CA1186319A - Alphasulfonyloxyketone acetals - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention provides alphasulfonyloxyketone acetals of the general formula (II) wherein R3 and R4, independently from each other,represent an alkyl group, or taken together, represent an alkylene group; R5 represents a substituted or unsubstituted alkyl group or an aromatic group; and Ar represents an aromatic group and R1 represents a hydrogen atom or a saturated aliphatic group, or Ar and R1 form a condensed ring together with the carbon atom to which they are bonded. The acetals can be hydrolyzed, or treated with an agent having affinity for oxygen, to yield an alpha-aromatic group substituted alkanoic acid or its ester of the general formula

Description

~18~;319 This application is divided out of Patent Application Serial No. 385,670. Application No. 385,670 relates to a novel process for preparation of alpha-aromatic group substituted alkanoic acids or esters thereof. More specifically, Application No. 385,670 pertains to a process for preparing alpha-aromatic group substituted alkanoic acids or esters thereof represented by the following general formula ,Rl Ar-CH-COOR2 (I) wherein Ar represents an aromatic group, Rl represents a ~ydrogen atom or a saturated aliphatic group, or Ar and Rl may form a condensed ring together with the carbon atom to which they are bonded, and R2 represents a hydrogen atom, an alkyl group, or a hydroxyalkyl group; and novel intermediate compounds useful in the aforesaid process.
Many of the compounds of general formula (I) are commercially valuable. For example, alpha-~4-isobutylphenyl) propionic acid correspQndingto a compound of general formula ~I) in which Ar is a 4~isobutylphenyl group~
is a methyl group, and R2 is a hydrogen atom, is known as "Ibuprofen'! which is an anti-inflammatory drug.

~' ~ 31~ 454627 Alpha-(6-methoxy-2-naphthyl)propionic acid corresponding to a compound of general formula (I) in which Ar is a 6-methoxy-2-naphthyl group, Rl is a methyl group, and R2 is a hydrogen atom is known as "Naproxen". Alpha-(4-difluoromethoxyphenyl)isovaleric acid, corresponding to a compound of general formula (I) in which, Ar is a 4-difluoromethoxyphenyl group, Rl is an isopropyl group, and R is a hydrogen atom is very effective as an acid moiety of pyrethroid insecticides.
Many processes have been known heretofore for the production of alpha-aromatic group substituted alkanoic acids.
They may be typically described below with reference to the pro-duction of alpha-(4-isobutylphenyl)-propionic acid (Ibupro~en).
(1~ A process which comprises reacting a 4-isobutyl-phenylacetic ester, produced in two steps from 4-isobutylacetophe-none, with an alkyl carbonate in the presence of a base to form the corresponding malonic ester, methylating the malonic ester with methyl iodide, hydrolyzing the methylation product, and sub-sequently thermally decomposing the product to obtain the desired propionic acid (British Patent No. 971,700)~

(2) A process which comprises converting 4-isobutylaceto-phenone into the corresponding hydantoin by the action of potas-sium cyanide and ammonium carbonate, hydrolyzing the hydantoin to an alpha-amino acid, alkylating it to a dialkylamino compound, and reducing it to form alpha-(4-isobutylphenyl)propionic acid (British Patent No. 1167192).

(3) A process which comprises subjecting 4-isobutyl-acetophenone and a monochloroacetic ester to the Darzens reaction ~1 8~i319 to form the corresponding epoxycarboxylic ester, hydrolyzing the ester, decar~oxylating the hydrolyzed product to form alpha-C4-isobutylphenyl)propionaldehyde, and the oxidizing the aldehyde to the desired propionic acid (British Patent No. 1160725).
(4~ ~ process whlch comprises condensing 4--2a-;~`7' isobutylbenzaldehyde with formaldehyde mercaptal S-oxide to form a ketone mercaptal S-oxide, reacting it with thionyl chloride to form an alpha-chloroketene mercaptal, alcoholizing it to form an alpha-(4-isobutylphenyl)-alpha-alkyl~hioacetic ester, and subjecting the ester to methylation, hydroly-sis, and reductive desulfuri~ation in this sequence to obtain the desired propionic acid ~United States Patent No. 4,242,519).
The processes (1) and (4) include many process steps and are not industrially advantageous. The process (2) is industrially disadvantageous because it includes a step of using a poisonous substance such as potassium cyanide.
The processes (1) and (3) are economically disadvantageous because the ethoxycarbonyl group introduced in the initial step is finally removed by performing decarboxylation in the final step.
It is apparent therefore that the provision of a novel and industrially advantageous processfor producing the compoundSof general formula (I~ will great~y contribute to the development of technology in the art.
Application No. 385,670 provides a process for preparing an alpha-aromatic group substituted alkanoic acid or its ester of the general formula Ar-CH-COO~2 (I) ~863~9 wherein Ar represents an aromatic group, Rl represents a hydrogen atom or a saturated aliphatic group, or Ar and Rl may form a condensed ring together with the car~on atom to which they are bonded, and R2 represents a hydrogen atom, an alkyl group, or a hydroxyalkyl group, characterized in that an alpha-sulfonyloxyketone acetal of the genexal foxmula oR3 OS02 R

Ar-C ~ CH - Rl (II) OR

wherein ~ and R4~ independently from each other, represent an alkyl group, or taken together, represent an alkylene group, R represents a substituted or un-substituted alkyl group or an aromatic group, and Ar and Rl are as defined above, is hydrolyzed, or treated with an agent having affinity for oxygen.
The term "aromatic group", as used in the present speci-fication and appended claims, is to be taken in its broadest meaning, and denotes a group of a cyclic compound having aroma-ticity. The aromaticity means a phenomenon wherein the xing is stabilized by the delocalization of ~ electrons. Generally, a ring having (4n + 2) conjugated ~ electrons is stable and exhibits aromaticity. Thus, the aromatic group, as used herein, refers to a group of compounds having (4n + 2) conjugated ~ electrons in the main ring. It can be classified roughly into aryl groups option-~8~3~9 ally having at least one substituent and heretoaromatic groups optionally having at least one substituent, which are described in detail below.
(a) Aryl groups optionally having at least one substituent The aryl groups are aromatic hydrocarbon groups of the monocy~licf polycyclic or condensed polycyclic type, and include, ~or example, phenyl, biphenyl and naphthyl.
The aryl groups may be unsubstituted, or have one or more substituents on the aromatic ring. Specific examples of the substituents include halogen atoms such as chlorine, bromine, ~luor~ner and iodine; lower alkyl groups such as methyl, ethyl, n-prapyl, isopropyl, n~butyl, isobutyl, and tert-butyl; cycloalkyl ~roups such as cyclohexyl and cyclopentyl, aralkyl groups such as benzyl; lower alkoxy groups such as methoxy, ethoxy, n-propoxy and isopropoxy; lower alkylthio groups such as methylthio, ethylthio, n-propylth~o, isopropylthio, and butylthio; arylthio groups such as phenylthio, tolylthio, and naphthylthio; alkenylthio groups such as alkylthio; aralkylthio such as benzylthio; acyloxy groups such as acetoxy; aroyloxy groups such as benzoyloxy; silyloxy groups such as tr~methylsilyloxy; lower alkenyl groups such as allyl and prenyl l(CH3)2C-CH-CH2-]; lower alkenyloxy groups such as allyloxy; aralkyloxy groups such as benzyloxy and phenethyloxy;
aryloxy groups such as phenoxy; lower haloalkyl groups such as trifluoroethyl and trifluoropropyl; lower haloalkoxy groups such as difluoromethoxy and trifluoromethoxy; 4- to 6-membered hetero-cyclic groups such as indolinyl, oxo-isoindolynyl thienyl, piper-- ~8S319 idino and phthalimido; 4- to 6-membered heterocycloxy groups such as thiazoyloxy, and pyridyloxy; a nitro group; aroyl groups such as benzoyl; acylamino groups such as acetylamino and propionylam-ino; aroylamino groups such as benzoylamino; and dialkylamino groups such as dimethylamino and dibenzylamino. When these sub-stituents are present, 1 to 5, preferably 1 to 3, of them are preferably present on the aromatic ring.
Specific examples of aryl groups having such substitu-ents on the aromatic ring include chlorophenyl, fluorophenyl, bro-mophenyl, iodophenyl, tolyl, ethylphenyl, isopropylphenyl, isobu-tylphenyl, tert-butylphenyl, cyclohexylphenyl, methoxyphenyl, ethoxyphenyl, isopropoxyphenyl, methylthiophenyl, ethylthiophenyl, n-propylthiophenyl, isopropylthiophenyl, butylthiophenyl, phenyl-thiophenyl, tolylthiophenyl, allylthiophenyl, benzylthiophenyl, acetoxyphenyl, trimethylsilyloxyphenyl, benzoyloxyphenyl, benzyl-phenyl, prenylphenyl, allyloxyphenyl, benxyloxyphenyl phenoxy-phenyl, tetrafluoroethoxyphenyl, trifluoroethylphenyl, trifluoro-methoxyphenyl, difluoromethoxyphenyl, oxo-isoindolinylphenyl, thioazolyloxyphenyl, nitrophenyl, benzoylphenyl, acetylaminophenyl, piperidinophenyl, fluorobiphenyl, acetylaminobiphenyl, and meth-oxynaphthyl, methylthionylphenyl, acetylamino-chloro-phenyl-chloro-cyclohexyl-phenyl.
(b~ Heteroaromatic groups optionally having at least one substituent The heteroaromatic group may be of any of the monocyclic or condensed polycyclic type. The heteroatom of the heteroaromatic ring may be nitrogen, oxygen or sul~ur. The heteroaromatic ring contains generally 1 to 4, preferably 1 to 3, such hetero atoms, ~.1 ~ ~86~19 and may be generally 5- or 14- membered, preferably 5- to 9-membered. Specific examples of such he-teroaromatic groups are thienyl, furyl, pyrrolyl, indolyl, phenothiazinyl, pyridyl, thia-zolyl, and benzothiazolyl.
The heteroaromatic group may be unsubstituted, or may contain one or more substituents on the ring. Examples of substi-tuents which may be present on the heterocyclic aromatic ring are lower alkyl groups such as methyl, ethyl, propyl and butyl; aryl groups such as phenyl and fluorophenyl; halogen atoms such as chlorine and fluorine, lower alkoxy groups such as methoxy, ethoxy and propoxy; aryloxyl groups such as a phenoxy lower alkyl groups such as methyl, ethyl, propyl, and butyl; aralkyl qroups such as benzyl; aryl groups such as phenyl, tolyl, and fluorophenyl;
halogen atoms such as fluorine, chlorine and bromine; lower alkoxy groups such as methoxy, ethoxy, and propoxy; cycloalkyl groups such as cyclohexyl and cyclopentyl; lower alkenyl groups such as allyl and prenyl; lower alkenyloxy groups such as ally-lo~y; aralkyloxy groups such as benzyloxy; aryloxy groups such as phenoxy; lower haloalkyl groups such as trifluoromethyl; lower alkylthio groups such as methylthio; arylthio groups such as phenylthio; aroyl groups such as benzoyl, toluoyl, and chloro-benzoyl; acyl groups such as acetyl; lower haloalkyl groups such as trifluoromethyl; and cycloalkyl groups such as cyclohexyl.
When these substituents are present, 1 to 8, preferably 1 to 3, of them are desirably present.
Thus, examples of heteroaromatic groups having such substituents include methylphenothiazinyl, methoxymethyl-pheno-,i.,~ .

~L18~i31~

thiazinyl, methylpyrrolyl, toluoyl-methylpyrrolyl, phenylthi~nyl, bromothienyl, trifluoromethylthienyl, benzoylth.ienyl, cyclohexyl-thienyl, ph.enoxythienyl, methyl-methoxy-indolyl, chlorobenzoyl-indolyl, acetylpyrrolyl, methyl-toluoyl-pyrrolyl, benzylpyrrolyl.
~ he term "saturated aliphatic group", as used in the present specification and the appended claims, denotes a linear, branched, or cyclic saturated aliphatic hydrocarbon group which may generally contain 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Examples of such saturated aliphatic groups include l~.near or hranched alkyl groups having 1 to 6 carbon atoms, especially lower alkyl groups such as methyl, ethyl, n-propyl, ~sopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isoamyl, and n hexyl, and cycloalkyl groups having 3 to 10 carbon atoms, espe-cially cycloalkyl groups having 3 to 7 carbon atoms, such as cy-clopropyl~ cyclopentyl, cyclohexyl, cycloheptyl.
~ xamples of the substituents which may be present on the alkyl group in the "su~tituted alkyl group" are halogen atoms such.as chlor~ne f bromine and fluorine; aryl groups such as phenyl; alkoxy groups such as methoxy and ethoxy; and alicyclic groups such as .[lR, 4R] or ~ 7a-~1863~9 ~lS, 4S)-7,7-dimethyl-2-oxobicyclo[2,2,1]heptan-1-yl Specific examples of such substituted alkyl groups include trifluoromethyl, d- or Q-10-camphoryl, and benzyl.
The "alkyl group" and "alkylene group", used in the present speci-fication and appended claims, may be any one of linear or branched types, and the alkylene groups are preferably lower alkylene groups such as ethylene propylene, butylene, trime~hylene, or tetramethylene.
The term "lower", as used in the present specification and appended claims to qualify a group or a compound means that the group or compound so qualified has not more than 6, preferably not more than 4, carbon atoms.
According to one embodiment of the process, the alpha-sulfonyloxyketone acetal of general formula (II) is hydrolyzed.
It has been found that when the compound of general formula (II) which is a specified acetal compound having a sulfonyloxy group (oSo2R5) at the 2-position and an aromatic group (Ar) at the l-position is hydrolyzed, a unique reaction takes place in which the sulfonyloxy group is split off and the aromatic group is shifted to the 2-position to give an alpha-aromatic group subsitutued alkanoic acid of general formula (I).
The hydrolysis reaction may be carried out in the absence of a solvent.
Desirably, however, it is carried out generally in an inert solvent. Examples of the inert solvent are aprotic polar solvents such as dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI), 1,4-dioxane, tetrahydrofuran (THF) diethylene glycol dimethyl ether (diglyme), hexamethylphosphoric triamide tHMPA), 1,2,-dimethoxyethane, and pyridino;
and protic polar solvents such as methanol, ethanol, ethylene glycolS and acetic acid These solvents may be used solely or as a mixture of two or more.
The reaction temperature is not critical, and can be varied widely according to the type of the starting ~8631~

material (II), etc. Generally, temperatures between about 0 C
and about 250C, preferably room temperature to about 200C, can be used. In order to promote the reaction, the reaction is con-veniently carried out at an elevated temperature, preferably from about 40C to the refluxing temperature of the reaction mixture, more preferably from about 50C to about 180C. The reaction may be carried out at atmospheric or elevated pressures.
Water required for hydrolysis of the compound of formula ~ may be incorporated in advance in a solvent of the type exemplified hereinabove and the compound of formula (II) may be mixed in the solvent to perform the reaction. Or it is possible to mix the compound of formula (II) in the solvent, add water to the mlxture, and react the water with the compound (II).
Alternatively, the compound of formula (II) is heated to a temperature within the above range in the above solvent in anhydrous conditions, and then water is added to hydrolyze the compound of formula (II). (see Examples 31 and 35 below).
From the standpolnt of the ease of operation, it is convenient to introduce the compound of formula (II) into a mix-ture of water and the above polar solvent.
The amount of water re~uired for hydrolysis is not critical, and can be varied widely depending upon the type of the compound (II) used, the reaction conditions, etc. Generally, it is used in an amount of at least l mole, preferably at least 5 moles, per mole of the compound of formula (II). If it is used in too large an amount, the solubility of the compound of formula (II) decreases. Hence, it is preferable not to use water in too exces-_~_ . . , . . .
, ~

