC1 _3):

δ 1.19 (3H, d, J = 7Hz), 2.40 (3H, s), 3.08 (3H, s), 3.14 (3H, s), 4.98 (1H, q, J = 7Hz), 6.94 (2H, d, J = 3Hz), 7.2-7.4 (3H, m), 7.80 (2H, d, J = 8Hz)

Example 69

As in Example 20, 1- (2-thienyl) -2-benzenesulfonyloxy-1-propanone dimethylacetal was prepared as a colorless oily product. Yield: 83%. 1- (2-thienyl) -2-hydroxy-1-propanone dimethylacetal was used as starting material. Infrared spectrum:

1360, 1190, 1060, 980, 925, 900, 590, 555 cm -1 ¹ H NMR (CDCl ₃ ):

δ 1.20 (3H, d, J = 7Hz), 3.08 (3H, s), 3.14 (3H, s), 3.14 (3H, s), 5.01 (1H, q, j) = 7H /), 6.8 7.1 (211, m), 7.2-7.4 (1H, m), 7.4-7.7 (3H, m), 7.9 8.1 ( 211, ni)

Example 70

Metal salt (1.30 g, 56.5 mmol) was dissolved in anhydrous ethanol (30 mL) and stirred at room temperature. A solution of 5.33 g (0.025 mol) of α-bromopropiophenone in 20 ml of anhydrous ethanol is added dropwise over 15 minutes. The mixture was stirred at room temperature for 40 minutes. Water (100 mL) was added and the mixture was extracted with diethyl ether (2 x 60 mL). The combined extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in ethanol containing 30 ml of catalytic metal sodium, and the solution was stirred at room temperature for 2 days. THE 3.

-151

Workup as described in Example 188 108 gives 4.477 g of 1-phenyl-2-hydroxy-1-propanone diethyl acetal as a colorless oily product.

Yield: 80.2%

Infrared spectrum:

2960, 1452, 1120, 1092, 1057, 1040, 772, 709 ^cm-1

NMR (CDC1 _3): δ 0.94 (3H, d, J = 6Hz), 1.05-1.40 (6H, m), 2.61 (1H, br s), 3.22 to 3, 83 (4H, m), 4.05 (1H, q, J = 6Hz), 7.1-7.7 (5H, m)

Example 71

3.33 g of acetanilide and 4.0 ml (5.2 g) of α-chloropropionyl chloride in 20 ml of carbon sulfide are stirred at room temperature. Subsequently, 7.0 g of finely powdered aluminum chloride was added in portions to the above mixture over a period of about 2 minutes. The mixture was stirred at room temperature for 25 minutes and then at reflux for 50 minutes. After cooling, the reaction mixture is separated into 2 phases. The upper layer was separated by decantation and the lower black layer was poured into ice water. The precipitated crystals were collected by filtration. Recrystallization from ethanol gave 1.860 g of 1- (4-acetylaminophenyl) -2-chloro-1-propanone as colorless crystals. The upper phase of the reaction mixture and the filtrate obtained during crystallization, the mother liquor obtained by recrystallization, were combined and extracted three times with 50 ml each of methylene chloride. The extract was washed with water (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 1.434 g of 1- (4-acetylaminophenyl) -2-chloro-1-propanone. The mother liquor was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, methylene chloride: ether). Recrystallization from methanol gives 0.868 g of the above product. Total product 4.116 g, 75% overall. Colorless crystals are obtained.

M.p .: 123-125 'C (from ethanol)

Infrared spectrum:

1690, 1675, 1595, 1540, 1415, 1320, 1360, 1180, 965, 860, 665 cm -1 ¹ H NMR (CDCl ₃ ):

δ 1.70 (3H, d, J = 7Hz), 2.18 (3H, s), 5.18 (1H, q, J = 7Hz), 7.63 (2H, d, J = 9Hz), δ , 95 (2H, d, J = 9Hz), 7.8-8.1 (1H, broad s)

Analysis (C _n H ^ _l2 ClNO formula:

date:

C: 58.54; H, 5.36; Cl, 15.71; N: 6.21% Found:

C: 58.59; H: 5.40; Cl, 15.63; N: 6.23%

Example 72

As in Example 17, 1- (4-acetylaminophenyl) -2-hydroxy-1-propanone dimethylacetal was prepared as a glass product. The starting material was 1- (4-acetylaminophenyl) -2-chloro-1-propopyrone. Without purification, the crude product was used in Example 73.

NMR _(CDCl3):?

δ 0.95 (3H, d, J = 7Hz), 2.14 (3H, s), 2.94 (1H, broad s), 3.21 (3H, s), 3.33 (3H, s) , 4.10 (1H, q, J = 7Hz), 7.37 (2H, d, J = 8Hz), 7.51 (2H, d, J = 8Hz), 8.93 (1H, broad s),

Example 73

The 1- (4-acetylaminophenyl) -2-hydroxy-1-propanone dimethylacetal obtained in Example 72 was dissolved in pyridine (5 mL) and methanesulfonyl chloride (0.60 mL, 0.89 g) was added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was cooled with ice and water (30 mL) was added. The temperature was then allowed to warm to room temperature, and the mixture was stirred for 10 minutes and then extracted with ethyl acetate (4 x 20 mL). The combined extracts were dried by addition of anhydrous sodium sulfate followed by anhydrous magnesium sulfate, and the organic solution was concentrated under reduced pressure. The residue was purified by column chromatography (Florisil methylene chloride and diethyl ether); This gives 1.537 g of 1- (4-acetylaminophenyl) -2-methanesulfonyloxy-1-propanone dimethylacetal as a colorless glassy product. Yield: 93% based on 1- (4-acetylaminophenyl) -2-chloro-1-propanone.

Infrared spectrum:

1675, 1610, 1540, 1350, 1175, 915, 525 cm -1 ¹ H NMR (CDCl ₃ ):

δ 1.14 (3H, d), 2.52 (3H, s), 3.08 (3H, s), 3.18 (3H, s), 3.24 (3H, s), 4.94 ( 1H, q, J = 7Hz), 7.36 (2H, d, J = 9Hz), 7.54 (2H, d, J = 9Hz), 8.52 (1H, broad s)

Example 74

1- (4-Fluorophenyl) -2-hydroxy-1-propanone dimethylacetal was prepared as in Example 17 as a pale yellow oily product. 1- (4-Fluorophenyl) -2-bromo-1-propanone was used as starting material. The product obtained can be used without further purification in Examples 70 and 76. Infrared spectrum:

2975, 2937, 1610, 1512, 1230, 1159, 1105, 1053, 982, 839 cm ^-1 MMR (CDCl ₃ ):

δ 0.93 (3H, d, J = 6Hz), 2.53 (1H, broad s), 3.23 (3H, s), 3.33 (3H, s), 4.08 (1H, broad q) , J = 6Hz), 6.83-7.18 (2H, m), 7.32-7.60 (2H, m)

Example 75

As in Example 7, 1- (4-fluorophenyl) -2-methanesulfonyloxy-1-propanone dimethylacetal was prepared as a colorless oily product. 1- (4-Chlorophenyl) -2-hydroxy-1-propanone dimethylacetal prepared according to Example 74 was used as starting material. Yield: 82.3% based on 1- (4-fluorophenyl) -2-bromo-1-propanone.