~L18~i3:~9 sive an amount.
In order to prevent the undesired cleavage of the acetal moiety of the compound of formula (II) by an acid, the hydrolysis is preferably carried out generally under neutral or basic (pH
about 7 - 14) conditions.
Since the sulfonyloxy groups (-OSO2-R5) at the 2-position is split off as sulfonic acid R5So3H in the hydrolysis reaction, it is convenient to cause a base to be present in the reaction system in order to maintain the reaction system under neutral to basic conditions during the proceeding of the reaction. Examples of the base which can be used for this purpose include alkali metal hydroxides such as potassium hydroxide and sodium hydroxide;
alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; alkali metal carbonates such as potassium car-bonate and sodium carbonate; alkaline earth metal carbonates such as magnesium and calcium carbonate; alkali metal bicarbonates such as potassium and sodium bicarbonate; al~ali metal carboxylates such as sodium formate, sodium acetate, potassium acetate and sodium propionate; alkalimetal phosphates such as sodium and potassium phosphate; and organic tertiary amines such as pyridine, triethylamine, and tributylamine. These inorganic or organic bases are conveniently used in an amount of generally at least 1 equivalent, preferably 1 to 10 equivalents, per mole of the com-pound of formula (II).
The hydrolysis reaction can be terminated generally with-in about 1 to about 250 hours although this depends upon the type of the starting compound of formula (II) and the reaction conditions.

~863~9 In the above hydrolysis reaction, the sulfonyloxy group (-OS02-R ) at the 2-position of the compound of formula (II) is split off, and the aromatic group (Ar) at the l-position is shifted to the 2~position. At the same time, either one of the acetal groups -oR3 and ~0~4 is split off, and the remaining one acetal grouP forms the group _oR2 in the compound of formula (I) (~n ~hich R is an alkyl group). Dependiny upon the conditions used in the hydrolysis, especially under strongly basic condi-tl,ons~ the ester (I) formed [the compound of formula (I) in which R is an alkyl group] further undergoes hydrolysis to form the compQund of ~formula (I) in which R2 is a hydrogen atom.

lOa-` ~8~i;319 When the compound of formula (II) in which R3 and R4 together form an alkylene group hydrolyzed, a corresponding compound of formula (I) is obtained in which R2 is a hydroxyalkyl group.
Accordi~ng to another embodiment of the process, the compound of general formula (II~ is treated with an agent having affinity for oxygen. It has been found that as a result of this treatment,the~sulfonyloxy group (-oSo2-R5) at the 2-position of the compound of general formula (II) is split off and the aromatic group (Ar) at the l-positionis shifted to the 2-position, to give the compound of formula (I). In this reaction, too, either one of the group -oR3 or -oR4 of the compound of general formula (II) forms the _oR2 group of the product of formula (I). Hence, the product of this reaction is the ester of formula (I) in which R2 is an alkyl group.
The term "agent having affinity for oxygen'7, as used herein~ denotes a compound having the ability to coordinate in such a way asto accept a lone electron pair of oxygen atom. Specific examples of the agent having affinity for oxygen include the following.
(a) Iodotrialkylsilanes of the formula A2 _ Si - I ~III) wherein Al, A2 and A3 are identical or different and each represent an alkyl group, esp~cially a lower alkyl group, such as iodotrimethylsilane and iodotriethylsilane.
(b) Trialkylsilyl perfluoroalkylsulfonates of the formula 7Al A - Si - S03 - A (IV) ~1~363:~

wherein A4 represents a perfluoroalkyl group, parti-cularly a lower perfluoroalkyl group, and Al, A , and A are as defined hereinabove, suc~ as trimethylsilyl trifluoromethanesulfonate, and trimethyl-silyl pentafluoroethanesulfonate.
(c) Lewis acids such as aluminum chloride, aluminum bromide, zinc chloride, tin chloride, titanium chloride, boron fluoride, and ~ron chloride.
These agents having affinity for oxygen may be used solely cr as a mixture of two or more. Especially preferred agents having affinity for oxygen used in this invention are iodotrimethylsilane, trimethylsilyl trifluoromethanesulfonate, ~ron chloride, aluminum chloride, and tin chloride.
The amount of the agent having affinity for oxygen used i5 not strictly limited, and can be varied widely according to the type of the compound of formula (II), and/or the type of the agent, Generally, it is used in an amount of at least 0.1 mole, prefe~ably a . 2 to 5.0 moles, more preferably 1.0 to 2.0 moles per mole of the compound of formula (II~.
The treatment of the compound of formula (II) with the agent having affinity for oxygen can be carried out in the absence of a solvent. Generally, the treatment is conveniently carried out in a solvent, especially an aprotic solvent. For example, where a Lewis acid or an iodotrialkylsilane is used as the agent having affinity for oxygen, halogenated hydrocarbons such as meth-ylene chloride, chloroform and 1,2-dichloroethane give especially ,., ,. .~
! \i~``~

~86~31~

good results. When the trialkylsilyl perfluoroalkanesulfonate ~s used as the agent, the halogenated hydrocarbons, acetonitrile and orthoformates are preferred as solvents.
The reaction in this embodiment proceeds very smoothly under mild conditions. The treating temperature is about -40C
to about 150C, preferably about -20C to -12a-~,1 ~1863~L9 about 100C, more preferably 10C to about 90C.
By treating the compound of formula (II) with the agent having affinity for oxygen under those conditions, the compound of formula (I~
results. When the agent having affinity for oxygen is a Lewic acid, the product and the agent may sometimes form a complex. In this case, the product may be isolated by adding water to the reaction mixture to deco~pose the complex and then subjecting it to usual isolating operations.
The compound of formula ~I) produced by the process of this inven-tion can be isolated from the reaction mixture by methods known per se, such as extraction9 chromatography, distillation, and crystallization.
The compounds of formula ~II) used as a starting material in the pro-cess for preparing compounds of formula I are novel compounds not described in the literature and are the subject of this divisional application.
The various groups in formula ~II) are exemplified as follows:
~1) Aryl groups optionally having at least substituent are preferred as the aromatic group Ar. More preferred are groups of the formula R6-Arl-, wherein Arl represents a phenylene or naphthylene group and R6 repres0nts a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkoxy group, a lower alkanoylamino group, an oxo-isoindolinyl group, or a phenyl group. A thienyl group can be cited as another preferred example of the aromatic group Ar.
~2) Lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, or butyl are preferred as the saturated aliphatic group Rl. Thus, a hydrogen atom and lower alkyl groups constitute a preferred class of Rl.
~3) Lower alkyl groups are suitable as the alkyl groups represented individually by R3 and R4. Lower alkylene groups such as ethylene, propylene, and trimethylene are suitable as the alkylene group formed by ~863~9 R3 and R4 taken together.

(4) Examples of preferred substituted or unsubstituted alkyl groups represented by R include unsubstituted lower alkyl groups, such as methyl, ethyl and butyl; lower haloalkyl groups such as trifluoromethyl; and a d- or Q-10-camphoryl. Preferred as the aromatic group R5 are substituted or unsubstituted phenyl groups of the formula R ~ wherein R7 represents a h~dro-gen atom, a halogen atom, a nitro group, or a lower alkyl group.
Among the compounds of formula (II) provided by thisinvention, preferred are those of the following compounds Ar2 _ C - CH Rl' (I-l) oR4 1 wherein Ar2 represents a group of the formula R6-Arl- or a thienyl group, Rl represen-ts a hydrogen atom or a lower alkyl group; R
and R4 , independently from each other, represent a lower alkyl group, or taken together, form a lower alkylene group; R repre-sents a lower alkyl group, a lower haloalkyl group, a d- or Q-10-camphoryl group or the group of the formula ~ R ; and Arl, R6 and R7 are as defined above.
In formula (II), Ar and R may form a condensed ring together with the carbon atom to which they are bonded. Specific examples of the compounds of formula (II~ in which Ar and Rl form a condensed ring are ,. ~,., 3~9 R30 oR4 R30 oR4 ~ ~ ~ 2 R ~ ~ oSo2-R5 Hydrolysis of these compounds or treatment thereof with the agent haYing affin~ty for oxygen by the process of this invention respectively yields the follo~ing compounds.

-14a-63~9 ~ ~ and ~ ~

The compounds of ~ormula (II) can be synthesized from alpha-haloketones of the general ~ormula ~ Ar-C-CH-R (V) ., .
~lerein X represents a halogen atom, and Ar and . R are as de~ined aboveg :~ through the route sho~m in the following reaction scheme.
P~eaction Scheme R5-So -Ma~
" X 1 R~OH o,R3 O,H or ~R~SO ) O oR3 oSo2-R5 Ar-C-~-R ~ Ar-C - CH-Rl ~ Ar-C ~ R

~ ~ oR3 f (VI) oR4 '' '" ~ ' Ar-C - CH_Rl , ~0,~ , .
(~II) . . - .
:~ 10 In the above scheme, M represents an alkali metal . ......... . and Hal represents a halogen atom, especially a chlorine~ .
atom, and Ar, Rl, R3, R4, R5 and X are as defined hereinabove.
e compound of formula (V) can be produced easily by subjecting a compound of the formula ~ . , . X
Rl _ CH - COCl (VIII) ; ~/herein R and X are as de~ined abo~e~
to the Friedel-Crafts reaction with a compound o~ the ; formula :
Ar-H tIY) -~8~i319 wherein Ar is as defined above, or by halogenating a compound of the formula o Ar-C-CH2-R (X) wherein Ar and Rl are as defined above, in a manner known per se.
__ The route in the ~eaction Scheme is described in detail ~elo~, Step (V) ~(VI) . . . _ . .
Th;s step invo~es the action of an alkali metal alkox-ide (~ OM) on the compound of the general formula (V) in the presence of the corresponding alc~hol ~R30H) to give an alpha-hydroxyketone acetal o~ general formula (VI). In the compound of general formula (VI) produced in this step, R4 is the same as R3.
Lith;`um alkoxides, sodium alkoxides and potassium alkoxides can he suita~ly used as the alkali metal alkoxide. The use of the sodium alkoxides is preferred because of their low cost. The amount of the alkali metal alkoxide is generally at least 1 mole per mole of the compound of formula (V), and the reaction can be completed rapidly if it is used in an amount of 1.5 to 3 moles 2~ per mole of the compound of formula (V). The amount of the alco-hol to be copresent may be at least 1 mole per mole of the com-pound of general formula (V~. ~dvantageously, the alcohol is used in excess to make it serve also as a solvent. It is also possible to add an aprotic solvent which does not participate in the xeaction, such as diethyl ether, tetrahydrofuran, DMF, or 1,2-di-methox~ethane. The reaction proceeds smoothly at a temperature ~8~ 9 of about -20C to about 100C. For the simplicity of the opera-tion, the reaction is preEerably carried out at room temperature to 60C.
According to another embodiment, this step can be per-formed by reacting the compound of formula (V) with the alkali metal alkoxide (R30M) in an aprotic solvent such as diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane to form an epoxy compound of formula (VII), and then reacting it with, an alcohol (R o~) in the presence of a catalytic amount of an alkali metal alkoxide (R OM) -to obtain an alpha-hydroxyketone acetal (VI) (see Examples 8 and 9). According to this process, a compound of formula (VI) in which R3 differs from R4 can also be produced.
The reaction between the compound of formula (v) and the alkali metal alkoxide (R30M) can be carried out usually at a tem-perature of about 0C to about 60C using 1 to 3 moles, per mole of the compound of formula (V), of the alkali metal alkoxide.
The reaction between the compound of formula (VII) and the alcohol (R40H) can be performed generally at a temperature of about 0C to about 100C by using at least one mole, per mole of the compound of formula (VII), of the alcohol. Preferably the alcohol is used in excess to make it serve also as a solvent.
According to still another embodiment of this step, the alpha-haloketone of general formula (V) is reacted in the presence of a dihydric alcohol such as ethylene glycol, propylene glycol or 1,3-propanediol with a mono-salt of the dihydric alcohol and an alkali metal to give -the alpha-hydroxyketone acetal of general formula (VI). This process gives a product corres-1~l8~i319 ponding to formula (VI) in which R3 and R4 together form an alky-lene group such as ethylene, propylene, or trimethylene (see Example III~.
The reaction can be performed generally at 0 C to 100C
by using at least l mole, preferably 1.5 to 3 moles, of the dihy-dric alcohol mono-salt of alkali me-tal in the presence of at least 0.~5 mole, preferably 2 to 10 moles, of the dihydric alcohol.
There can be added an aprotic solvent which does not participate in the reaction such as diethyl ether, tetrahydrofuran or 1,2-1 a d~methoxyethane Compounds of formula (VI) obtained in the above step wherein Ar is other than the phenyl and 4-chlorophenyl group, and those ~n ~hich Rl is other than a hydrogen atom are novel com-pounds not described in the literature, and constitute a part of the present invention.
Typical examples of such compounds (VI) are given below in addttion to those shown in the Examples. The compound (VI) wherein Ar is 4-prenylphenyl, R is methyl; Ar is N-methyl-phenothiazinyl, Rl is hydrogen or methyl; Ar is l-methylpyrrolyl, R is hydrogen on methyl; Ar is 2-fluoro-4-biphenylyl, Rl is methyl; Ar is 2-acetylamino-4-biphenylyl, R1 is methyl; Ar is 4-chlorophenyl, Rl is isopropyl; and 3-chloro-4-(3-pyrrolin-l-yl) phenyl, Rl is methyl.
Step (VI)~
.
This step involves the action of an O-sulfonylating agent of the formula R -SO2-Hal or (R SO2)2O on the alpha-hydroxy-ketone acetal of formula (VI) obtained in the above step to form the compound of general formula (II).