-161

188 108

Infrared spectrum:

2940, 1610, 1512, 1359, 1228, 1180, 1160, 1098, 1067, 1045, 972, 918 cm

NMR (CDC1 _3):

δ 1.15 (3H, d, J = 6Hz), 3.06 (3H, s), 3.21 (3H, s), 3.24 (3H, s), 4.96 (1H, q, J = 6Hz), 6.88-7.16 (2H, m); 7.32-7.58 (2 H, m)

Example 76

1- (4-Fluorophenyl) -2- (p-toluenesulfonyloxy) -1-propanone dimethylacetal was prepared as crystals as described in Example 20. O. p .: 96-99 'C. 1- (4-Fluorophenyl) -2-hydroxy-1-propanone dimethylacetal prepared in Example 74 was used as starting material. Yield: 76.2% based on 1- (4-fluorophenyl) -2-bromo-1-propanone.

Mp: 101 ° C (from methanol)

Infrared spectrum:

2948, 1605, 1510, 1360, 1346, 1192, 1181, 1090, 1053, 932, 918, 820, 786, 670, 561 cm * '

MMR spectrum:

(CDCl 3): δ 1.05 (3H, d, J = 6Hz), 2.40 (3H, s), 3.08 (3H, s), 3.10 (3H, s), 4.93 (1H , q, J = 6Hz), 6.82-7.08 (2H, m), 7.16-7.46 (4H, m), 7.73 (2H, d, J = 8Hz)

Analysis for C ₁₈ H ₂₁ FO ₃ S:

Calculated: C, 58.68; H, 5.75; Found: C, 58.98; H: 5.96%

Example 77

8.57 g of 1- (6-methoxy-2-naphthyl) -1-propanone (U.S. Patent No. 2,683,738) are dissolved in 60 ml of anhydrous dioxane and the solution is stirred at room temperature. To the solution was added 13.57 g of pyridinium hydrobromide perbromide and the mixture was stirred for 1 hour. 200 ml of a 3% aqueous sodium hydrogen sulfite solution are added and the mixture is stirred at room temperature for 3 hours; the precipitating crystals are filtered off, washed with water and dried over potassium hydroxide in vacuo; This gives 11.66 g of 1- (6-methoxy-2-naphthyl) -2-bromo-1-propanone (m.p. 73-75 'C) as pale yellow crystals. Yield: 99%

O. p .: 68-69 'C

NMR (CDC1 _3): δ 1.90 (3H, d, J = 7Hz), 3.85 (3H, s), 5.36 (1H, q, J = 7Hz), 6.9-7.3 (2H, m), 7.5-8.1 (3H, m), 8.38 (1H, broad s)

Analysis for Cj CH^ BrBrj:

Calculated: C, 57.35; H, 4.47; Br, 27.26; Found: C, 57.27; H, 4.66; Br: 27.23%

Example 78

1- (6-methoxy-2-naphthyl) -2-hydroxy-1-propanone dimethylacetal was prepared as in Example 3 in the form of a colorless oily product. 1- (6-methoxy-2-naphthyl) -2-bromo-propanone was used as starting material. Yield: 100%. After purification by column chromatography and standing at room temperature, the product crystallizes. (Florisil, methylene chloride). Colorless crystals are obtained. O. p .: 56-59 'C

Infrared spectrum:

3500, 1637, 1610, 1488, 1276, 1215, 1175, 1118, 1106, 1040, 859 cm * ¹ MMR (CDCl ₃ ):

δ 0.97 (3H, d, J = 7Hz), 2.48 (1H, broad s), 3.20 (3H, 2). 3.36 (3H, s), 3.82 (3H, s), 4.14 (1H, q, J = 7Hz), 7.00-7.24 (2H, m), 7.40-7, 98 (4H, m) Analysis for C C ^H ^ OO ^:

Found: C, 69.54; H, 7.30; Found: C, 69.25; H, 7.28%

Example 79

As in Example 7, 1- (6-methoxy-2-naphthyl) -2-methanesulfonyloxy-1-propanone dimethylacetal was prepared as a colorless oily product. 1- (6-methoxy-2-naphthyl) 2-hydroxy-1-propanone dimethylacetal was used as starting material. Yield: 84%

Infrared spectrum:

1640, 1615, 1492, 1360, 1280, 1182, 901, 820 cm ^-1

NMR (CDC1 _3):

δ 1.19 (3H, d, J = 7Hz), 3.09 (3H, s), 3.22 (3H,

s), 3.31 (3H, s), 3.87 (3H, s), 5.05 (1H, q, J = 7Hz), 7.04-7.24 (2H, m), 7.42 -7.94 (4H, m)

Analysis calculated for C ₁₇ H ₂₂ O ₆ S: C, 57.61; H, 6.26; S, 9.05. Found: C, 57.21; H, 6.02; S: 8.85%

Example 80 350 mg of metal sodium are dissolved in anhydrous methanol and the solution is stirred at room temperature. To this solution was added 2.93 g of 1- (6-methoxy-2-naphthyl) -2-bromo-1-propanone after stirring for 24 hours. Water (50 mL) was added and the mixture was extracted with methylene chloride (4 x 15 mL). The combined extracts were dried over anhydrous magnesium sulfate followed by anhydrous potassium carbonate and then concentrated under reduced pressure to give crude 1- (6-methoxy-2-naphthyl) -2-hydroxy-1-propanone dimethylacetal (2.845 g). The crude product (1.11) was dissolved in anhydrous pyridine (3 mL) and stirred at room temperature. To the solution was added 993 mg of d-10-camphorsulfonyl chloride and the mixture was stirred for 40 minutes. After adding 20 ml of water, the mixture was extracted three times with 10 ml of methylene chloride. The combined extracts were dried over anhydrous magnesium sulfate followed by anhydrous potassium carbonate. The organic phase is concentrated under reduced pressure and the residual oil is purified by column chromatography (Florisil, methylene chloride). 1.467 g of 1- (6-methoxy-2-naphthyl) -2- (d-10-camphorsulfonyloxy) -1-propanone dimethylacetal are obtained in the form of a colorless glass. Yield: 76.8% (based on 1- (6-methoxy-2-naphthyl) -2-bromo-1-propanone). The MMR

-171

The product was composed of a 1 to 1 mixture of diastereomers.

Dissolve 1.067 g of the material thus obtained in 4 ml of methanol and allow to stand at 2-4 ° C for 2 days. 355 mg of colorless crystals are obtained. O. p .: 908: 5 'C. The crystals were recrystallized from methanol to give 220 mg of diastereomer as a pure product.

Mp .: 102-105 'C [α] D + 32.5 ° (c = 1, chloroform)

Infrared spectrum:

2950, 1753, 1634, 1611, 1487, 1354, 1273, 1219, 1180, 1166, 1068, 1042, 990, 919, 899, 862, 840 ^cm-1

NMR (CDC1 _3): δ 0.87 (3H, s), 1.12 (3H, s), 1.23 (3H, d,

J = 6Hz), 1.3-2.7 (7H, m), 3.04 (1H, d, J = 15Hz),

3.24 (3H, s), 3.35 (3H, s), 3.86 (3H, s), 3.86, (1H, d, J = 15Hz), 5.15- (1H, q, J = 6Hz), 7.04-7.26 (2H, m), 7.46-7.98 (4H, m)

Analysis calculated for C ₂₆ H ₃₃ O ₇ S: C, 63.78; H, 6.79; S, 6.55. Found: C, 63.66; H, 7.06; S: 6.57%

The other diastereomer can be isolated by liquid chromatography as a colorless oil (column: Microprorasil, Waters Co., column size: 7.8 mm x 30 cm; solvent: hexane: ethyl acetate = 9: 1).

[a] // + 4,2 '(c = 0.143, chloroform)

Infrared spectrum:

2950, 1750, 1631, 1608, 1485, 1352, 1271, 1216, 1172, 1062, 1040, 985, 914, 895, 855, 810 cm -1 ¹ H NMR (CDCl ₃ ):

δ 0.91 (3H, s), 1.14 (3H, s), 1.26 (3H, d, J = 6Hz),

1.3-2.7 (7H, m), 3.29 (1H, d, J = 5Hz), 3.30 (3H, s), 3.42 (3H, s), 3.74 (1H, d, J = 15Hz), 3.96 (3H, s), 5.20 (1H, q, J = 6Hz), 7.10-7.30 (2H, m), 7.50-8.02 ( 4H, m)

Example 81

1.922 g (5.000 mmol) of 1- (4-chlorophenyl) -2- (p-toluenesulfonyloxy) -1-propanone dimethylacetal and 500 mg (5.00 mmol) of calcium carbonate were stirred at 110 ° C. The oil was kept in an oil bath for 4 days in a 4: 1 mixture of dimethylformamide and water. Work-up as in Example 36 gave 337 mg of a colorless oily product. The oil contains 238 mg of methyl α- (4-chlorophenyl) propionic acid according to the MMR spectrum. Yield: 12.0%.

Example 82

Example 17 (1- (4-chlorophenyl) -2-hydroxy-1-propanone dimethylacetal) was prepared as a colorless oily product, starting from 1- (4-chlorophenyl) -2-bromo. Without further purification, this product was used for Example 83.

Infrared spectrum:

3450, 2975, 2930, 1600, 1492, 1398, 1108, 1095, 1052, 1016, 980, 829, 743 ^cm-1 18

Example 83

As in Example 20, 1- (4-chlorophenyl) -2- (p-toluenesulfonyloxy) -1-propanone dimethylacetal was prepared as white crystals. Mp .: 76-77 ° C; 1- (4-Chlorophenyl) -2-hydroxy-1-propanone-dimethylacetal prepared according to Example 82 was used as starting material. Yield: 86% based on 1- (4-chlorophenyl) -2-bromo-1-propanone.

Mp .: 78-78 ° C (from methanol)

Infrared spectrum:

2945, 1601, 1493, 1364, 1347, 1195, 1188, 1094, 1057, 1110, 936, 919, 822, 789, 669, 565 cm -1 ¹ H NMR (CDCl ₃ ):

δ 1.05 (3H, d, J = 6Hz), 2.40 (3H, s), 3.08 (3H, s), 3.10 (3H, s), 4.93 (1H, q, J = 6Hz), 7.25 (4H, s),

7.27 (2H, d, J = 8Hz), 7.76 (2H, d, J = 8Hz) Analysis for (C, _g H ₂ SO ₂ Cl):

date:

C: 56.17; H, 5.50; · Cl. 9.21; S: 8.33% found:

C: 56.22; H, 5.48; Cl: 9.13; S, 8.32%

Example 84

1- [4- (1-Oxo-2-isoindolinyl) phenyl] -2-chloro-1-1-propanone was prepared as colorless crystals as in Example 71; starting material is 2-phenyl-1-isoindolinone and α-chloropropionyl chloride. Yield: 89%.

Example 85

1- [4- (1-Oxo-2-isoindolinyl) phenyl] -2-hydroxy-1-propanone dimethylacetal was prepared as described in Example 17; starting from 1- [4- (loxo-2-isoindolinyl) phenyl] -2-chloro-1-propanone. Yield: 83%. Colorless crystals, m.p. 130-135 ° C.

Infrared spectrum:

3530, 1680, 1515, 1385, 1310, 1120, 1045, 740 ^cm-1

NMR (CDC1 ₃₎ δ 0.96 (3H, d, J = 7Hz), 2.36 (1H, br s), 3.20 (3H, s), 3.33 (3H, s), 4 10 (1H, broad q, J = 7Hz), 4.80 (2H, s), 7.4-7.6 (5H, m), 7.8-8.0 (3H, m) Anal. For the Hj / NOJ formula:

Calculated: C, 69.70; H. 6.47; N, 4.28%. Found: C, 69.63; H, 6.49; N: 4.21%

Example 86

1- [4- (1-Oxo-2-isoindolinyl) phenyl] -2-methanesulfonyloxy-1-propanone dimethylacetal was prepared as colorless crystals as in Example 73. Starting material is 1- [4- (1-oxo-2-isoindolinyl) phenyl] -2-hydroxy-1-propanone dimethylacetal; yield: 95%

Infrared spectrum:

1695,1520,1390, 1350,1340,1175,975,910,740 cm ¹

-181

188 108

NMR (CDC1 _3): δ 1.20 (3H, d, J = 7Hz), 3.11 (3H, s), 3.24 (3H,

s), 3.30 (3H, s), 4.81 (2H, s), 5.00 (1H, q, J = 7Hz),

7.4-7.6 (5H, m), 7.8-8.0 (3H, m)

Example 87

As described in Example 48, methyl [alpha] - [4- (1-oxo-2-isoindolinyl) -phenyl] -propionic acid is obtained in the form of colorless crystals. 1- [4- (1-Oxo-2-isoindolinyl) phenyl] -2-methanesulfonyloxy-1-propanone dimethylacetal was used as starting material. Yield: 86%.

Example 88

In the same manner as in Example 17, 1- (4-biphenyl) -2-hydroxy-1-propanone dimethylacetal was prepared as colorless crystals. 1- (4-biphenyl) -2-bromo-1-propanone is used as starting material; She. mp 78.5-80.0 ° C (from ether / n-hexane). Yield: 95%.

MMR (CDCl ₃ ) δ 100 (3H, d, J = 7Hz), 2.44 (1H, d, J = 3.1Hz),

3.23 (3H, s), 3.37 (3H, s), 4.14 (1H, q, d, J = 7Hz),

7.2-7.7 and 7.55 (m and s, 9H)

Infrared spectrum:

1118, 1102, 1045, 1007, 979, 838, 770, 735, 695 ^cm-1

Analysis for C ₁₇ H ₂₀ O ₃ :

Calculated: C, 74.97; H, 7.40; Found: C, 74.88; H, 7.27%

Example 89

In the same manner as in Example 7, 1- (4-biphenyl) -2-methanesulfonyloxy-1-propanone-dimethylacetal was prepared as a colorless oily product. 1- (4-Biphenyl) -2-hydroxy-1-propanone dimethylacetal was used as starting material. The product was used without purification in Example 90. Infrared spectrum:

1490, 1357, 1335, 1177, 1123, 1100, 1065, 1045, 971, 916, 847, 811, 773, 753, 740, 702, 538, 527 cm-1 MMR (CDCl ₃ ):

δ 1.21 (3H, d, J = 7Hz), 3.03 (3H, s), 3.24 (3H, s), 3.31 (3H, s), 5.01 (1H, q, J) 7Hz), 7.1-7.7 (m) - 7.56 (s) full 9H

Example 90

The methyl ester of α- (4-biphenyl) -propionic acid was prepared as in Example 21 in the form of a colorless oily product. Prepared according to example. Yield: 80.5% (based on 1- (4-biphenyl) -2-hydroxy-1-propanone dimethylacetal).

MMR (CDCl3): δ 1.47 (3H, d, J = 7Hz), 3.55 (3H, s), 3.68 (1H, q, J = 7Hz), 7.1-7.56 (9H, m)

Infrared spectrum:

1741, 1490, 1215, 1167, 765, 701 ^cm-1

Example 91

Example 57 was prepared using methyl 1- (4-biphenyl) -2-methanesulfonyloxy-1-propanone dimethylacetate as the starting material, m.p. yield: 68% (based on 1- (4-biphenyl) -2-hydroxy-ϊ-propanone dimethylacetal).