i,, ~

3~9 Examples of the O-sulfonylating agent include aromatic group subst~tuted sulfonyl halides such as benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p nitrobenzenesulfonyl chloride and naphthalene sulfonyl chloride; and alkanesulfonyl halides or alkanesulfonic anhydrides, such as methanesulfonyl chloride, butanesulfonyl chloride, methane-sul~onic anhydride, trifluoromethanesulfonic anhydride, trifluoro-methanesulfonyl chloride, d-10-camphorsulfonyl chloride, and Q-10-camphorsulfonyl chloride.
The reaction is desirably carried out under neutral to basic conditions, and from this standpoin-t, the reaction is advantageously carried out in the presence of at least 1 mole, per mole of the compound of formula ~VI), of a tertiary amine such. as triethylamine, pyridine, or 4-dimethylaminopyridine. In this way, the reaction can be performed at a relatively low tem-perature of from about 0 C to room temperature. It is also possible to add an aprotic solvent which does not participate in the reaction, such as methylene chloride or diethyl ether.
As described above, the compound of general formula (II) as the starting material in the process of this invention can be produced in two steps from the alpha-haloketone of general formula (V). It can also be produced by other methods, such as a method which comprises oxidizing a l-(aromatic group)-l-alkoxy-l-alkene of the formula OR
Ar-C=CH-R (XI) wherein Ar, Rl, and R3 are as defined hereina~ove, to form the epoxy compound of formula ~VII), producing the alpha-, ~8S3~

hydroxyketone acetal of formula (VI) from the epoxy compound as above, and further performing the step (VI)--~ (II); a process which comprises acetalizing the corresponding alpha-sulfonyloxy-ketone to the compound of general formula (II); and a method which comprises reducing an alpha-oxoketone acetal of the following formula OR O
~ 1 Ar - C - CR (XII) OR
wherein Ar, Rl, R3, and R are as defined above, to form the alpha-hydroxyketone acetal of formula (VI), and subject-ing it to the step (VI)--~(II).
Thus, the alpha-sulfonyloxyketone acetal of formula (II) as the starting material in the process of this invention can be produced by various easy methods with a lesser number of steps.
The compounds of formula (I) which can be produced by the process of this invention include many compounds useful in such fields as pharmaceuticals and agricultural chemicals. Typi-cal examples of such useful compounds are Ibuprofen, Naproxen, and alpha-[4-(1-oxo-2-isoindolinyl)phenyl]propionic acid (anti-inflammatory agent, Indoprofen)~ Typical examples also include alpha-(2-thienyl)propionic acid, methyl alpha-(~-acetylaminophenyl) propionate~ alpha-[4-(tert-butyl)-phenyl]isovaleric acid, methyl alpha-(4-alkoxyphenyl)-isovalerates, alpha-(4-biphenylyl)propionic acid, methyl alpha-(4-difluoromethoxyphenyl)isovalerate, and methyl alpha-(4-alkoxyphenyl)propionates which are known as important --~0--synthetic intermediates for anti-inflammatory agents, and insec-ticides.
The following Examples illustrate the present invention more specifically.
Example 1 9.81 q of p toluenesulfonyl chloride was dissolved in 10 ml of anhydrous pyridine, and the mixture was stirred at room temperature, To the solution was added dropwise over 10 minutes lQ ml o~ an anhydrous pyridine solution of 6.65 g of alpha hydroxypropiophenone dimethyl acetal, and the mixture was stirred for 48 hours. The reaction mixture was poured onto 200 ml of ice water, and stirred for 2 hours. The resulting precipitate was collected by filtration, washed with water, and dried in vacuum over potassium hydroxide to give 10.91 g of alpha-(p-toluenesulf-onyloxy)propiophenone dimethyl acetal as colorless crystals.
Yield 92%
mp: 62 - 63C (from ligroin) IR (KBr): 1360, 1190, 1175, 1090, 1060, 1040, 910, 710 cm NMR (CDC13): ~1.07 (3H, d, J=6Hz), 2.73 (3H, s), 3.08 (3H, s), 3.15 (3H, s) r 4.95 (lH, q, J=6Hz), 7.33 (7H, m), 7.77 (2H, d, J=9Hz).
For C18H22O5S:
Calculated: C, 61.70; H, 6.33; S, 9.15%.
Found: C, 61.72; H, 6.26; S, 9.19%.

1~8~3~g Example 2 19.0 g of p-isobutylpropiophenone was dissolved in a mixture of 15 ml of anhydrous diethyl ether and 5 ml of anhydrous dioxane, and the solution was stirred at room temperature. Bro-mine (17.6 g~ was added dropwise over 25 minutes, and the mixture was stirred ~or 2.5 hours. Water (50 ml) was added, and the mix-ture was extracted with 20 ml of diethyl ether three times. The extract was washed with 50 ml of water four times, dried over anhydrous magnesium sulfate, and concentrated under reduced pres-sure. The residue was dissolved in 30 ml of hot methanol, and cooled to -40QC. The precipitate was collected by filtration, and washed with cold methanol to give 21.88 g of alpha-bromo-p-isobutylpropiophenone as colorless crystals.
Y~eld: 81%
mp: 63 - 66C.
IR(KBr): 2950, 1680, 1608j 1419, 1260, 1250, 1167, 955, 862 cm 1, NMR (CDC13): ~0.91 (6H, d, J=7Hz), 1.87 ~3H, d, J=7Hz), 1.8 - 2.2 (lH, m), 2.52 (2H, d, J=7Hz), 5.25 (lH, q, J=7Hz), 7.22 (2H, d, J=9Hz), 7.92 (2H, d, J=9Hz).
For C13H17OBr:
Calculated: C, 58.00; H, 6.37; Br, 29.69%
Found: C, 57.80; H, 6.27; Br, 29.~2%
Example 3 -Sodium methoxide (1.134 g) was dissolved in 20 ml of anhydrous methanol, and the solution was stirred at room tempera-~1~6;3~9 ture in an atmosphere of argon. To the solution was added drop-wise over 30 minutes at room temperature 20 ml of an anhydrous methanol solution of 2.692 g of alpha-bromo-p-isobutylpropiophen-one. After the addition, 50 ml of water was added to the reaction mixture, and the mixture was extracted with 20 ml of diethyl ether three times. The extract was washed with 20 ml of water, dried over anhydrous magnesium sulfate and potassium carbonate, and concentrated under reduced pressure in the presence of a small amount of potassium carbonate to give 2. 370 g of alpha~hydroxy-p-isobutylpropiophenone dimethyl acetal as a colorless oily sub-stance. The yield was 94%. For elemental analysis, the product was purified by column chromatography (Florisil*; methylene chloride~.
IR (neat): 35ao, 2950, 1460, 1100, 1050, 980, 850, 800~ 740 cm 1~
NMR (CDC13)o ~0~91 (6H, d, J=7Hz), 0.96 (3H, d, J-7Hz), 1.6 - 2.1 (lH, m), 2.43 (2II, d, J=7Hz), 2.57 ~lH, broad s), 3.20 (3H, s), 3.30 (3H, s), 4.06 (lH, q, J=7Hz), 7.08 ~2H, d, J=9Hz), 7.33 (2H, d, J=9Hz).
For Cl 5H24O3:
Calculated: C, 71.39; H, 9.59%.
Found: C, 71.39, H, 9.48%.
Example 4 26.84 g of isobutylbenzene and 29.34 g of aluminum chloride were stirred under ice cooling in 20 ml of carbon disul-~ide. To the mixture was added dropwise ov~r 30 minutes 40.63 g * Trademark ` ~1863~9 of alpha-chloropropionyl chlorlde, and the mixture was stirred under ice cooling for 1.5 hours. It was further stirred for 30 minutes at room temperature. The reaction mixture was poured onto 200 ml of ice water, and 100 ml of conc. hydrochloric acid was added. The mixture was extracted with 100 ml of diethyl ether four times. The extract was washed with 100 ml of water and then four times with 50 ml of a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was dis-solved in 40 ml of methanol at an elevated temperature, treated with activated charcoal, and cooled to -40C. The precipitated crystals were collected by filtration, washed with cooled methanol to give 17.83 g of alpha-chloro-p-isobutylpropiophenone as color-less crystals having a melting point of 51 to 53 C.
Yield: 4Q%
IR(KBr): 2950, 1690, 1608, 1419, 1357, 1266, 1180, 956, 861 cm 1.
NMR (CDC13): ~0.91 (6H, d, J=7Hz), 1.71 (3H, d, J=7Hz), 1.5 - 202 (lH, m), 2.52 (2H!
d, J=7Hz), 5.20 (lH, q, J=7Hz), 7.23 (:2H, d, J=9Hz), 7.91 (2H, d, J=9Hz).
For C13H17OCl:
Calculated: C, 69.47; H, 7.63; Cl, 15.78%
Found: C, 69.56i H, 7.44i Cl, 15.76%.
Example 5 $odium methoxide (0.979 g) ~as dissolved in 10 ml of anhydrous methanol, and the solution was stirred at room tempera-~8~3:19 ture in an ar~on atmosphere. To the solution was added dropwise over 20 minutes 10 ml of an anhydrous methanol solution of 2.036 y of alpha-chloro-p-isobutylpropiophenone and the mixture was further stirred at room temperature for 4 hours. Usual work-up as in Example 4 ~ave 2.158 g (yield 95%) of alpha-hydroxy-p-isobutyl-propiophenone dimethyl acetal as a pale yellow oil. Yield 95%.
Example 6 In a similar operation as in Example 1, alpha-(p-toluene-sulfonyloxy)-p-isobutylpropiophenone dimethyl acetal was prepared as colorless crystals from alpha-hydroxy-p-isobutylpropiophenone dimethyl acetal.
Yield: 89%
mp: 64 ~ 65C ~from hexane) IR (~Br): 2960f 1360r 1185~ 1090~ 1050~ 930 915, 780 cm 1.
NMR (CDC13): ~0.88 (6H~ d, J=7Hz) ~ 1.09 (3H~ d, J=7HZ) ~ 1.5-2.1 (lH~ m) ~ 2.40 (3H~
s) ~ 2.42 (2H~ d, J=7HZ) ~ 3.07 (3H~
s) ~ 3.15 (3H~ s) ~ 4.93 (lH~ q~ J=7Hz) 6.9-7.4 (6~ m), 7.72 (2H~ d, J=9Hz).
For C22H30O5S:
Calculated: C, 64.99; H, 7.44i S~ 7.89%
Found: C, 64.78; H~ 7.26; S, 7.93~.
Example 7 . . .
Methanesulfonyl chloride ( 2.94 ~) was dissolved in 5 ml of anh~drous pyridine, and the solution was stirred under ice cooling. To the solution was added dropwise over 15 minutes 10 ml j, .,,~

:~8~i3~9 of an anhydrous pyridine solution of 3.23 g of alpha-hydroxy-p-isobutylpropiophenone dimethyl acetal. The mixture was stirred under ice cooling for 1 hour, and at room temperature for 30 min-utes. Water (30 ml) was added, and the mixture was stirred for 1 hour. The mixture was extracted with 10 ml of methylene chloride three times. The extract was washed with 10 ml of water three times r dried over anhydrous magnesium sulfate, and concentrated in the presence of a small amount of anhydrous potassium carbonate.
The oily residue was purified by column chromatography (Florisil*;
meth~lene chloride) to give 3. 347 g of alpha-(methanesulfonyloxy)-p-isobutyl-propiophenone dimethyl acetal as a colorless oil.
Yield: 79 %
IR(neat): 2960, 1350, 1175, lOg5, 1065, 1040, 915 cm 1.
NMR (CDC13): ~0.88 (6H, d. J=7HZ), 1.16 (3H, d, J=7Hz), 1.6 - 2.1 (lH, m), 2.44 (2H, d, J=7HZ), 3.06 (3H, s), 3.18 (3H, s), 3.26 (3H, s), 4.95 (lH, q, J=7HZ), 7.10 (2H, d, J=8Hz), 7.32 (2H, d, J=8Hz) .
For Cl 6H26O5S:
Calculated: C~ 58.16; H, 7.93; S, 9.69% .
Found: C, 58.06; H, 7.80; S, 9.60%.
Example 8 Sodium methoxide (9. 20 ~) was suspended in 10 ml of anhydrous diethyl ether, and in an atmosphere of argon, the solu-tion was stirred under ice coolin~. To the solution was added dropwise over 40 minutes 80 ml of an anhydrous diethyl ether solu-r~ i * Trademark <

~863~9 tion of 15.0 g of alpha-bromo-p-methoxypropiophenone. After the addition, the insoluble matter was separated by filtration in a stream of argon. The filtrate ~JaS concentrated under reduced pressure to give 7.8 8 g of 1-(4-methoxyphenyl)-1-methoxy-1, 2-epoxypropane as a pale red oil.
Yield: 68%
NMR (CDC13): ~1.00 (3H, d, J=6Hz), 3.23 (3H, s), 3.52 ~lH, q, J=6HZ), 3.82 (3H, s), 6.92 (2H, d, J=7HZ), 7.38 (2H, d, J=7HZ).
Example 9 7. 88 g of 1-(4-methoxyphenyl)-l~methoxy 1, 2 -epoxypropane and 200 mg of sodium methoxide were stirred in 30 ml of anhydrous methanol at room temperature for 15 hours. Water (50 ml) was added to the reaction solution, and the mixture was extracted with 20 ml of diethyl ether three time~. The extracts were dried over anhydrous magnesium sulfate and anhydrous potassium carbonate, and concentrated under reduced pressure in the presence of a small amount of anhydrous potassium carbonate to give 8.26 g of alpha-hydroxy-p-methoxypropiophenone dimethyl acetal as a colorless oil.
For elemental analysis, this product was purified by column chromatography (Florisil*; methylene chloride).
Yield: 61%
IR (neat): 3520, 1050 cm NMR (CDC13): ~0.~4 (3H, d. J=7Hz), 2.35 (lH, d, J=4EIz), 3.20 (3H, S), 3.33 (3H, s), * Trademark -27-~L~8~i3~

3.78 ~3H, s), 4.05 (lH, dq, J=4 and 7Hz), 6.18 (2H, d, J=9HZ), 7.35 (2H, d, J-9Hz).
For C12H184 Calculated: C, 63.70; H, 8.02%
Found: C, 63.98; H, 8.08%.
Example 10 2.67 g of p-toluenesulfonyl chloride was dissolved in

5 ml of anhydrous pyridine, and the solution was stirred at room temperature. To the solution was added dropwise over 10 minutes 5 ml of an anhydrous pyridine solution of 1.58 g of alpha-hydroxy-p-methoxypropiophenone dimethyl acetal. The mixture was stirred or 72 hours. Ice water (about 20 g) was added, and the mixture was extracted with 20 ml of diethyl ether three times. The ex-tracts were washed with 20 ml of water, dried over anhydrous magnesium sulate, and concentrated under reduced pressure in the presence of a small amount of anhydrous potassium carbonate to ~ive 2.12 g of alpha-(p-toluenesulfonyloxy)-p-methoxy-propiophen-one dimethyl acetal as a pale yellow oil.
Yield: 80%
IR (neat): 1600, 1510, 1350, 1245, 1170, 1090, 1055, 1035, 905 sm 1.
NMR (CDC13): ~1.07 (3H, d, J=7Hz), 2.40 (3H, s), 3.07 (3H, s), 3.12 (3H, s), 3.75 (3H, s), 4~92 (lEI, q, J=7Hz), 6.7 -7.0 (2H, m), 7.1 - 7.4 (4H, m), 7.73 (2H, d, J=8Hz).