Example 92

1,1-Dimethoxy-2-hydroxy-1,2,3,4-tetrahydronaphthalene was prepared as in Example 17. The starting material is 2-bromo-1-oxo-1,2,3,4-tetrahydronaphthalene. The resulting material was used in Example 93 without further purification. Infrared spectrum:

138, 1080, 1058, 767 cm '

Example 93

As in Example 7, 1,1-dimethoxy-2-methanesulfonyloxy-1,2,3,4-tetrahydro-naphthalene is obtained in the form of colorless crystals; She. mp 113-114.5 ° C. The starting material used is the 1,1-dimethoxy-2-hydroxy-1,2,3,4-tetrahydronaphthalene prepared in Example 92. Yield: 46.5% (based on 2-bromooxo-1,2,3,4-tetrahydronaphthalene).

Mp: 113-114.5 ° C (recrystallized from methylene chloride / diethyl ether / n-hexane)

Infrared spectrum:

1361, 1340, 1206, 1175, 1141, 1033, 1060, 1050, 981, 959, 949, 917, 847, 781, 768, 625, 546, 530, 510 cm ^"1

MMR (CDCl ₃ ): δ 2 37 (2H, m), 2.9 (2H, m), 2.94 (3H, s), 2.98 (3H, s), 3.43 (3H, s) ), 5.27 (1H, t, J = 3Hz), 7.17 (3H, in), 7.63 (1H, m)

Analysis (C | _Ig H ₃ O ₅ S) Calcd: C: 54.53; H, 6.34; S, 11.20; Found: C, 54.73; H, 6.36; S: 11.10%

Example 94

Following the procedure described in Example 54, methyl indane-1-carboxylic acid can be prepared. The starting material is 1,1-dimethoxy-2-methanesulfonyloxy-1,2,3,4-tetrahydronaphthalene. Yield: 4%.

Example 95

The methyl ester of α-phenylpropionic acid can be prepared as described in Example 58; 51.4% yield19

-191

188,108 May; starting material is 1-phenyl-2- (p-toluenesulfonyloxy) -1-propanone dimethylacetal and tin chloride.

Example 96

2-Bromo-1- (4-difluoromethoxy-phenyl) -1-propanone was prepared as in Example 77 in the form of a colorless oily product; starting from 1- (4-difluoromethoxy-phenyl) -1-propanone.

MMR (CDCl3): δ 1.92 (3H, d, J = 7Hz), 5.23 (1H, q, J = 7Hz),

6.58 (1H, t, J = 72Hz), 7.15 (2H, d, J = 9Hz), 8.00 (2H, d, J = 9Hz)

Example 97

1- (4-Difluoromethoxy-phenyl) -2-hydroxy-1-propanone dimethylacetal was prepared as in Example 17 in the form of a colorless oily product. The starting material was 2-bromo-1- (4-difluoromethoxy / phenyl) -propanone.

Infrared spectrum:

3600, 3200, 1515, 1385, 1230, 1130, 1050, 840 cm ^-1

NMR (CDC1 _3): δ 0.95 (3H, d, J = 7Hz), 2.37 (1H, d, J = 3 Hz);

3.23 (3H, s), 3.33 (3H, s), 4.10 (1H, dq, J = 3 and 7Hz), 6.52 (1H, t, J = 74Hz), 7.10 ( 2H, d, J = 9Hz), 7.49 (2H, d, J = 9Hz)

Example 98

In the same manner as in Example 7, 1- (4-difluoromethoxy-phenyl) -2-methanesulfonyloxy-1-propanone-dimethylacetal was prepared in the form of a colorless oily product, starting from 1 - (4-Difluoromethoxy-phenyl) -2-hydroxy-1-propanone dimethylacetal was used. Yield: 55% (starting from 1- (4-difluoromethoxy-phenyl) -1-propanone). Infrared spectrum:

1515, 1360, 1235, 1180, 1130, 1100, 1070, 1045, 975, 920, 540, 530 cm -1 ¹ H NMR (CDCl 3:

δ 1.18 (3H, d, J = 7Hz), 3.09 (3H, s), 3.15 (3H, s), 3.18 (3H, s), 4.98 (1H, q, J = 7Hz), 6.53 (1H, t, J = 74Hz), 7.10 (2H, d, J = 9Hz), 7.45 (2H, d, J = 9Hz)

Example 99

In a similar manner to Example 77, 2-bromo-1- (4-difluoromethoxy-phenyl) -3-methyl-1-butanone can be prepared as a colorless oily product. 1- (4-Difluoromethoxy-phenyl) -3-methyl-1-butanone is used as starting material.

Infrared spectrum:

1690, 1605, 1230, 1120, 1055 cm -1 ¹ H NMR (CDCl ₃ ):

δ 1.02 (3H, d, J = 7Hz), 1.21 (3H, d, J = 7Hz),

2.1-2.8 (1H, m), 4.85 (1H, d, J = 9Hz), 6.60 (1H, t, J = 74H _Z), 7.18 (2H, d, J = 9Hz), 8.03 (2H, d, J = 9Hz)

Example 100

Following the procedure of Example 17, 1- (4-difluoromethoxy-phenyl) -2-hydroxy-3-methyl-1-butanone-dimethylacetal can be obtained in the form of a colorless oily product; starting from 2-bromo-1- (4-difluoromethoxy-phenyl) -3-methyl-1-butanone.

Infrared spectrum:

3600, 3300, 1515, 1390, 1230, 1130, 1050 cm -1 MMR (CDCl ₃ ):

δ 0.69 (3H, d, J = 6Hz), 0.88 (3H, d, J = 6Hz),

1.2-1.7 (1H, m), 2.50 (1H, d, J = 3Hz), 3.22 (3H, s), 3.24 (3H, s), 3.70 (1H, dq, J = 3 and 6Hz), 6.50 (1H, t, J = 74Hz), 7.07 (2H, d, J = 9Hz), 7.52 (2H, d, J = 9Hz)

Example 101

In the same manner as in Example 13, 1- (4-difluoromethoxy-phenyl) -2-methanesulfonyloxy-3-methyl-1-butanone-dimethylacetal can be obtained in the form of a colorless oily product. The starting material is 1- (4-difluoromethoxy-phenyl) -2-hydroxy-3-methyl-1-butanone dimethylacetal. Yield: 76% (obtained from 1- (4-difluoromethoxy-phenyl) -3-methyl-1-butanone). Leaving the resulting material to stand at low temperature, the product crystallizes.

O.p .: 60-61 'C Infrared spectrum:

1515, 1350, 1230, 1180, 1145, 1080, 1055, 1035, 975 cm ^-1

MMR (CDCl3): δ 0.67 (3H, d, J = 6Hz), 0.91 (3H, d, J = 6Hz),

1.4-1.9 (1H, m), 3.17 (3H, s), 3.19 (3H, s), 3.22 (3H, s), 4.75 (1H, d, J = 4Hz), 6.50 (1H, t, J = 74Hz), 7.08 (2H, d, J = 9Hz), 7.50 (2H, d, J = 9Hz)

Example 102

In the same manner as in Example 54, methyl 4- (difluoromethoxy-phenyl) -propionic acid methyl ester was obtained in a yield of 51%. 1- (4-Difluoromethoxy-phenyl) -2-methanesulfonyloxy-1-propanone was used as starting material (Example 98).

Infrared spectrum:

1745, 1515, 1385, 1230, 1160, 1130, 1050 cm -1 ¹ H NMR (CDCl ₃ ):

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

Example 103

0.368 g of 1- (4-difluoromethoxy-phenyl) -2-methanesulfonyloxy-3-methyl-1-butanone-dimethylacetal and

0.100 g of calcium carbonate under reflux al-201

188 108 was heated to reflux for 3 days in 3 ml water / methanol (3: 7). The reaction mixture is worked up in a known manner; Purification by chromatography afforded 0.132 g of methyl α- (4-difluoromethoxy-phenyl) -isovaleric acid as a colorless oily product. Yield: 51%.

NMR (CDC1 _3):

0.71 (3H, d, J = 7Hz), 1.02 (3H, d, J = 7Hz),

2.0-2.5 (1H, m), 3.14 (1H, d, J = 11Hz), 3.63 (3H, s), 6.47 (1H, t, J = 74Hz), 7, 02 (2H, d, J = 9Hz), 7.31 (2H, d, J = 9Hz)

Example 104 In a 1: 4 mixture of water and dimethylformamide (1: 4), 0.368 g of 1- (4-difluoromethoxy-phenyl) -2-methanesulfonyloxy-3-methyl-1-butanone was dissolved in 0.100 g of calcium carbonate. The solution was heated at 110 ° C for 12 days and then refluxed for 3 days. The reaction mixture is worked up in the usual manner; 78 mg of methyl α- (4-difluoromethoxy-phenyl) -isovaleric acid are obtained. Yield: 30%.

Example 705

Dissolve 230 mg of metal sodium in 3 ml of anhydrous methanol. To the solution was added a solution of 1.43 g of 2-bromo-1- (4-ethoxyphenyl) -3-methyl-1-butanone in 2 ml of anhydrous methanol. The mixture was stirred at room temperature for 1.5 hours and then at 50 ° C for 45 minutes. Workup in the usual manner gave crude 1- (4-ethoxyphenyl) -2-hydroxy-3-methyl-1-butanone dimethylacetal (1.344 g) as a colorless product. The product can be used for Example 106 without further purification. Infrared spectrum:

3600-3300, 1610, 1515, 1485, 1400, 1250, 1175, 1115, 1050, 990, 925, 840, 810 cm '

NMR (CDC1 _3):

δ 0.68 (3H, t, J = 6Hz), 0.87 (3H, d, J = 6Hz), 1.39 (3H, t, J = 7Hz), 1.2-1.7 (1H, m), 2.50 (1H, d, J = 3Hz), 3.22 (3H, s), 3.24 (3H, s), 3.68 (1H, dd, J = 3 and 5Hz), 4 , 01 (2H, q, J = 7Hz), 6.82 (2H, d, J = 9Hz), 7.37 (2H, d, J = 9Hz)

Example 106

As described in Example 13, 1- (4-ethoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone dimethylacetal can be obtained as colorless crystals. 1- (4-Ethoxyphenyl) -2-hydroxy-3-methyl-1-butanone dimethylacetal was used as starting material. Yield: 62%. (Calculated for 2-bromo-1- (4-ethoxyphenyl) -3-methyl-1-butanone).

M.p .: 83-87 ° C

Infrared spectrum:

1610, 1335, 1260, 1245, 1175, 955, 850, 840 cm -1 ¹ H NMR (CDCl ₃ ):

δ 0.71 (3H, d, J = 6Hz), 0.94 (3H, d, J = 6Hz), 1.40 (3H, t, J = 7Hz), 1.5-1.9 (1H, m), 3.18 (3H,

s), 3.20 (3H, s), 3.24 (3H, s), 4.02 (2H, q, J = 7Hz),

4.57 (1H, d, J = 3Hz), 6.85 (2H, d, J = 9Hz), 7.37 (2H, d, J = 9Hz)

Example 707

724 mg of 1- (4-ethoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone dimethylacetal and 200 mg of calcium carbonate were dissolved in 7 ml of a 3: 7 mixture of water and methanol and refluxed. Boil for 11 hours. The mixture was worked up and purified in the usual manner to give 467 mg of methyl α- (4-ethoxyphenyl) isovaleric acid as a colorless oily product. Yield: 99%. Boiling point: 160 ° C (oil bath temperature), 17 torr. '

MMR (CDCl3): δ 0.70 (3H, d, J = 6Hz). 1.01 (3H, d, J = 6Hz),

1.38 (3H, t, J = 7Hz), 2.0-2.6 (1H, m), 3.07 (1H, d, J = 10Hz), 3.30 (3H, s), 3, 97 (2H, q, J = 7Hz), 6.80 (2H, d, J = 9Hz), 7.20 (2H, d, J = 9Hz) Anal.

Calculated: C, 71.16; H, 8.53; Found: C, 70.93; H: 8.52%

Example 108

As described in Example 105, 2.58 g of 1- (4-methoxyphenyl) -2-hydroxy-3-methyl-1-butanone dimethylacetal was obtained as a colorless oily product. 2.71 g of 2-bromo-1- (4-methoxyphenyl) -3-methyl-1-butanone are used as starting material; the resulting material was used without further purification in Example 109:

Infrared spectrum:

3600-3300, 1615, 1515, 1255, 1175, 1115, 1045, 840 cm ^-1

NMR (CDC1 _3): δ 0.70 (3H, d, J = 6Hz), 0.87 (3H, d, J = 6Hz);

1.2-1.7 (1H, m), 2.53 (1H, broad s), 3.33 (3H, s), 3.34 (3H, s), 3.69 (1H, d, J). = 5Hz), 3.78 (3H, s), 6.83 (2H, d, J = 9Hz), 7.40 (2H, d, J = 9Hz)

Example 709

The 1- (4-methoxyphenyl) 2-hydroxy-3-methyl-1-butanone dimethylacetal (2.58 g) obtained in Example 108 was dissolved in 5 ml of anhydrous pyridine and the solution was stirred under ice-cooling. Methanesulfonic anhydride (2.00 g) was added and the mixture was stirred under ice-cooling for 4 hours and then at room temperature for 2 hours. Water (20 ml) was added; the mixture was stirred at room temperature for 1 hour and then extracted with diethyl ether (3 x 20 mL). The combined extracts were washed with water (5 x 5 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily product was purified by column chromatography (Florisil, methylene chloride); 3.10 g of 1- (4-methoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone dimethylacetal are thus obtained in the form of a colorless oil.

-211

188 108 Ban. Leaving the resulting material at room temperature crystallizes. Yield: 93% (based on 2-bromo-1- (4-ethoxyphenyl) -3-methyl-1-butanone).

Mp .: 71.5-73 ° C

Infrared spectrum:

1620, 1525, 1355, 1260, 1180, 1105, 1055, 980, 970, 960, 945, 865, 850 cmMMR spectrum (CDC1 _3):

δ 0.69 (3H, d, J = 6Hz), 0.89 (3H, d, J = 6Hz),

1.5-1.9 (1H, m), 3.14 (3H, s), 3.16 (3H, s), 3.21 (3H, s), 3.76 (3H, s), 4 , 72 (1H, d, J = 4Hz), 6.82 (2H, d, J = 9Hz), 7.36 (2H, d, J = 9Hz)

Example 110

As in Example 107, methyl methyl alpha- (4-methoxyphenyl) isovaleric acid was prepared as a colorless oily product. 1- (4-methoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone dimethylacetal was used as starting material. Yield: 94%

Infrared spectrum:

1740, 1515, 1255, 1160, 1040, 830 cm-1 NMR (CDCl ₃ ):

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

Example 111

To a suspension of 0.65 g of sodium hydride (55% in mineral oil) in 10 ml of anhydrous tetrahydrofuran is added 2.7 ml of ethylene glycol under ice-cooling. After stirring at room temperature for 40 minutes, 2.71 g

2-Bromo-1- (4-methoxyphenyl) -3-methyl-1-butanone was added and stirring continued at 60 ° C for 12 hours. After adding 50 ml of water, the reaction mixture was extracted three times with 30 ml of methylene chloride. The combined extracts were washed with water (10 mL), dried over magnesium sulfate, and concentrated in vacuo. The oily residue was purified by column chromatography (Florisil, methylene chloride). In this way, 719 mg

2-Hydroxy-1- (4-methoxyphenyl) -3-methyl-1-butanone ethylene acetal is obtained in the form of a colorless oily product. Yield: 29%.