Example ll In a similar operation as in Example 2 ~ alpha-bromo-p-(tert-butyl~lsovalerophenone was prepared as a colorless liquid from p-(tert-butyl)isovalerophenone.
Yield: 72 %
bp: 128 ~ 140C/l torr.
IR (neat): 2960t 1680~ 1600 cm NMR (CDC13) ~1~00 (3H~ d, J=7Hz) I 1~20 (3H~ d, J=7Hz) ~ 1~35 (9Hr s) r 2~2 ~ 2~7 (lH, m), 4.90 (lEI, d, J=9HZ) ~ 7~47 (2H, d, J=lOHz) r 7~90 (2HI d, J=lOHz).
For C15H21B~
Calculated: C, 60~61; Ht 7~12; Br, 26~89%o Found: C, 60~71~ H~ 7~11; Br, 26~58%~
Example 12 Sodlum methoxide (l. 62 y) was dissolved in 20 ml of anhy-drous methanol, and the solution was stirred at room temperature under an atmosphere of argon. To the resulting solution was added 20 ml of an anhydrous methanol solution of 2 ~ 64 g of alpha-bromo-p-(tert-butyl)isovalerophenone over 15 minutes and the mix-ture was stirred at room temperature for 18 hours.
Usual work-up as in Example 3 gave 2.~4 g of alpha-h~droxy-p-(tert-butyl)isovalerophenone dimethyl acetal as a pale yellow oil.
Yield: 98 %
IR (neat): 2950 r 1110 ~ 1040 cm -~;

i3~L~

NMR (CDC13): ~0.70 (3H, d, J=7Hz), 0.90 (3EI, d, J=7Hz), 1.32 (9H, s), 1~0 - 1.6 (lH, m~, 2.45 (lH, broad s), 3.22 (3H, s), 3.25 (3H, s), 3.67 (lH, d, J=6Hz), 7.33 (4H, s).
Example 13 Methanesulfonyl chloride (1.90 g) was dissol~ed in 5 ml of anhydrous pyridine, and the solution was stirred at room temp-erature, and to the solution was added dropwise over 10 minutes 5 ml of an anhydrous pyridine solution of 2.34 g of alpha-hydroxy-p-(tert-butyl)isovalerophenone dimethyl acetal. The mixture was stirred at this temperature further for 24 hours. Usual work-up and separation as in Example 7 gave 1.63 g of alpha-(methanesulfonyloxy)-p-(tert-butyl)isovalerophenone dimethyl ace-tal as a colorless oil (upon standing at room temperature, this compound crystallized).
Yield: 55%
mp: 80 - 86C
IR (neat): 2960, 1357, 1176, 1060, 955 cm NMR (CDC13): ~0.70 (3H, d, J=7Hz), 0.90 (3H, d, J=7Hz), 1.32 (9H, s), 1.4 - 1.9 (lH, m), 3.17 (3H, s), 3.20 (3H, s), 3.26 (3H, s), 4.76 (lH, d, J=4Hz)~
7.37 (4HI s).
For C18H30O5S
Calculated: C, 60.30; H, 8.44; S, 8.95%.
Found: C, 60.07; H, 8.23; S, 9.07~.

~i3~

Example 14 Benzene (lO0 ml) was added to a mixture of 7.12 g of alpha-acetoxyacetophenone, 7.44 g of ethylene glycol and 0.200 g of p-toluenesulfonic acid monohydrate, and the mixture was heated under reflux. Water generated was removed by means of a Dean-Stark device secured to the reactor. After refluxing for 21 hours, 4. ao g of ethylene glycol was added. The mixture was further heated under reflux for 6 hours. Water generated was distilled off. After cooling, 30 ml of a saturated aqueous solution of sodium hydrogen carbonate and 20 ml of water were successively added, and the mixture was extracted with 30 ml of diethyl etner twice. The extracts ~ere washed with lO ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pres-sure to give 7.874 g of a residue. The residue was determined by NMR and GLC to be a mixture of alpha-acetoxyacetophenone ethylene acetal and alpha-hydroxyacetophenone ethylene acetal. The mixture was dissolved in 20 ml of methanol, and 0.300 g of potassium car-bonate was added. The mixture was stirred at room temperature for 4 hours. Water (200 ml) was added, and the precipitated colorless crystals were collected by filtration and dried overnight in vacuum on potassium hydroxide to give 4.79 g of alpha-hydroxyacetophenone ethylene acetal.
Yield: 67%
NMR (CDC13): ~2.10 (lH, broad s), 3.70 (2H, broad s), 3.7 - 4.0 (2H, m), 4.0 - 4.2 ~2H, m), 7.2 - 7.6 (5~I, m).

~7 i3~

Example 15 Pyridine (5 ml) was added to 0.900 g of alpha-hydroxy-acetophenone ethylene acetal, and the mixture was stirred under ice cooling. To the mixture was added 1.08 g of p-toluenesulfonyl chloride, and the mixture was stirred ~or 2 hours under ice cool-ing and then for 1 hour at room temperature. The reaction mixture was again cooled with ice. Water (10 ml) was added, and the mix-ture was stirred for 1 hour and extracted with 2 0 ml of diethyl ether three times. The extracts were washed with 10 ml of water twice, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1.584 g of a crystalline residue.
The residue was washed with a small amount of hexane to give 1. 330 g of alpha-(p-toluenesulfonyloxy)acetophenone ethylene acetal as colorless crystals.
Yield: 80%
NMR (CDC13): ~2.40 (3H,s), 3.7 - 3.9 (2H, m), 3.9 - 4.1 (2H, m), 4.11 (2H, s), 7.1 - 7.5 (5H, m), 7.55 (2II, d, J=8Hz).
Example 16 In a similar operation in Example 15, alpha-(p-bromo-benzenesulfonyloxy)acetophenone ethylene acetal was prepared as colorless crystals from alpha-hydroxyacetophenone ethylene acetal.
Yield: 86%
NMR (CDC13): ~3.7 - 3.9 (2H, m), 3.9 - 4~1 (2H, m), 4.16 (2II, s), 7.2 - 7.5 (5H, m), 7 . 63 ( 4H, s).

;::

~1363~9 Example 17 Metallic sodium (0.46 g) was dissolved in 10 ml of anhy-drous methanol, and the solution was stirred at room temperature.
To the solution was added dropwise over 10 minutes 10 ml of an anhydrous methanol solution of 2.19 g of 1-(2-thienyl)-2-bromo-1-propanone and the mixture was stirred further for 3.5 hours at room temperature. Usual work-up as in Example 3 gave 1.900 g of 1-(2-thienyl)-2~hydroxy-l~propanone dimethyl acetal as a colorless oil.
Yield: 94%
IR (neat~: 3450, 1110, 1055, 980, 855, 710 cm ~ MR (CDC13): ~1.05 (3H, d, J=7Hz), 2.54 (lH, broad s)~
3.26 (3H, s), 3.30 (3EI, s) 4.16 (lH, broad q, J=7Hz), 6.9 - 7.2 (2H, m), 7.2 - 7.4 (lH, m).
Example 18 0.606 g of 1-(2-thienyl)-2-hydroxy-1-propanone dimethyl acetal was dissolved in 5 ml of pyridine, and the solution was stirred under ice cooling. To the solution was added over 1 min-ute 0.30 ml of methanesulfonyl chloride, and the mixture was stir-red for 5 minutes under ice cooling and then for 5 hours at room temperature. Water (30 ml) was added, and the mixture was stirred for 30 minutes at room temperature, and extracted with 30 ml of diethyl ether three times. The extracts were washed with 10 ml of water twice, dried over anhydxous magnesium sulfate and anhy-drous potassium carbonate, and concentrated under reduced pressure.
The residue was purified by column chromatography (Florisil*, * Trademark -33-1~363~9 methylene chloride) to give 0.788 g of 1-(2-thienyl)-2-(methane-sulfonyloxy)-l-propanone dimethyl acetal as a colorless oil.
Yield: 94%
IR (neat): 1360, 1180, 1120, 1055, 990, 975, 930, 905, 855, 810, 715, 540, 525 cm 1 NMR ~CDC13): ~1.27 (3H, d, J=7 Hz), 3.09 (3H, s), 3.27 (6H, s), 5.02 (lH, q, J=7 Hz),

6.9 - 7.1 (2H, m), 7.2 - 7.4 (lH, m).
For CloH16O5S2 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 10 ml of anhydrous pyridine, and the solution was stirred at room tem-perature. To ~he solution was added dropwise over 15 minutes 10 ml o~ an anhydrous pyridine solution of 1.93 g of alpha-hydroxy-p-isobutylpropiophenone dimethyl acetal~ and the mixture was stirred for 72 hours. By a similar work-up to Example 1, 2.62 g of alpha-(benzenesulfonyloxy)-p-isobutylpropiophenone dimethyl acetal was obtained as colorless crystals.
Yield: 88%
mp: 79 - 82C.
IR (KBr~: 2950, 1362, 1195, 1097, 1043, 990, 921, 813, 594 cm 1.
NMR (CDC13): ~0.86 (6H, dr J=7Hz), 1.08 (3H, d, J=7Hz), 1.6 - 2.1 (1~, m), 2.41 (2H, d, J=7Hz), 3.02 (3H, s), 3.10 , " 1~8631g (3H, s), 4.94 (lH, 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 (2H, m).
Example 20 . .
1.91 g of p-toluenesulfonyl chloride was dissolved in 10 ml of anhydrous pyridine, and the solution was stirred at room temperature. To the solution was added dropwise over 10 minutes 10 ml of an anhydrous pyridine solution of 1.13 g of alpha-hydroxy-propiophenone diethyl acetal, and the mixture was stirred for 72 hours. Usual work-up and purification by column chromatography (Florisil*, methylene chloride) gave 1.16 g of alpha-(p-toluene-sulfonyloxy)-propiophenone diethyl acetal as a colorless oil.
Yield: 85%
IR (neat): 2980, 1360, 1192, 1l78, 1087, 1055, 1042, 920 cm 1 NMR (CDC13): ~0.8 - 1.3 (9H, m), 2.38 (3H, s), 3.1 - 3.6 (4~, m), 4.89 (lH, q, J=7Hz), 7.1 - 7.5 (7H, m), 7.80 (2H, d, J=9Hz).

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 alpha-(p-toluenesulfonyloxy)propiophenone dimethyl acetal and 0.150 g of calcium carbonate was heated under reflux for 72 hours in 10 ml of a mixture of water and methanol (3:7 b~ weight). Water (10 ml was added, and the mixture was * Trademark ~35~

~86319 extracted with 10 ml of diethyl ether three times. The extracts were washed with 10 ml of water, and dried over anhydrous magne-sium sulfate. The product was quantitatively analyzed by gas chromatography (internal standard method) and found to contain 0.162 g of methyl alpha-phenylpropionate. Yield 66%.
Example 22 1.75 g of alpha-(p-toluenesulfonyloxy)propiophenone dimethyl acetal and 0.500 g of calcium carbonate were heated under reflux for 72 hours in 33 ml of a mixture of water and methanol (3:7 by weight). ~ater (50 ml) was added, and the mixture was extracted with 30 ml of diethyl ether three times. The extracts were washed with 30 ml of water, and concentrated under reduced pressure to about 5 ml. Methanol (12 ml), 5 ml of water, and 7 ml of a 10% aqueous solution of potassium hydroxide were added to the residue, and the mixture was heated under reflux for 5 hours.
Water (30 ml) was added, and the mixture was washed with 20 ml of diethyl ether five times. The aqueous layer was adjusted to pH 1 with conc. hydrochloric acid, and extracted with 20 ml of diethyl ether four times. The extracts were washed with 20 ml of water, dried over anhydrous maynesium sulfate, and concentrated under reduced pressure to give 0.358 g of alpha-phenylpropionic acid as a colorless oil. Yield 48%. This product completely agreed with an authentic sample in IR and NMR spectral data.
Examples 23 to 35 0.526 g of alpha-(p-toluenesulfonyloxy)propiophenone dimethyl acetal and an equimolar amount of each of the various ~.

~8~31~

bases shown in Table 1 were heated on an oil bath in 10 ml of each of the various solvents shown in Table 1. Water (10 ml) was added, and the mixture was extracted with 10 ml of diethyl ether three times. The extracts were washed with 10 ml of water and dried over anhydrous magnesium sulfate.
The product was analyzed for methyl alpha-phenylpropio-nate by gas chromatography in the same way as in Example 21.
The results are shown in Table 1.

Table 1 . _ Example Solvent (mix- Base Bath Reaction Yield of ing ratio) tempe- time methyl alpha-rature (hours) pionate (%) 23Dioxane-water CH3COOK 110 216 54.3 24(6 4) CaCO3 110 64 56.6 25DMF-water CH3COOK 150 14 40.3 26(6 4) CH3COOK 150 14 55.6 27(6 4) CaCo3 100 94 54.6 28(6 4) CaCO3 100 72 54.4 29(6 4) CaCO3 100 94 54.3 30DMSO water CaCO3 100 72 58.5 31Anhydrous _ 150(*) 7 34.2 _ methanol . ....
(*) ~eated in a 30 ml sealed tube.

:~L86319 Table 1 (Continued) . . .

Example Solvent ~mix~ Base Bath Reaction Yield of ing rat~o) tempe- time methyl alpha-rature phenylpro-( C) (hours) pionate (%) 32 Methanol: CH3COOK110 72 60.8 water (7:3) 33 Methanol: CaCO3 110 64 63.0 water (6:4) 34 Methanol: CaCO3 110 72 33.3 water (4:6) aAciedtic CH3COOK130 14 39.0 Example 36 0.410 g oE alpha-(p-toluenesulfonyloxy)-p-isobutylpro-piophenone dimethyl acetal and 0.100 g of calcium carbonate were heated under reflux in a mixture of water and methanol (3: 7 by weight) ~or 22 hours. Water (15 ml) was added, and the mixture was extracted with 10 ml of diethyl ether three times. The extra-cts were washed with 10 ml of water, dried over anhydrous magne-sium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (silica gel, methy-lene chloride) -to give 0.180 g of methyl alpha-(4-isobutylphenyl) propionate as a colorless oil. Yield 81~. This product complet-ely agreed with an authentic sample in IR and NMR spectral data.

. ~

~L31 8~i3~:9 Example 37 0.910 g of alpha-(p-toluenesulfonyloxy)-p-isobutylpro-piophenone dimethyl acetal and 1.25 g of potassium carbonate were heated for 20 hours under reflux in 26 ml of a mixture of water and methanol (3:7 by weight). ~ater (30 ml) was added, and the mixture was washed with 10 ml of methylene chloride four times.
The aqueous layer was adjusted to pH 2 with dilute hydrochloric acid, and extracted with 20 ml of methylene chloride four times.
The extracts were washed with 30 ml of water, dried over anhydrous magnesium sulfate to give 0.335 g of alpha-(4-isobutylphenyl) propionic acid as colorless crystals having a melting point of 71 to 75C. Yield 73%. This product completely a~reed with an au~h-entic sample in IR and NMR spectral data.
Example 38 .. . ...
0.991 g of alpha-(methanesulfonyloxy)-p-isobutylpropio-phenone dimethyl acetal and 0.300 g of calcium carbonate were heated under reflux for 72 hours in 10 ml of a mixture of water and methanol (3:7 by weight). Usual work-up followed by alkaline hydrolysis of the crude product as in Example 22 gave 0.519 g of alpha-(4-isobutylphenyl)propionic acid as colorless crystals having a melting point of 73 to 75C. Yield 84%. This product completely agreed with an authentic sample in IR and NMR spectral data.
Example 39 2.12 g of alpha-(p-toluenesulfonyloxy)-p-methoxy-propiophenone dimethyl acetal and 0.560 g of calcium carbonate were heated under reflux for 13 hours in 20 ml of a mixture of :, i f ~.

- ~8~i3~9 water and methanol (3:7 by weight). Usual work-up followed by alkaline hydrolysis o~ the crude product as in Example 22 gave 0.714 g of alpha-(4-methoxyphenyl)propionic acid as pale yellow crystals having a melting point of 47 to 50C. Yield 57%.
Example 40 0.735 g of alpha-(methanesulfonyloxy)-p-(tert-butyl)iso-valerophenone dimethyl acetal and 0.200 g of calcium carbonate were heated under reflux for 72 hours in 10 ml of a mixture of water and methanol ~3:7 by weight). Usual work-up as in Example 36 and purification by column chromatography (si]ica gel t methy-lene chloride) to give methyl alpha-[4-(tert-butyl)phenyl]isoval-erate as a colorless oil.
~ R (neat~: 2965, 1745, 1165, 1025 cm 1 NMR (CDC13: ~0.71 ~3H, d, J=7Hz), 1.02 (3H, d, J=7Hz), 1.32 (9H, sl! 2.1-2.6 (lH, m), 3.10 (lH, d, J=llHz), 3.60 (3H, s), 7.1-7.4 (4H, m).
For C16H242 Calculated: Cl 77.37; H, 9.74%
Found: C, 77.26; H, 9.62%.
Example 41 . _ 0.668 g of alpha-(p-toluenesulfonyloxy)acetophenone ethylene acetal was dissolved in 8 ml of 1,3-dimethyl-2-imidazoli-dinone (DMI), and 200 mg of calcium carbonate and 0.2 ml of water were added. The mixture was heated at 180C for 22 hours with stirring. After cooling, 30 ml of water was added, and the mix-ture was extracted with 20 ml of diethyl ether three times. The ;3~9 extracts were ~ashed with 10 ml of water twice, and dried over an-hydrous magnesium sulfate. The a~ueous layers were combined, and 4 ml of conc. hydrochloric acid was added. The mixture was extra-cted with 20 ml of diethyl ether three times. The extracts were washed with 10 ml of water twice and dried over anhydrous magne-sium sulfate. The residues left after concentrating under reduced pressure the extracts obtained in neutrality and acidity respec-tively were combined, and 400 ml of potassium hydroxide was added.
The mixture was heated under reflux for 16 hours in a mixture of 6 ml of methanol and 2 ml of water. After cooling, 30 ml of water was added, and the mixture was washed with 20 ml of diethyl ether three times. The aqueous layer was acidified to a pH of about 2 by adding about 7 ml of 3.5% hydrochloric acid and extracted with 20 ml of diethyl ether three times. The extracts were washed with 10 ml of water, dried over anh~drous magnesium sulfate, and con-centrated under reduced pressure to give 92 mg of a residue. This residue was found to be a mixture of benzoic acid and phenylacetic acid by its NMR and GLC of its methyl ester resulting from treat-ment with diazomethaneO NMR spectral data showed that it contain-ed 65 my (yield 27%) of benzoic acid and 27 mg (yield 10%) of phenylacetic acid.
Example 42 0.798 g of alpha-(p-bromobenzenesulfonyloxy)acetophenoneethylene acetal was dissolved in 8 ml of DMI, and 200 mg of calcium carbo-nate and 0.5 ml of water were added. The mixture was heated at 160 C for 18 hours with stirring. In the same way as in Example ~;.

1~8~319 41, the reaction mixture was worked up and the crude product was subjected to alkaline hydrolysis to yield 84 mg of a semisolid.
The semisolid was found by NMR to be a mixture of benzoic acid and phenylacetic acid (7.0:4~5 by mole). Accordingly, the mixture was determined to contain 49 mg (yield 20% of benzoic acid and 35 mg (yield 13%) of phenylacetic acid.
Example 43 0.560 g of 1-(2-thienyl)-2-(methanesulfonyloxy)-l-propa-none dimethyl acetal and 0.200 g of calcium carbonate were heated under reflux for 42 hours in a mixture of water and methanol (3:7 by weight). Water (30 ml~ was added, and the mixture was extra-cted with 30 ml of die-thyl ether three times. The extracts were washed with lO ml of water twice, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 316 mg of me-thyl alpha-(2-thienyl)propionate as a colorless oil. This pro-duct completely agreed with an authentic sample in IR and NMR
spectral data. Yield 93% (in crude form).
The crude oil was subjected to simple distillation at 130 C (bath temperature) and 17 torr to give 279 mg of a pure product.
Yield 82% (after purification).
The aqueous layers obtained by extraction were combined, and 6 ml of conc. hydrochloric acid was added. The mixture was extracted with 15 ml of diethyl ether three times. The extracts were washed with lO ml of water twice, dried over anhydrous magne-sium sulfate, and concentrated under reduced pressure to give 20 mg of alpha-(2-thienyl)-propionic acid as a colorless oil. Yield 6%. This product completely agreed with an authentic sample in IR

~ ~86315~

and NMR spectral data.
Example 44 0.565 g of 1-(2-thienyl)-2-(methanesulfonyloxy)-1-pro-panone dimethyl acetal and 0.202 g of calcium carbonate were heated under reflux for 21 hours in 6 ml of a mixture of water and methan-ol (3:7 by weight). To the reaction mixture was added 0.420 g of sodium hydroxide, and the mixture was stirred at room temperature for 15 hours and then heated under reflux for 2 hours. Water (30 ml) was added, and the mixture was washed with 20 ml of diethyl ether. Conc. hydrochloric acid (4 ml) was added to the a~ueous layer/ and the mixtllre was extracted wi~h 20 ml of dlethyl ethQr three times. The extracts were washed with 10 ml of water, dried over anhydrous magnesium sulfate r and concentrated under reduced pressure to give 0.299 g of alpha-(2-thienyl)propionic acid as a colorless oil. Yield 95%.
Example 45 . . .
Sodium hydroxide (0.420 g) was dissolved in 6 ml of a mixture of wa-ter and methanol ~3:7 by weight), and 0.574 g of 1-(2-thienyl)-2-(methanesulfonyloxy)-1-propanone dimethyl acetal was added. The mixture was heated under reflux for 21 hours. Water (40 ml) was added, and the mixture was washed with 20 ml of diethyl ether. Conc. hydrochloric acid (3 ml) was added to the aqueous layer, and the mixture was extracted with 20 ml of diethyl ether three times. The ex-tracts were washed with 5 ml Gf water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 0.2gl g o~ alpha-(2-thienyl)propionic acid as a colorless oil. Yield 91%.

" ~863~g Example 46 0.674 g of 1-(2-thienyl)-2-(p-toluenesulfonyloxy)-1-propanone dimethyl acetal and 0.200 g of calcium carbonate were heated under reflux for 12 hours in 10 ml of a mixture of water and methanol (3:7 by weight). Usual work-up as in Example 36 gave an oily crude product, which was subjected to simple distillation at 110 to 120C (bath temperature) and 17 torr to give 0.253 y of methyl alpha-(2-thienyl)propionate as a colorless oil. Yield 79%.
Example 47 0.684 g of 1-(2-thienyl)-2-(benzenesulfonyloxy)-1-pro-panone dimethyl acetal and 0.200 g of calcium carbonate were heat-ed under reflux for 8 hours in 10 ml of a mixture of water and methanol (3:7 by weight). Usual work-up as in Example 36 gave an oily crude product, which was subjected to simple distillation at 110C (bath temperature) and 15 torr to give 0.277 g of methyl alpha-(2-thienyl)propionate as a colorless oil. Yield 81%.
Example 48 0.299 g of alpha-(methanesulfonyloxy)-p-acetylaminopro-piophenone dimethyl acetal and 0.090 g of calcium carbonate were heated under reflux for 21 hours in 3 ml of a mixture of water and methanol ~3:7 by weight). Water (30 ml) was added, and the mix-ture was extracted with 20 ml of methylene chloride three times.
The extracts were washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crystalline residue The residue was purified by column chroma-tography (silica gel, methylene chloride-diethyl ether) to give ''~-'i . . , .

~3~863~

0.186 g of methyl alpha~(4-acetylaminophenyl)propionate as color-less crystals.
Yield: 93%
mp: 107 - 109C (from ethanol-hexane) IR (KBr): 1740, 1665, 1610, 1555, 1515, 1415, 1330, 1160r 860, 840 cm 1 NMR (CDC13): ~1.46 (3H, d, J=7Hz), 2.11 (3H, s), 3.64 (3H, s), 3.67 (lH, q, J=7Hz), 7.17 (2H, d, J=8Hz), 7.53 (2H, d, J=8Hz), 8.17 (lH, broad s).
For C12H15NO3:
Calculated: C. 65.14; H. 6.83; N. 6.33%
Found: C. 64.94; H. 7.00; N. 6.27%.
Example 49 0.329 g of alpha-(benzenesulfonyloxy)-p-isobutylpropio-phenone dimethyl acetal and 0.10 g of calcium carbonate were heated under reflux for 10 hours in 10 ml of a mixture of water and meth-anol (3:7 by weight). Similar work-up to Example 48 and purifi-cation by column chromatography (silica gel, methylene chloride) gave 0.181 g of methyl alpha-(4-isobutylphenyl)propionate as a colorless oil. Yield 82%.
Example 50 0.392 g of alpha-(benzenesul~onyloxy)-p-isobutylpropio-phenone dimethyl acetal was heated in 4 ml of a mixture of water and pyridine (1:3 by weight) over an oil bath at 100C for 19 hours. Similar work-up to Example 48 and purification by column chromatography (silica gel, methylene chloride) gave 0.164 g of ~' ~363~9 methyl alpha-(4-isobutylphenyl)propionate as a colorless oil.
Yield 74%.
Example 51 0.392 g of alpha-(benzenesulfonyloxy)-p-isobutylpropio-phenone dimethyl acetal was mixed with 10 ml of a mixture of water and methanol (3:7 by weight) and 2 ml of a 10% aqueous solution of potassium hydroxide, and the mixture was heated under reflux for 9 hours. Water (30 ml) was added, and th~ mixture was washed with 15 ml of methylene chloride our times. The aqueous layer was ad-justed to pH less than 1 with conc. hydrochloric acid, and extra-cted with 15 ml of methylene chloride four times. The extracts were dried over anhydrous ma~nesium sulfate, and concentrated under reduced pressure to give 0.138 g of alpha-(4-isobutylphenyl) propionic acid as colorless crystals having a melting point of 73 to 75C. Yield 67%.
_xample 52 0.150 g of alpha-(p-toluenesulfonyloxy)propiophenone diethyl acetal and 0.05 g of calcium carbonate were heated under reflux for 72 hours in 10 ml of a mixture of water and methanol (3:7 by weight). Water (20 ml) was added, and the mixture was extracted with 5 ml of diethyl ether four times, and dried over anhydrous magnesium sulfate. The product was quantitatively analyzed by gas chromatography (internal standard method), and found to contain 23 mg of ethyl alpha-phenylpropionate. Yield 32%.

. ~ .
I~ ~
" .

i3~9 Example 53 0.978 g of alpha-(methanesulfonyloxy)-p-fluoropropio-phenone dimethyl acetal and 0.33 g of calcium carbonate were heated under reflux for 24 hours in 15 ml of mixture of water and methanol (3:7 by weight). By the same work-up and purification as in Example 49, 0.454 g of methyl alpha-(4-fluorophenyl)propionate was obtained as a colorless oil.
Yield: 76%
IR (neat): 1744, 1607, 1513, 1460, 1439, 1340, 1230, 1210, 1170, 1160, 840, 796 cm 1 NMR (CDC13): ~1.46 (3H, d~ J=7Hz), 3.60 (3H, s), 3.67 (lH, q, J=7Hz), 6.8-7.4 (4H, m).
Example 54 0.490 g of 1-(6-methoxy-2-naphthyl)-2-(methanesulfony-loxy)-l-propanone dimethyl acetal and 0.140 g of calcium carbonate were heated under reflux for 5 hours in 10 ml of a mixture of ~
water and dimethyl formamide (1:4 by weight). Water (20 ml) was added, and the mixture was extracted with 7 ml of methylene chloride four times. The extracts were washed with 10 ml of water four times, dried over anhydrous magnesium sulfate, and concen-trated under reduced pressure. The residue was purified by column chromatography (silica gel, methylene chloride) to give 0.323 g of methyl alpha-(6-methoxy-2-naphthyl)propionate as colorless crys-tals having a melting point of 65 to 68C. Yield 94%. The pro-duct completely agreed with an authentic sample in IR and NMR
spectral data.