Infrared spectrum:

3600-3400, 1620, 1520, 1255, 1175, 1040, 845 cm ^-1

MMR (CDCl ₃ ): δ 0.88 (3H, d, J = 6Hz), 0.90 (3H, d, I = 6Hz),

1.2-1.7 (1H, m), 2.55 (1H, broad d, J = 5Hz),

3.5-4.2 (5H, m), 3.77 (3H, s), 6.83 (2H, d, J = 9Hz), 7.36 (2H, d, 9Hz)

Example 112

In the same manner as in Example 13, 1- (4-methoxyphenyl) 2-methanesulfonyloxy-3-methyl-1-butanone-ethylene acetal was prepared as colorless crystals.

The starting material was 2-hydroxy-1- (4-methoxyphenyl) 3-methyl-1-butanone ethylene acetal. Yield: 78%.

M.p .: 82-83 ° C

Infrared spectrum:

1610,1510,1335,1250,1170,1050,970,940,930, 815 cm ' ¹

MMR (CDCl3): δ 0.91 (6H, d, J = 7Hz), 1.5-1.9 (1H, m), 2.99 (3H, s), 3.6-4.2 ( 4H, m), 3.75 (3H, s), 4.67 (1H, d, J = 4Hz), 6.83 (2H, d, J = 9Hz), 7.34 (2H, d, J = 9 Hz)

Example 113 5 ml of a 3: 7 w / v mixture of methanol and 495 mg of 1- (4-methoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone-ethylene-acetal and 150 mg of calcium carbonate are dissolved and the solution is refluxed for 48 hours. Work up the mixture in the usual manner and purify by column chromatography; 307 mg of 2-hydroxyethyl a- (4-methoxyphenyl) isovaleric acid are obtained in the form of a colorless oily product. Yield: 81%.

Infrared spectrum:

3600-3200, 1735, 1610, 1510, 1255, 1170, 1160, 1035, 830 cm -1 ¹ H NMR (CDCl ₃ ):

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

Example 114

350 mg of 1-phenyl-2- (p-toluenesulfonyloxy) -1-propanone dimethylacetal, 0.20 mL of trimethylsilyl trifluoromethanesulfonate and 1 mL of ortho-formic acid trimethyl ester at 65 ° C 9 stir for an hour. The mixture was worked up in the usual manner to afford the methyl ester of α-phenylpropionic acid. Yield: 50.5% by liquid chromatography (similar to Example 57).

Example 115

According to Example 58, a-phenylpropionic acid methyl ester was prepared in 80% yield. The starting material was 1-phenyl-2- (p-toluenesulfonyloxy) -1-propanone dimethylacetal, which was treated with ferric chloride.

Example 116

By the procedure of Example 80, 1- (6-methoxy-2-naphthyl) -2-hydroxy-1-propanone-dimethylacetal and 1-10-camphorsulfonyl chloride were reacted with 1- (6-methoxy-2-naphthyl) -2- (1). -10-camphorsulfonyloxy) -1-propanone dimethylacetal is prepared as a mixture of two diastereomers. This mixture was recrystallized twice from methanol to give a sheet

One of the diastereoisomers was obtained in the form of colorless crystals (188 108), m.p. 93-96 ° C, [α] ³ -32.2 (c = 0.801, chloroform). The IR and MMR spectral data of this product are all identical to one of the diastereomers of 1- (6-methoxy-2-naphthyl) -2- (d-10-camphorsulfonyloxy) -1-propanone-dimethylacetal prepared according to Example 80. α] θ + 32.5 ° (c = 1, chloroform),

The 1-10-camphorsulfonyl chloride used as starting material was prepared from the commercially available 1-10-camphorsulfonic acid ammonium salt ([α] ²⁵ D -18.4 ° (c = 5.3, water)) using thionyl chloride. as described at Sutherland H. and R.L. Shriner... J Am Chem Soc, 58, 62 (1936), [a] ^{6 2} D -32.3 ° (c = 1.36, chloroform) , m.p. 58-64 ° C.

Example 117

555 mg of the diastereomer of 1- (6-methoxy-2-naphthyl) -2- (1-10-camphorsulfonyloxy) -1-propanone-dimethyl-acetal prepared in Example 116 were reacted according to the procedure of Example 56, 249 mg of (+) - α- (6-methoxy-2-naphthyl) propionic acid methyl ester was obtained in 90% yield with IR and MMR spectral data identical to those of Example 56. Product rotation [α] θ + 75.0 ° (c = 0.949, chloroform).

Example 118

To a solution of 799 mg of 1- (6-methoxy-2-naphthyl) -2-hydroxy-1-propanone dimethylacetal and 3 ml of anhydrous pyridine at room temperature was added 833 mg of p-toluenesulfonyl chloride and the mixture was stirred at room temperature for 3 hours. days. Water (30 ml) was added and the mixture was extracted three times with 10 ml of dichloromethane each. The extracts were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The oily residue was chromatographed on a silica gel column eluting with dichloromethane. Yield: 1.019 g (81.9%) of 1- (6-methoxy-2-naphthyl) -2- (p-toluenesulfonyloxy) -1-propanone dimethylacetal as a colorless oil.

IR Spectrum: (Clearly):

1612, 1489, 1360, 1278, 1192, 1178, 899, 560 cm ^-1 .

NMR Spectrum (CDC1 _3, δ ppm):

1.13 (3H, d, J = 7Hz), 2.40 (3H, s), 3.13 (3H, s), 3.21 (3H, s), 3.88 (3H, s), δ , 04 (1H, q, J = 7Hz), 7.0-7.9 (10H, m).

(The letters mean s = singlet; d = doublet; q = quadruplet; m = multiplet)

Example 119

To a solution of 132 mg of metal sodium and 5 ml of anhydrous methanol was added 879 mg of 1- (6-methoxy-2-naphthyl) -2-bromo-1-propanone and the solution was stirred at room temperature for 7 hours. Water (20 mL) was added and the mixture was extracted three times (10 mL each with dichloromethane). The extracts were combined, 2 drops of pyridine were added and dried over anhydrous magnesium sulfate and evaporated in vacuo. The crude 1- (6-methoxy-2-naphthyl) -2-hydroxy-1-propanone dimethylacetal thus obtained was dissolved without purification in 2 ml of anhydrous pyridine, to which was added 0.60 ml of benzenesulfonyl chloride at room temperature with stirring. the mixture was stirred for 20 hours. Water (10 mL) was added and the mixture was extracted three times (10 mL each with dichloromethane). The extracts were combined, washed with water (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The oily residue was chromatographed on a silica gel column eluting with dichloromethane. There was thus obtained 1.24 g (82.0% of starting material of 1- (6-methoxy-2-naphthyl) -2-bromo-m-1-propanone) of 1- (6-methoxy-2-naphthyl) -2-. (benzenesulfonyloxy) -1-propanone dimethylacetate as a colorless oil.

IR spectrum (pure):

1637, 1612, 1488, 1456, 1365, 1278, 1190, 925, 900, 761, 598 ^cm-first

NMR Spectrum (CDC1 _3, δ ppm):

1.153 H, d, J = 711 (s), 3.10 (311, s). 3.18 (311s). 5.08 (1H, q, J 7Hz), 7.0 8.1 (1H, m).

Example 120

Trimethyl iodosilane (0.53 mL, 0.75 g) was dissolved in dichloromethane (10 mL) under argon and 1.074 g of 1- (6-methoxy-2-naphthyl) -2- (1.04 g) was added to the solution under stirring at room temperature for 20 minutes. p-toluenesulfonyloxy) -1-propanone-dimethylacetal and 10 ml of anhydrous dichloromethane are added and the mixture is stirred at the same temperature for 40 minutes. 20 ml of a 20% aqueous solution of sodium thiosulphate are added and the mixture is stirred overnight. The organic layer was washed five times with 20 mL portions of 20% aqueous sodium thiosulfate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography over silica gel using chloroform as eluent. There was thus obtained 495 mg (81%) of the methyl ester of α- (6-methoxy-2-naphthyl) -propionic acid, which had the same NMR spectral data as in the product of Example 54.

Example 121 g (14.8 mmol) of 1- (5-bromo-6-methoxy-2-naphthyl) -2-methanesulfonyloxypropan-1-one neopentylene acetal and 4 g of the moist form of the basic IRC 50 resin under pressure is placed in a reactor. After Ii / 144, 144 ml of aleion and 48 ml of water are added to the reaction mixture, and the reaction mixture is maintained at 120 ° C and 5 atmospheres for 8 hours.

TLC showed 2- (5-bromo-6-methoxy23) in 95% yield.

-231

188 108

2-Naphthyl) -propionic acid 2-hydroxymethyl-2-methyl-propyl ester is formed. The acetone was distilled off from the reaction mixture and the resulting slurry was transferred to a pressurized reactor; the solvent ratio is then adjusted to 48 ml water / 150 ml acetone. Concentrated sulfuric acid (7 ml) was added and the reaction mixture was heated at 80 ° C for 3.4 hours at 3.4 atmospheres. The acetone was then distilled off in vacuo, the mixture was extracted with methylene chloride (300 mL) and the organic layer was extracted with aqueous sodium hydroxide. The aqueous layer was separated and 2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid precipitated after addition of a concentrated salt band. Yield: 3.35 g. Mp: 167-170 ° C. Recrystallization from acetone / water gave a white crystalline product. Yield: 57.6% of 1- (5-bromo-6-methoxy-2-naphthyl) -2-methanesulfonyloxypropan-1-one neopentylene acetal.

Claims (35)