3J ~
Example 55 0.354 g of 1-(6-methoxy-2-naphthyl)-2-methanesulfony-loxy-l-propanone dimethyl acetal and 0.10 y of calcium carbonate were heated under reflux for 28 hours in 8 ml of a mixture of water and methanol (3:7 by weiyht). Water (20 ml) was added, and the mixture was extracted with 10 ml of methylene chloride three times. The extracts were washed with 20 ml of watex, dried over anhydrous magnesium sulfate and concentrated under reduced pres-sure to gi~e 0.]73 g of methyl alpha-(6-methoxy-2-naphthyl)propio-nate as colorless crystals. Yield 73%.
Example 56 One of two possible diastereomers of 1-(6-methoxy-2-naphthyl)-2-(d-10-camphorsulfonyloxy)-1-propanone dimethyl acetal was provided (m.p. 102 - 105C; [c~]25 + 32.5 (c=l, chloroform)).
170 mg of this diastereomer and 40 mg of calcium carbonate were heated at a bath temperature of 110C for 14 hours in 5 ml of a mixture of water and dimethyl formamide (1:4 by weight). Water (20 ml) was added, and the mixture was extracted with 10 ml of diethyl ether four times. The extracts were washed with 10 ml of water four times, dried o~Ter anhydrous magnesium sulfate, and con-centrated under reduced pressure. The residue was purified by column chromatography (silica gel, methylene chloride) to give 68 mg of methyl (-)-alpha-(6-methoxy-2-naphthyl~propionate as color-less crystals.
Yield: 80.2%
m.p.: 94.5 - 95C

~ .~

~ 8~3~9 [~]25 : -73.2 (c=l, chloro~orm) IR (KBr): 2970, 1739, 1602, 1450, 1334, 1270, 1231, 1205, 1172, 1158, 1028, 893, 856, 823 cm 1.
The product agreed in N~ spectral data with the methyl alpha-(6-methoxy-2-naphthyl)propionate obtained in Example 54.
Example 57 0.31 ml (0.44 g) of iodotrimethylsilane and two drops of cyclohexene were stixred in 5 ml of anhydrous methylene chloride at room temperature in an atmosphere of argon. To the mixture was added dropwise 4 ml of an anhydrous methylene chloride solution of 529 mg of 1-phenyle2-(p-toluenesulfonyloxy)-1-propanone dimethyl acetal. The mixture was stirred at room temperature for 3 hours.
Then, 5 ml of a saturated aqueous solution of sodium hydrogen car-bonate was added. The organic layer was washed successively with 5 ml of a 10% aqueous solution of sodium thiosulfate, 5 ml of wa-ter, 5 ml of a 10% aqueous solution of sodium hydrogen carbonate and 5 ml of water, and dried over anhydrous magnesium sulfate. The product was quantitatively analyzed by gas chromatography (inter-nal standard method) and found to contain 226.4 mg of methyl alpha-phenylpropionate. Yield 91.9%.
Examples 58 to 62 176 mg of 1-phenyl-2-~p-toluenesulfonyloxy)-1-propanone dimethyl acetal and each of the agents having affinity for oxygen shown in Table 2 in the amounts indicated were stirred in 4 ml of anhydrous methylene chloride at each of the temperatures shown in Table 2. Water (5 ml) was added, and the mixture was extracted ~,j , ~.~863~

with 5 ml of methylene chloride four times. The extracts were washed with 10 ml of water, and dried over anhydrous magnesium sulfate.
The product was analyzed for methyl alpha-phenyl-prop-ionate by gas chromatography in the same way as in Example 57.
The results are shown in Table 2~

Table 2 Agent having Reaction conditions Yield of affinity for methyl alpha-Example oxygen Temperature Time pionate (mole ratio) ( C) (hours) (%) 58 AlC13 (0.6) 0 1 52.5 59 AlCL3 (0.7) Refluxing temperature 1 63.6 AlC13 (1.0) Refluxing temperature 0.7 69.3 61 Alcl3 (1-4) 0 1 68.0 62 TiC14 (3.0) Refluxing temperature 10 16.8 _ Example 63 3.849 g of 1-(4-chlorophenyl)-2-(p-toluenesulfonyloxy)-l-propanone dimethyl acetal was stirred at room temperature in an argon atmosphere in 10 ml of anhydrous methylene chloride. A

solution obtained by dissolving 1.71 ml (2.40 g) of iodotrimethyl-silane and 2 drops of cyclohexene in 2 ml of anhydrous methylene chloride was added dropwise at room temperature, and the mixture ~ ~' , . ~

~36~9 was stirred for 30 minutes. The same work-up as in Example 57 gave an oily crude product, which was found by its N~IR spectrum to contain 1.61 g of methyl alpha-(p-chlorophenyl)propionate.
Yield 81.0%.
Example 64 -0.20 ml (0.28 g) of iodotrimethylsilane and one drop of cyclohexene were stirred in 8 ml of anhydrous methylene chloride at room temperature in an argon atmosphere. Then, 6 ml of an anhy-drous methylene chloride solution of 490 mg (l.00 millimole) of l-(6-methoxy-2-naphthyl)-2-(d-lO-camphorsulfonyloxy)-l-propanone dimethyl acetal having an [~25 of +32.5 (c=l.00, chloroform) was added dropwisel and the mixture was stirred at room temperature for l hour. Ten milliliters of a saturated aqueous solution of sodium hydrogen carbonate was added. The same work-up as in Example 57 followed by purification with column chromatography (silica gel, methylene chloride) to give 230 mg of methyl (R) (-)-alpha-(6-methoxy-2-naphthyl)propionate as colorless crystals having a melting point of 85 to 92C. Yield 94.2%. This product was found to be optically pure by NMR spectroscopy using an optically active shifting agent Eu (TFC)3.
Example 65 By a similar operation to Example 17, l-(4-methoxyphe-nyl)-2-hydroxy-l-propanone dimethyl acetal was prepared as a pale yellow oil from l-(4-methoxyphenyl)-2-bromo-l-propanone. Without purification, the crude product was used in the reaction of Example 66.

y~
. . .

3~9 Example 66 By a similar operation to Example 7, 1-(4-methoxy-phenyl)-2-methanesulfonyloxy-1-propanone dimethyl acetal was pre-pared as a light yellow oil from the l-(4-methoxyphenyl)-2-hydroxy -l-propanone dimethyl acetal obtained in Example 65. Yield 80.1%
[from 1-(4-methoxyphenyl)-2-bromo-1-propanone].
IR (neat): 2935, 1615, 1517, 1358, 1257, 1176, 1100, 1065, 145, 915 cm 1.
NMR (CDC13): ~1.18 (3H, d, J=6Hz), 3.09 (3H, s), 3.21 (3H, s), 3.28 (3H, s), 3.80 (3EI, s), 4.97 (lH, q, J=6Hz), 6.87 (2Hr d, J=9Hz), 7.37 (2H, d, J=9EIz).
Example 67 1.007 g (3.308 millimoles) of 1-(4-methoxyphenyl)-2-methanesulfonyloxy-l-propanone dimethyl acetal and 330 mg (3.30 millimoles) of calcium carbonate were refluxed with stirring for 20 hours in 10 ml of a mixture of water and methanol (3:7 by wei-ght). By the same work-up and purification as in Example 49, 597 mg of methyl alpha-(4-methoxyphenyl)propionate was obtained as a colorles-s oil. Yield 92.9%.
NMR (CDC13): ~1.47 (3H, d, J=7Hz), 3.61 (3H, s), 3 67 (lH, q, J=7Hz), 3.73 (3H, s), 6.83 (2H, d, J=9Hz), 7.19 (2H, d, J=9Hz).
~xample 68 In a similar way to Example 20, 1-(2-thienyl)-2-(p-toluenesulfonyloxy)-l-propanone dimethyl acetal was prepared as a colorless oil in a yield of 64% from 1-(2-thienyl)-2-hydroxy-1-.~

- - -363~9 propanone dimethyl acetal.
IR ~neat): 1360, 1190, 1180, 1060, 9&5, 925, 905, 820, 790, 710, 665, 565 cm 1.
NMR (CDC13): ~1.19 (3H, d, J=7Hz), 2.40 (3H, s), 3.08 ~3H, s), 3.14 (3~I, s), 4.98 (lH, q, J=7Hz), 6.94 (2H, d, J=3Hz), 7.2-7.4 (3H, m), 7.80 (2H, d, J=8Hz).
Example 69 In a similar way to Example 20, 1-(2-thienyl)-2-(benze-nesulfonyloxy)-l-propanone dimethyl acetal was prepared as a color-less oil in a yield of 83% from 1-(2-thienyl)-2-hydroxy-1-propa-none dimethyl acetal and benzenesulfonyl chloride.
IR (neat): 1360, 1190, 1060, 980, 925, 900, 5S0, 555 cm 1.
NMR (CDC13): ~-1.20 (3H, d, J=7Hz), 3.08 (3H/ s), 3.14 (3H, s)~ 5.01 (lH, q, J=7Hz), 6.8-7.1 (2H, m), 7.2-7.4 (lH, m), 7.4-7.7 (3H, m), 7.9-8.1 (2H, m).
Example 70 ~letallic sodium (1.30 g, 56.5 millimoles) was dissolved in 30 ml of anhydrous ethanol, and the mixture was stirred at room temperature. To the solution was added dropwise over 15 minutes 20 ml of an anhydrous ethanol solution of 5.33 g (0.025 mole) of alpha-bromopropiophenone, and the mixture was stirred further for 40 minutes at room temperature. ~ater (100 ml) was added, and the mixture was extracted with 60 ml of diethyl ether twice. The ex-tracts were washed with water, dried over anhydrous magnesium sul-`7~' ~;3~

fate and anhydrous potassium carbonate, and concentrated under re-duced pressure. The residue was dissolved in 30 ml of anhydrous ethanol containing a catalytic amount of metallic sodium dissolved therein, and the solution was stirred for 2 days at room tempera-ture~ Usual work-up as in Example 3 gave 4.497 g of 1-phenyl-2-hydroxy-l-propanone diethyl acetal as a colorless oil.
Yield: 80.2%
IR (neat): 2960, 1452, 1120, 1092, 1057, 1040, 772, 709 cm 1.
N~IR (CDC13): ~0.94 (3H, d, J=6Hz), 1.05-1.40 (6H, m), 2.61 (lH, broad s), 3.22-3.83 (4H, m), 4.05 (lH, q, J=6Hz), 7.1-7.7 (5H, m).
Example 71 ....
Acetanilide (3.33 g) and 4.0 ml (5.2 g) of alpha-chloro-propionyl chloride were stirred at room temperature in 20 ml of carbon disulfide. Then, 7.0 g of finely pulverized aluminum chloride was added in portions over 2 minutes. The mix-ture was stirred at room temperature for 25 minutes, and heated under reflux for 50 minutes with stirring. After cooling, the reaction mixture separated into two layers. The upper layer was removed by decantation, and the lower layer which was black and tarry was poured into ice water. The precipitated crystals were collected by filtration. Recrystallization from ethanol gave 1.860 g of l-(4-acetylaminophenyl)-2-chloro-l~propanone as colorless crystals. The upper layer of the reaction mixture, the filtrate formed during collection of the crystals, and the mother liquor of :

~L~81~319 recrystallization were combined, and extracted with 50 ml of meth-ylene chloride three times. The extracts were washed with 50 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Recrystallization of the residue from ethanol ~ave 1.434 g of 1-(4 acetylaminophenyl)-2-chloro-1-propan-one. The mother liquor was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, methylene chloride and ether). Recrystallization from methanol gave 0.868 ~ of the above product further. The total amount of the product was 4.162 g, and the total yield was 75%.
Colorless crystals.
m.p.: 123 - 125C (from ethanol) IR (KBr): 16gO, 1675, 1595, 1540, 1415, 1320, 1360, 1180, 965, 860, 665 cm 1.
NM~ (CDC13): ~1.70 (3H, d, J=7Hz), 2.18 (3H, s), 5.18 (lH, q, J=7Hz), 7,63 (2H, d, J=9Hz), 7.95 (2H, d, J=9Hz), 7.8-8.1 (lH, broad s) .
For CllH12ClN2 Calculated: C. 58.54; H. 5.36; Cl. 15.71; N. 6.21%
Found: C. 58.59; H. 5.40; Cl. 15.63; N. 6.23o Example 72 .. ..... . _ By a similar operation to ~xample 17, 1-(4-ace-tylamino-phenyll-2-hydroxy-1-propanone dimethyl acetal was prepared as a glassy substance from l-(4-acetylaminophenyl)-2-chloro-1-propanone.
~ithout purification, the crude product was used in the reaction in Example 73.

;;~ -55-~.~8G3~9 NMR (CDC13): ~0.95 (3II, d, J=7EIz), 2.14 (3H, s), 2.94 (lH, broad s), 3.21 (3H, s), 3.33 (3H, s), 4.10 ClH, q, J=7Hz), 7.37 (2H, d, J=8Hz), 7.51 (2H, d, J=3Hz), 8.93 (lH, broad s).
Example 73 All of the 1-(4-acetylaminophenyl)-2-hydroxy-1-propa-none dimethyl acetal obtained in Example 72 was dissolved in 5 ml of pyridine/ and 0.60 ml (0.89 g) of methanesulfonyl chloride was added. The mixture was stirred at room temperature for 5 hours.
The reaction mixture was cooled with ice, and 30 ml of water was added. The temperature was returned to room temperature, and the mixture was stirred for 10 minutes, and extracted with 20 ml of ethyl acetate four times. The extracts were dried by adding successively anhydrous sodium sulfate and anhydrous magnesium sulfate thereto, and concentrated under reduced pressure. The residue was purified by column chromatography (Florisil, methylene chloride and diethyl ether) to give i.537 g of 1-(4-acetylamino-phenyl)-2-methanesulfonyloxy-1-propanone dimethyl acetal as a colorless glassy substance. Yield 93% [from 1-(4-acetylamino-phenyl)-2~chloro-1-propanone].
IR (I~Br): 1675, 1610, 1540, 1350, 1175, 915, 525 cm NMR (CDC13: ~1.14 (3H, d, J=7Hz), 2.52 (3H, s), 3.08 (3H, s), 3.18 (3H, s), 3.24 (3II, s), 4.94 (lH, q, J=7Hz), 7.36 (2H, d, J=9Hz) 7.54 (2H, d, J=9Hz), 8.52 (lH, broad s)~