A process for the preparation of a substituted carboxylic acid derivative of the formula (I) and the esters of these compounds, wherein Ar is optionally substituted with halogen, C 1-6 alkyl, C 1-4 alkoxy, phenyl or naphthyl, C 1-4 alkylcarbonylamino, or 1-3 halogen (C 1-4) phenyl or naphthyl substituted by alkoxy, or a 5-6 membered heterocyclic group containing one ring member, or an optionally substituted oxo substituted one or eight membered ring carbon atom containing a nitrogen atom containing a nitrogen atom; . R ¹ is hydrogen or C 1-5 alkyl, R 'may form together with the adjacent carbon atom a fused ring, R ^{2 is} hydrogen, C 1-4 alkyl, or hydroxy (C 1-6) alkyl, Ar and R 'may be taken together to form an indane ring together with a trapped alkylene group, characterized in that it is an α-sulfonyloxy ketone acetal of formula II wherein R ³ and R ^J are independently C 1 -C 4 alkyl, or together C 1-4 alkylene, or one together with the intervening carbon and oxygen They can form a 5-7 membered heterocyclic ring, R ⁵ is C 1 -C 4 alkyl or phenyl, naphthyl or camphoryl optionally substituted with halo or C 1 -C 4 alkyl, Ar and R ¹ are as defined above, (a) hydrolyzed in the presence of a base at a temperature between 0 ° C and 250 ° C, or b) with an oxygen scavenger such as iodine tri (C 1-4) alkylsilane, tri (C 1-4) alkylsilyl perfluoro (C 1-4) xanesulfonate or Lswis acid -40 At a temperature of from about 150 ° C to about 150 ° C in an aprotic solvent. (Priority: September 9, 1981) A process for the preparation of a substituted carboxylic acid derivative of the formula (I) and the esters of these compounds, wherein Ar is optionally substituted with halogen, C 1-6 alkyl, C 1-6 alkoxy, phenyl or naphthyl, C 1-4 alkylcarbonylamino, or 1-3 halo (C 1-4) phenyl or naphthyl substituted by alkoxy, or a 5-6 membered heterocyclic group containing one sulfur atom as a ring member, or a phenyl or naphthyl group containing from 8 to 10 carbon atoms substituted by oxo substituted one membered ring containing a nitrogen atom; . R ¹ is hydrogen or C 1-5 alkyl, R 'may form together with the adjacent carbon atom a fused ring, R ^{2 is} hydrogen, C 1-4 alkyl, or hydroxy (C 1-6) alkyl, Ar and R ^{1 taken} together with a bonded alkylene group may form an indane ring, characterized in that it is an α-sulfonyloxy ketone acetal of formula (II) wherein R ³ and R ⁴ are independently C 1 -C 4 alkyl, or together C 1-4 alkylene, or together with the intervening carbon and oxygen atoms 5-7 membered heterocyclic ring, R ⁵ is C 1 -C 4 alkyl or phenyl, naphthyl or camphoryl optionally substituted with halo or C 1 -C 4 alkyl, Ar and R ¹ are hydrolyzed in the presence of a base at 0 ° C to 250 ° C in an inert solvent. (Priority: October 15, 1980) 3. A process for the preparation of a substituted carboxylic acid derivative of formula (I) having an aromatic group at the α-position and esters of these compounds, wherein: Ar is optionally substituted with halogen, C 1-6 alkyl, C 1-4 alkoxy, phenyl or naphthyl, C 1-4 alkylcarbonylamino, or 1-3 halogen (C 1-4) phenyl or naphthyl substituted by alkoxy, -241 188 108 or 5-6 membered heterocyclic groups containing one sulfur atom as ring member or phenyl or naphthyl group optionally substituted with oxo and substituted with 8 to 10 carbon atoms containing one ring member substituted by a fused ring, R ¹ is hydrogen or C 1-5 alkyl, R ¹ may form together with the adjacent carbon atom a fused ring, R ^{2 is} hydrogen, C 1-4 alkyl, or hydroxy (C 1-6) alkyl, Together with Ar and R ¹ , taken together with an attached alkylene group, they may form an indane ring, characterized in that it is an α-sulfonyloxy ketone acetal of formula II wherein R ³ and R ⁴ are each independently C 1 -C 4 alkyl or A C 4 alkylene group, or together with the intervening carbon and oxygen atoms They can form a 5-7 membered heterocyclic ring, R ⁵ is C 1 -C 4 alkyl or phenyl, naphthyl or camphoryl optionally substituted with halo or C 1 -C 4 alkyl, Ar and R ¹ are as defined above with an oxygen scavenger such as iodine tri (C 1 -C 4) alkylsilane, tri (C 1 -C 4) alkylsilyl perfluoro (C 1 -C 4) alkanesulfonate or Lewis acid at -40 ° C to 150 ° C in an aprotic solvent. (Priority: June 15, 1981) A process for the preparation of a compound of the formula I in which Ar is 4-isobutylphenyl, R ¹ is methyl and R ² is hydrogen, (C 1 -C 4) alkyl, or hydroxy (C 1 -C 6) alkyl, Ar and R ^{1 taken} together with a trapped alkylene group may form an indane ring, characterized in that a compound of formula (II) wherein Ar and R ¹ are as defined herein, R ³ and R ⁴ each independently represent a C 1-4 alkyl group, or together a C 1-4 alkylene group, or together with the intervening carbon and oxygen atom may form a 5-7 membered heterocyclic ring, R ⁵ is C 1 -C 4 alkyl or phenyl, naphthyl or camphoryl optionally substituted with halogen or C 1 -C 4 alkyl, and is hydrolyzed in the presence of a base at 0 to 250 ° C. (Priority: September 11, 1980) The process according to claim 2, wherein the hydrolysis is carried out at a temperature between 50 and 180 ° C. (Priority: October 15, 1980) The process according to claim 2, wherein the hydrolysis is carried out in a proton-free or proton-polar solvent. (Priority: October 15, 1980) The process according to claim 2, wherein the hydrolysis is carried out under neutral or alkaline conditions. (Priority: October 15, 1980) The process according to claim 2, wherein the hydrolysis is carried out in the presence of a base. (Priority: October 15, 1980) 9. The process of claim 8, wherein the base is present in an amount of at least 1 molar equivalent relative to the compound of Formula II (Priority: October 15, 1980). 10. The process according to claim 3, wherein the oxygen scavenger is iodine tri (C1-C4) alkylsilane, tri (C1-C4) alkylsin-perfluoro (C1-C4) -. alkanesulfonate or Lewis acid. (Priority: June 15, 1981) 11. The process according to claim 3, wherein the compound of formula II is reacted with iodine trimethylsilane, trimethylsilyl trifluoromethanesulfonate, aluminum chloride, tin chloride, ferric chloride. (Priority: June 15, 1981) 12. The process of claim 3, wherein the oxygen scavenger is used in an amount of at least 0.1 molar equivalent relative to the compound of formula (II). (Priority: June 15, 1981) 13. The process of claim 3, wherein the oxygen scavenger is used in an amount of from 0.2 to 5.0 molar equivalents per mole of the compound of formula (II). (Priority: June 15, 1981) 14. The process of claim 3, wherein the oxygen scavenger is treated at a temperature of -40 'C to 150' C. (Priority: June 15, 1981) 15. The method of claim 3, wherein the oxygen scavenger is treated at a temperature of -20 ° C to 100 ° C. (Priority: June 15, 1981) A process for the preparation of a compound of formula (I) according to claim 2 wherein Ar is 6-methoxy-2-naphthyl and R ¹ is methyl, and R ³ , R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compound of formula II is hydrolyzed. (Priority: October 15, 1980) 17. A process according to claim 3 for the preparation of a compound of formula I wherein: Ar is 6-methoxy-2-naphthyl and and R ¹ is methyl and R ³ , R ⁴ and R ⁵ are as defined in claim I, wherein the corresponding compound of formula II is treated with an oxygen scavenger. (Priority: June 15, 1981) 18. A, 2. A process according to claim 1 for the preparation of compounds of formula I wherein: -251 188 108 Ar is 4-isobutylphenyl and R ¹ is methyl and where R ³ , R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compound of formula (II) is hydrolyzed. (Priority: 1980. October 15) 19. A process according to claim 3 for the preparation of compounds of formula I wherein Ar is 4-isobutylphenyl and R ¹ is methyl and wherein R ³ , R ⁴ and R ⁵ are as defined in claim 1, wherein the corresponding compound of formula II is treated with an oxygen scavenger. (Priority: June 15, 1981) A process for the preparation of a compound of formula I according to claim 2 wherein Ar is lower 4-alkoxyphenyl, R ¹ is isopropyl and R ³ , R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compound of formula (II) is hydrolyzed. (Priority: June 15, 1980) 21. A process according to claim 3 for the preparation of compounds of formula I wherein Ar is lower 4-alkoxyphenyl, R ¹ is isopropyl and R ³ , R ⁴ and R ⁵ are as defined in claim 1, wherein the corresponding compound of formula (II) is treated with an oxygen scavenger. (Priority: June 15, 1981) 22. A process according to claim 2 for the preparation of compounds of formula I wherein Ar is lower 4-alkoxyphenyl, R ¹ is methyl and R ³ , R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compound of formula (II) is hydrolyzed. (Priority: June 15, 1980) 23. A process according to claim 3 for the preparation of compounds of formula I wherein Ar is 4- (C 1 -C 4) alkoxyphenyl, R ¹ is methyl and R ³ , R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compound of formula (II) is treated with an oxygen scavenger. (Priority: June 15, 1981) 24. A process for the preparation of compounds of formula I according to claim 2, wherein Ar is 4- (difluoromethoxy) phenyl, R ¹ is isopropyl and R ^J, R ⁴ and R ⁵ are as defined in claim 1, characterized in that the hydrolysis of the (II) compound. (Priority: June 15, 1980) 25. A process according to claim 3 for the preparation of compounds of formula I wherein Ar is 4- (difluoromethoxy) phenyl, R ¹ is isopropyl-p ¹ and R ³ , R ⁴ and R ⁵ are as defined in claim 1, wherein the corresponding compound of formula (II) 26 is treated with an oxygen scavenger. (Priority: June 15, 1981) 26. The process of claim 2 for the preparation of compounds of formula I wherein Ar is 2-thienyl, R ¹ is methyl and R ³ , R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compound of formula (II) is hydrolyzed. (Priority: June 15, 1980) 27. A process according to claim 3 for the preparation of compounds of formula I wherein Ar is 2-thienyl, R ¹ is methyl and R ³ , R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compound of formula (II) is treated with an oxygen scavenger. (Priority: June 15, 1981) 28. The process of claim 2 for the preparation of compounds of formula I wherein Ar is 4-acetylaminophenyl, R ¹ is methyl and R ³ , R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compounds of formula II are hydrolyzed. (Priority: June 15, 1980) 29. A process according to claim 3 for the preparation of compounds of formula I wherein Ar is 4-acetylaminophenyl, R ¹ is methyl and R ³ , R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compounds of formula II are treated with an oxygen scavenger. (Priority: June 15, 1981) 30. A process according to claim 2 for the preparation of compounds of formula I wherein Ar is 4- (1-oxo-2-isoindolinyl) phenyl, R 'is methyl and R ³ , R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compounds of formula II are hydrolyzed. (Priority: June 15, 1980) A process for the preparation of a compound of formula (I) according to claim 3 wherein Ar is 4- (1-oxo-2-isoindolinyl) phenyl, R * is methyl and R ³ , R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compounds of formula II are treated with an oxygen scavenger. (Priority: June 15, 1981) 32. A process according to claim 2 for the preparation of compounds of formula I wherein Ar is 4-biphenyl, R ¹ is a methyl group and R ³ , R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compound of formula (II) is hydrolyzed. (Priority: June 15, 1980) 33. A process according to claim 3 for the preparation of compounds of formula I wherein Ar is 4-biphenylyl, R ¹ is methyl and -261 188 108 R ³ , R ⁴ and R ⁵ have the same meaning as in claim 1, wherein the corresponding compound of formula II is treated with an oxygen scavenger. (Priority: June 15, 1981) 34. A process according to claim 2 for the preparation of compounds of formula I wherein Ar is 4- (tert-butyl) phenyl, R ¹ is isopropyl and R ³ , R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compounds of formula II are hydrolyzed. (Priority: June 15, 1980) 35. The process of claim 3 for the preparation of a compound of formula I wherein: Ar is 4- (tert-butyl) phenyl, R ¹ is isopropyl and R ^3, R ⁴ and R ⁵ are as defined in claim 1, characterized in that the corresponding compound of formula (II) is treated with an oxygen-absorbing material ^10. (Priority: June 15, 1981)