~863~9 Example 74 In the same way as in Example 17, 1-(4-fluorophenyl)-2-hydroxy-l-propanone dimethyl acetal was prepared as a pale yellow oil from l-(4-~luorophenyl)-2-bromo-1-propanone. Without purifi-cation, this product was used in the reactions of Examples 70 and 76.
IR (neat~: 2975, 2937, 1610, 1512, 1230, 1159, 1105, 1053, 982, 839 cm 1~
NMR (CDC13): ~0.93 (3H, d, J=6Hz), 2.53 (lH, broad s), 3.23 ~3H, s), 3.33 (3H, s), 4.08 (lEI, broad ~, J=6Hz), 6.83-7.18 (2EI, m), 7.32-7~60 (2H ! m~.
Example 75 By the same operation as in Example 7, 1-(4-fluorophe-nyl)-2-methanesulfonyloxy-1-propanone dimethyl acetal was prepared as a colorless oil from the 1-(4-chlorophenyl)-2-hydroxy-1-propa-none dimethyl acetal obtained in Example 74. Yield 82.3% [from 1-(4-fluorophenyl)-2-bromo-1-propanone~.
IR (neat): 2940, 1610, 1512, 1359, 1228, 1180, 1160, 1098, 1067, 1045, 972, 918 cm 1.
NMR (CDC13): ~1.15 (3H, d, J=6Hz), 3.06 (3H, s), 3.21 (3H, s), 3.24 (3H, s), 4.96 (lH, q, J=6EIz), 6.88-7.16 (2H, m), 7.32-7.58 (2H, m).
Example 76 In the same way as in Example 20, 1-(4-fluorophenyl)-2-(p-toluenesulfonyloxy)-l-propanone dimethyl acetal was prepared as colorless crystals havin~ a meltin~ point of 96 to 99C from the 1-(4-fluorophenyl)-2-hydroxy-1-propanone dimethyl acetal obtained ~8~;3~9 in Example 74. Yield 76.2% [rom 1-(4-fluorophenyl)-2-bromo-1-propanone].
m.p.: 101C (from methanol) IR (KBr): 2948, 1605, 1510, 1360, 1346, 1192, 1181, 1090, 1053, 932, 918, 820, 786, 670, 561 cm 1.
NMR (CDC13): ~1.05 (3H, d~ J=6~z), 2.40 (3H, s), 3.08 (3H, s), 3.10 (3H, s), 4.93 (lII, q, J=6Hz), 6.82-7.08 (2H, m), 7.16-7.46 (4H, m), 7.73 (2H, d, J=8Hz).
For C18H21FO3S
Calculated: C. 58.68; ~. 5.75%
Found: C. 58.98; H. 5.96%.
Example 77

8.57 g of 1-(6-methoxy-2-naphthyl)-1-propanone (United States Patent 2,683,738) was dissolved in 60 ml of anhydrous dio-xane and the solution was stirred at room temperature. To the solution was added 13.57 g of pyridinium hydrobromide perbromide, ~ollowed by stirring for an additional one hour. 200 ml of a 3%
aqueous solution of sodium bisulfite was added to the mixture and, after stirring at room temperature for 3 hours, the precipitated crystals were filtered, washed with water and dried in vacuo over potassium hydroxide to obtain 11.66 g of 1-(6-methoxy-2-naphthyl)-2-bromo l-propanone having a melting point of 73 - 75C as pale yellow crystals. Yield 99%.
m.p.: 68 - 69C (from benzene).

.~

~186319 NMR (CDC13): ~1.90 (3H, d, J=7Hz), 3.85 (3H, s), 5.3~
(lH, q, J=7Hz), 6.9-7.3 (2H, m), 7.5-8.1 (3H, m), 8.38 (lH, broad s).
For C14H13Br2 Calculated: C. 57.35; H. 4.47; Br. 27.26%
Found: C. 57.27; H. 4.66; Br. 27.23%.
Example 78 In a similar operation to Example 3, 1-(6-methoxy-2-naphthyl)-2-hydroxy-1-propanone dimethyl acetal was prepared as a colorless oil from 1-(6-methoxy-2-naphthyl)-2-bromo-1-propanone.
Yield, 100%. The product crystallized after it was purified by column chromatography (Florisil, methylene chloride) and allowed to stand at room temperature.
Colorless crystals.
m.p.; 56 - 59 C.
IR (KBr): 3500~ 1637, 1610, 1488, 1276, 1215, 1175, 1118, lla6, 1040, 859 cm 1.
NMR (CDC13): ~0.97 (3H, d, J=7Hz), 2.48 (lH, broad s), 3.20 (3H, s), 3.36 (3H, s), 3.82 (3H, s), 4.14 (lH, q, J=7Hz), 7.00-7.24 (2H, m), 7.40-7.98 (4H, m).
For C16H204 Calculated: C. 69.54; H. 7.30%
Found: C. 69.25; H. 7.28%.
Example 79 In a similar operation to Example 7, 1-(6-methoxy-2-naphthyl)-2-methanesulfonyloxy-1-propanone dimethyl acetal was pre-pared as a colorless oil from l-(6-methoxy-2-naphthyl)-2-hydroxy-1:186319 l-propanone dimethyl acetal. Yield, 84%.
IR (neat): 1640, 1615, 1492, 1360, 1280, 1182, 901, 820 cm 1.
NMR (CDC13): ~1.19 (3H, d, J=7Hz), 3.09 (3H, s), 3.22 (3~I, s), 3.31 (3H, s), 3.87 (3H, s), 5.05 (lH, ~, J=7Hz), 7.04-7.24 (2H, m), 7.42-7.g4 ~4H, m).
For C17H22O6S:
Calculated: C. 57.61; H. 6.26; S. 9.05%
Found: C. 57.21; H. 6.02; S. 8.85%.
Example 80 350 mg of sodium metal was dissolved in 40 ml of anhy-drous methanol and the solution was stirred at room temperature.
2.93 g of 1-(6-methoxy-2-naphthyl)-2-bromo-1-propanone was added to the solution, followed by stirring for 24 hours. 50 ml of water was added to the mixture which was then extracted with methy-lene chloride (15 ml x 4). The extract was dried over anhydrous magnesium sulfate and anhydrous potassium carbonate and concentra-ted under reduced pressure to obtain 2.845 g of a crude product of 1-(6-methoxy-2-naphthyl)-2-hydroxy-1-propanone dimethyl acetal.
1.11 g of the crude product was dissolved in 3 ml of anhydrous py-ridine, followed by stirring at room temperature. 993 mg of d-10-camphorsulfonyl chloride was added to the solution and the mixture was stirred for 40 minutes 20 ml of water was added to the mix-ture which was then extracted with methylene chloride (10 ml x 3).
The extract was dried by adding successively anhydrous magnesium ~6319 sulfate and anhydrous potassium carbonate to the extract and con-centrated under reduced pressure. The residual oil was purified by column chromatography (Florisil, methylene chloride) to yield 1.467 g of 1-(6-methoxy-2-naphthyl)-2-(d-10-camphorsulfonyloxy)-l-propanone dimethyl aceta] as a colorless glass-like substance.
Yield, 76.8% [from 1-(6-methoxy-2-naphthyl)-2-bromo-1-propanone].
The product was found to be a l:l mi~ture of two diastereomers by high performance liquid chromatography and NMR spectrum.
1.067 g of the product thus obtained was dissolved in 4 ml of methanol and the solution was allowed to stand for 2 days at 2 to 4C to obtain 355 mg of colorless crystals having a melting point of 90 - 95C. The crystals were further recrystallized from methanol to obtain 220 mg of one of the diastereomers as a pure product.
m.p.: 102 - lQ5C.
[~]D ~32.5 (c=l, chloroform).
IR (KBr): 2950, 1753, 1634, 1611, 1487, 1354, 1273, 1219, 1180, 1166, 1068, 1042, 990, 919, 899, 862, 840 cm 1.
NMR (CDC13): ~0.87 (3Hr s), 1.12(3H, s), 1.23 (3H, d, J=6EIz), 1.3-2.7 (7H, m), 3.04 (lH, d, J=15 Hæ~, 3.24 (3H, s), 3.35 (3H, s), 3.86 (3H, s), 3.86 (lH, d, J=15Hz), 5.15 (lII, q, J=6Hz), 7.04-7.26 (2H, m), 7.46-7.98 ~4H, m).
For C26H33O7S:
Calculated: C. 63.78; H. 6.79; S. 6.55%
Found: C. 63.66; Il. 7.06; S. 6.57%.

,J ~,, ~863~9 .~r.

The other diastereomer was separated from the mixture as a colorless oil by high performance liquid chromatoyraphy [column: Microporasil manufactured by Waters Co.; column size:
7.8 mm x 30 cm; developing solvent: hexane + ethyl ace-tate (9:1)].
[~]D +4.2 (c_0.143, chloroform).
IR (KBr): 295Q, 1750, 1631, 1608, 1485, 1352, 1271, 121G, 1172, 1062, 1040, 985, 914, 895, 855, 810 cm 1.
NMR (CDC13): ~0.91 (3Hr s) 1 1.14 (3H, s), 1.26 (3H, d, J=6Hz), 1.3-2~7 (7H, m), 3.29 (lH, d, J=15Hz), 3.30 (3H, s), 3.42 (3H, s), 3.74 (lH, d, J=15Hz), 3.96 (3H, s), 5.20 (lH, q, J=6Hz), 7.10-7.30 (2H, m), 7.50-8.02 (4H, m).
Example 81 1.922 g (5.000 millimoles) of 1-(4-chlorophenyl)-2-(p-toluenesul-fonyloxy)-1-propanone dimethyl acetal and 500 mg (5.00 millimoles) of calcium carbonate were heated with stirring at 110C (bath temperature) for 3 days in a mixture of dimethyl formamide and water (4:1 by weight). Usual work-up as in Example 36 gave 337 mg of a colorless oil. The oil was found ~o contain 238 mg of methyl alpha-(4-chlorophenyl)propionate by NMR spectroscopy. Yield 12.0%.
Example 82 By a similar operation to Example 17, 1-(4-chlorophenyl) -2-hydroxy-1-propanone dimethyl acetal was prepared as a colorless oil from l-(4-chlorophenyl)-2-bromo-1-propanone. Without further purification, this product was used in the reaction of Example 83.

j~, .. .

3~9 IR (neat): 3450, 2975, 2930, 1600, 1492, 1398, 1108, 1095, 1052, 1016, 980, 829, 743 cm 1.
Example 83 In the same way as in Example 20, 1-(4-chlorophenyl)-2-(p-toluenesulfonyloxy)-l-propanone dimethyl acetal was prepared as white crystals havin~ a melting point of 76 to 77C from the 1-(4-chlorophenyl)-2-hydroxy-1-propanone dimethyl acetal obtained in Example 82. Yield 86% [from 1-(4-chlorophenyl)-2-bromo-1-propa-none].
m.p.: 78 - 79C (from methanol) IR (KBr): 2945, 1601, 1493, 1364, 1347, 1195, 1188, lQ94, 1057, 1110, 936, 919, 822, 789, 669, 565 cm 1 NMR (CDC13): ~1.05 (3H, d, J=6Hz), 2.40 (3H, s), 3.08 (3H, s), 3.10 (3H, s), 4.93 (lH, q, J=6Hz), 7.25 (4H, s), 7.27 (2H, d, J=8Hz), 7.76 (2H, dl J=8Hz).

Calculated: C. 56.17; H. 5.50; Cl. 9.21; S. 8.33%
Found: C. 56.22; ~1. 5.48; C1. 9.13; S. 8.32%.
Example 84 In the same way as in Example 71, 1-[4-(1-oxo-2-isoin-dolinyl)phenyl]-2-chloro-1-propanone was prepared as colorless crystals in a yield of 89% from 2-phenyl-1-isoindolinone and alpha-chloropropionyl chloride.

....
,~ , ~18~3~L9 Example 85 -In the same way as in Example 17, 1-[~-(1-oxo-2-isoin-dolinyl)phenyl]-2-hydroxy-1-propanone dimethyl acetal was obtained from l-[4-(1-oxo-2-isoindolinyl)-phenyll-2-chloro-1-propanone in a yield of 83% as colorless crystals having a melting point of 130 to 135c.
IR (KBr): 3530, 1680, 1515, 1385, 1310, 1120, 1045, 740 cm 1.
NMR (CDC13): ~0.96 (3H, d, J--7Hz), 2.36 (lH, broad s), 3.20 (3H, s), 3.33 (3H, s), 4.10 (lH, broad q, J=7Hz), 4.80 (2H, s), 7.4-706 (5H, m), 7.8-8.0 (3H, m).
For ClgH21NO4;
Calculated: C. 69.70; H. 6.47; N. 4.28%
Found: C. 69.63; H. 6.49; N~ 4.21%.
Example 86 _ _ In the same way as in Example 73, 1-[4-(1-oxo-2-isoin-dolinyl)-phenylJ-2-methanesulfonyloxy-1-propanone dimethyl ace-tal was prepared in a yield of 95% as colorless crystals from 1-[4-(1-oxo-2-isoindolinyl)phenyl~-2-hydroxy-1-propanone dimethyl acetal and methanesulfonyl chloride.
IR (KBr): 1695, 1520, 1390, 1350, 1340, 1175, 975, 910, 740 cm 1 NMR (CDC13): ~1.20 (3H, d, J=7Hz), 3.11 (3H, s), 3.24 (3H, s), 3.30 (3H, s), 4.81 (2H, s), 5.00 (lH, q, J=7Hz), 7.4-7.6 (5H, m), 7.8-8.0 (3H, m).

3~

Example 87 In the same way as in Example 48, methyl alpha-[4-(1-oxo~2-isoindolinyl)phenyl~propionate was prepared in a yield of 86% as colorless crystals from 1-[4-(1-oxo-2-isoindolinyl)phenyl~-2-methanesulfonyloxy-1-propanone dimethyl acetal.
Example 88 By the same operation as in Example 17, 1-(4-biphenyl-yl)-2-hydroxy-1-propanone dimethyl acetal was prepared as color-less crystals having a melting point of 78.5 to 80C in a yield of 95% from 1-(4-biphenylyl)-2-bromo-1-propanone.
m.p.: 78.5 - 80 C (from ether/n-hexane) NMR (CDC13): ~1.00 (3H, d~ J=7Hz), 2.44 (lH, d, J=3.1Hz), 3.23 (3H, s), 3.37 (3H, s), 4.12 (lH, q, d, J-7Hz, 3.1Hz), 7.2-7~7 and 7.55 (m and s, 9H) IR (KBr): 1118, 1102, 1045, 1007, 979, 838, 770, 735, 695 cm 1 For C17H203 Calculated: C. 74.97; H. 7.40%
20Found: C. 74.88; ~I. 7.27%.
~xample 89 .
In the same way as in Example 7, 1-(4-biphenylyl)-2-methanesulfonyloxy-l-propanone dimethyl acetal was prepared as a colorless oil from l-(4-biphenylyl)-2-hydroxy-1-propanone dimethyl acetal. Without purification, this product was used in the reac-tion of Example 90.

~L8~319 IR (neat): 1490, 1357, 1335, 1177, 1123, 1100, 1065, 1045, 971, 916, 847, 811, 773, 753, 740, 702, 538, 527 cm 1.
NMR (CDC13): ~1.21 (3H, d, J=7Hz), 3.03 (3H, s), 3.24 (3EI, s), 3.31 (3H, s), 5.01 (lH, q, J=7Hz), 7.1-7.7 (m) - 7.56 (s) total 9H.
Example 90 _ _ In a similar way to Example 21, methyl alpha-(4-biphen-ylyl)propionate was prepared as a colorless oil from the l-~4-bi-phenylyl)-2-methanesulfonyloxy-1-propanone dimethyl acetal obtained in Example 89. Yield 80.5% [from 1-(4-biphenylyl)-2-hydroxy-1-propanone dimethyl acetal].
NMR ~CDC13): ~1.47 (3H, d, J=7Hz), 3.55 (3H, s), 3.68 (lH, q, J=7Hz), 7.1-7.56 (9II, m).
IR (neat): 1741, 1490, 1215, 1167, 765, 701 cm Example 91 By a similar operation to Example 57, methyl alpha-(4-biphenylyl)propionate was prepared from the l-(4-biphenylyl)-2-methanesulfonyloxy-l-propanone dimethyl acetal obtained in Example 89. Yield 68% ~from 1-(4-biphenylyl)-2-hydroxy-1-propanone dime-thyl acetal].
Example 92 By a similar operation as in Example 17, l,l-dimethoxy-2-hydroxy-1,2,3,4-tetrahydronaphthalene was prepared from 2-bromo-l-oxo~1,2,3,4-tetrahydronaphthalene. Without purification, this product was used in the reaction shown in Example 93.
IR (neat): 1138, 1080, 1058, 767 cm 1.

-~6~
,~.~', ~ . .

363i~9 Example 93 .
In a similar way to Example 7, 1,1-dimethoxy-2-methane-sulfonyloxy-1,2,3,4-tetrahydronaphthalene was prepared as color-less crystals having a melting point of 113 to 114.5C from the 1,1-dimethoxy-2-hydroxy-1,2,3,4-tetrahydronaphthalene obtained in Example 92, Yield 46.5% (from 2-bromo-1-oxo-1,2,3,4-tetrahydrona-phthalene).
m.p.: 113 - 114.5C (from methylene chloride/diethyl ether/n-hexane) IR (KBr): 13fil, 1340, 1206, 1175, 1141, 1033, 1060, lQ50, 981, 959, 949, 917, 847, 781, 768, 62S, 546, 530, 510 cm 1 NMR ~CDC13); ~2.37 (2H, m), 2.9 (2H, m), 2.94 (3H, s), 2.g8 (3H, s), 3.43 (3H, s), 5.27 (lH, t, J=3Hz), 7.17 (3H, m), 7.63 (lH, m).
For C13H18O5S:
Calculated: C. 54.53; H. 6.34; S. 11.20%
Found: C. 54.73; H. 6.36; S. 11.10%.
Example 94 By a similar operation to Example 54, methyl indane-l-carboxylate was prepared from l,l-dimethoxy-2-methanesulfonyloxy-1,2,3,4-tetrahydronaphthalene. Yield 4%.
Example 95 In a similar operation to Example 58, methyl alpha-phenylpropionate was prepared in 51.4% yield from 1-phenyl-2-(p-toluenesulfonyloxy)-l-propanone dimethyl acetal and tin chloride.

~8fi3~9 Example 96 _ In a similar way to Example 77, 2-bromo-1-(4-difluoro-methoxyphenyl)-l-propanone was prepared as a colorless oil from 1-(4-difluoromethoxyphenyl)-1-propanone.
NMR (CDC13): ~1.92 (3H, d, J=7Hz), 5.23 (lH, ~, J=7Hz)~ 6.58 (lH, t, J=72Hz), 7.15 (2H, d, J=gHz), 8.00 (2H, d, J=9Hz).
Example 97 By a similar operation to Example 17, 1-(4-difluoro-methoxyphenyl)-2-hydroxy-1-propanone dimethyl acetal was prepared as a colorless oil from 2-~romo-1-(4-difluoromethoxyphenyl)-propanone.
IR (neat): 360Q ~ 3200, 1515, 1385, 1230, 1130, 1050, 840 cm 1.
NMR (CDC13): ~0.95 (3H, d, J=7Hz), 2.37 (lH, d, J=3Hz), 3.23 (3H, s), 3.33 (3H, s), 4.10 (lH, dq, J=3 and 7Hz), 6.52 (lH, t, J=74Hz), 7.10 (2H, d, J=9Hz), 7.49 (2H, d, J=9Hz).
Example 98 .
In a similar way to Example 7, 1-(4-difluoromethoxy-phenyl)-2-methanesulfonyloxy-1-propanone dimethyl acetal was pre-pared as a colorless oil from the l-(4-difluoromethoxyphenyl)-2-hydroxy-l-propanone dimethyl acetal obtained in Example 97. Yield 55~ [from 1-(4-difluoromethoxyphenyl)-l~propanone].
IR (neat): 1515, 1360, 1235, 1180, 1130, 1100, 1070, 1045, 975, 920, 540, 530 cm 1 .. ..

3~9 NMR (CDC13): ~1.18 (3H, d, J=7Hz), 3.09 (3H, s), 3.15 ~3H, s), 3.18 (3H, s), 4.98 (lH, q, J=7Hz), 6.53 (lH, t, J=74Hz), 7.10 (2H, d, J=9Hz), 7.45 (2H, d, J=9Hz).
Example 99 In a similar way to Example 77, 2-bromo-1-(4-difluoro-methoxyphenyl)-3-methyl-1-butanone was prepared as a colorless oil from 1-(4-difluoromethoxyphenyl)-3-methyl-1-butanone.
IR (neat): 1690, 1605, 1230, 1120, 1055 cm NMR (CDC13): ~1.02 (3H, d, J=7Hz), 1.21 (3H, d, J=7Hz), 2.1-2.8 (lH, m), 4.85 (lH, d, J=9Hz), 6~60 (lH, t, J=74Hz), 7.18 (2H, d, J=9Hz), 8.03 (2H, d, J=9Hz).
:Example 100 By a similar operation to Example 17, 1-(4-difluoro-methoxyphenyl)-2-hydroxy-3-methyl-1-butanone dimethyl acetal was prepared as a colorless oil from 2-bromo-1-(4-difluoromethoxy-phenyl)-3-methyl-1-butanone.
IR (neat): 3600-3300, 1515, 1390, 1230, 1130, 1050 cm 1.
NMR (C~C13): ~Q.69 (3H, d, J=6Hz), 0.88 (3M, d, J=6Hz), 1.2-1.7 (lH, m), 2.50 (lH, d, J=3Hz), 3.22 (3H, s), 3.24 (3H, s), 3.70 (lH, d~, J=3 and 6Hz), 6.50 (lH, t, J=74Hz), 7.07 (2H, d, J=9Hz), 7.52 (2H, d, J=9Hz).
Example 101 -In a similar way to Example 13, 1-(4-difluoromethoxy-~863~g phenyl)-2-methanesulfonyloxy-3-methyl-1-butanone dimethyl acetal was prepared as a colorless oil from l-(4-difluoromethoxyphenyl)-2-hydroxy-3-methyl-1-butanone dimethyl acetal.
Yield 76% [from 1-(4-difluoromethoxyphenyl)-3-methyl-1-butanone].
On standing at low temperatures, this product crystal-lized.
m.p.: 60 - 61C.
IR (KBr): 1515, 1350, 1230, 1180, 1145, 1080, 1055, 1035, 975 cm 1.
NMR (CDC13): ~0.67 (3H, d, J=6Hz), 0.91 (3H, d, J=6Hz), 1.4-1.9 (lHr m), 3.17 (3H, s), 3.19 ~3H, s), 3.22 (3H, s), 4.75 (lH, d, Ja 4Hæ), 6.50 (lH, t, J=74Hz), 7.08 (2H, d, J=9Hz), 7.50 (2H, d, J=9Hz).
Example 102 ~ . .
By a similar operation to Example 54, methyl alpha-(4-di~luoromethoxyphenyl)propionate was prepared in a yield of 51%
from the l-(4-difluoromethoxyphenyl)-2-methanesulfonyloxy-1-pro-panone dimethyl acetal obtained in Example 98.

IR (neat): 1745~ 1515, 1385, 1230, 1160, 1130, 1050 NMR (CDC13): ~1.46 (3H, d, J=7Hz), 3.61 (3H, s), 3.67 (~lH, q, J=7Hz), 6.43 (lH, t, J=74Hz), 7.02 (2H, J=9Hz), 7.26 (2H, J=9Hz).
Example 103 0.368 g of 1-(4-difluoromethoxyphenyl)-2-methanesul-,,, ,~, ~1;18~3~9 fonyloxy-3-methyl-1-butanone dimethyl acetal and 0.100 g of cal-cium carbonate were heated under reflux in 3 ml of a mixed solvent of water and methanol (3:7 by weiyht) for 18 days. usual work-up followed by chromatographic separation gave 0~132 g of methyl ~-(4-difluoromethoxyphenyl)isovalerate as a colorless oil. Yield 51%.
NMR (CDC13): ~0.71 (3H, d, J=7Hz), 1.02 (3H, d, J=7Hz), 2.0-2.5 (lH, m), 3.14 (lH, d, J=llHz), 3.63 (3H, s~, 6.47 (lH, t, J=74Hz), 7.02 (2H, d, J=9Hz), 7.31 (2H, d, J=9Hz).
Example lQ4 In 3 ml of a mixed solvent of water and DME 51:4 by weight), 0.368 g of 1-(4~difluoromethoxyphenyl)-2-methanesulfony-loxy-3-methyl-1-butanone and 0.100 g of calcium carbonate were heated at 110C for 12 days, then refluxed for 3 days. After usual work-up and separation, 78 mg of methyl ~-(4-difluorometh-oxyphenyl)isovalerate was obtained. Yield 30%.
Example 105 230 mg of sodium metal was dissolved in 3 ml of anhy-drous methanol. To the solution was added a anhydrous methanolsolution (2 ml) of 1.43 g of 2-bromo-1-(4-ethoxyphenyl)-3-methyl-l-butanone. The mixture was stirred at room temperature for 1.5 hours, then at 50C for 45 minutesO Usual work-up gave 1.344 g of a crude product of l-(4-ethoxyphenyl)-2-hydroxy-3-methyl-1-butanone dimethyl acetal as a colorless without further puri-fication, oily substance. The crude product was subjected to the reaction in Example 106.

.1~

~ ~863~g IR (neat): 3600-3300, 1610, 1515, 1485, 1400, 1250, 1175, 1115, 1050, 990, 925, 840, 810 cm 1.
NMR (CDC13): ~0.68 (3H, t, J=6Hz), 0.87 (3H, d, J=
611z), 1.39 (3H, t, J=7Hz), 1.2-1.7 (lH, m), 2.50 (lH, d,J=3Hz), 3.22 (3H, s), 3.24 (3H, s), 3.68 (lH, 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 ., _ In a similar way as in Example 13, 1-(4-ethoxyphenyl)-2-methanesulfonyloxy-3-methyl-1-butanone dimethyl acetal was pre-pared as colorless crystals from the 1-(4-ethoxyphenyl)-2-hydroxy~

3-methyl-1-butanone dlmethyl acetal obtained in Example 105.

Yield 62% [from 2-bromo-1-(4-ethoxyphenyl)-3-methyl-1-butanone].

m.p.: 83 - 87C.

IR (KBr): 1610, 1335, 1260, 1245, 1175, 955, 850, 840 cm 1 NMR (CDC13): ~0.71 (3H, d, J=6Hz), 0.94 (3H, d, J=6Hz), 1.40 (3H, t, J=7Hz), 1.5-1.9 (lH, m), 3.18 (3H, s), 3.20 (3H, s), 3.24 (3H, s), 4.02 (2H, q, J=7Hz), 4.S7 (lH, d, J=

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

Example 107 _ In 7 ml of a mixture of water and methanol (3:7 by wei~ht), 724 m~ o~ 1-(4-ethoxyphenyl)-2-methanesulfonyloxy-3-methyl-l-butanone dimethyl acetal and 200 mg o~ calcium carbonate ~i~63~

were heated under reflux ~or 11 hours. After usual work-up and purification~ 467 mg of methyl ~-(4-ethoxyphenyl)isovalerate was obtained as a colorless oil. Yield 99%~
b.p.: 16QC (bath temperature)/17 Torr.
NMR (CDC13): ~0.70 (3H, d, J=6Hz), 1.01 (3H, d, J=
6Hz), 1.38 (3H, t, J=7Hz), 2.0~2.6 (lH, m), 3.07 (lH, d, J=lOHz), 3.30 t3H, s), 3.97 (2H, ~, J=7Hz), 6.80 (2H, d, J=
9Hz), 7.20 (2H, d, J=9Hz).
For C14H2Q3 Calculated: C. 71.16, H. 8.53%
Found: C. 70.93; H. 8.52%.
Example 108 In a similar way as in Example 105, 2.58 g of the crude product of l-(4-methoxyphenyl)-2-hydroxy-3-methyl-1-butanone dime-thyl acetal was prepared as a colorless oil from 2.71 g of 2-bromo_l-(4-methoxyphenyl)-3-methyl-1-butanone and subjected to the reaction in Example 109 without purification.
IR ~neat): 3600-3300, 1615, 1515, 1255, 1175, 1115, 1045, 840 cm 1.
NMR ~CDC13): ~0.70 (3H, d, J=~Hz), 0.87 (3H, d, J=6Hz), 1.2-1.7 (lH, m), 2.53 (lH, broad s), 3.33 (3H, s), 3.34 (3H, s), 3.69 (lH, d, J=5Hz), 3.78 (3H~ s), 6.83 (2H, d, J=9Hz), 7.40 (2H, d, J=9Hz).
Example 109 2.58 g of the 1-(4-methoxyphenyl)-2-h~droxy-3-methyl-1-butanone dimethyl acetal obtained in Example 108 was dissolved in . . . ~.

5 ml of anhydrous pyridine, and the solution was stirred under ice-cooling. To the solution was added 2.00 g of methanesulfonic anhydride, and the mixture was stirred for 4 hours under ice-cooling, then for 2 hours at room temperature. To the mixture was added 20 ml of water, and the mixture was stirred for 1 hour at room temperature, extracted with 20 ml of diethyl ether three times. The extracts were washed with 5 ml of water twice and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chroma-tography (Florisil, methylene chloride) to yield 3.10 g of 1-(4-methoxyphenyl)-2-methanesulfonyloxy-3-methyl-1-butanone dimethyl acetal as a colorless oil (upon standing at room temperature, this compound crystallized). Yield 93% [from 2-bromo-1-(4-methoxy-phenyl)-3-methyl-1-butanone~.
m.p.: 71.5 - 73C.
IR (KBr): 1620/ 1525, 1355, 1260, 1180, 1105, 1055, 980, 970, 960, 945, 865, 850 cm 1.
NMR (CDC13): ~0.69 (3H, d, J=6Hz), 0.89 (3H, d, J=6Hz), 1.5-1.9 (lH, m), 3.14 ~3H, s)~
3.16 (3H, s), 3.21 (3H, s), 3.76 (3H, s), 4.72 (lH, d, J=4Hz), 6.82 (2H, d, J=
9Hz), 7.36 (2H, d, J=9Hz).
Example 110 In a similar way as in Example 107, methyl ~-(4-meth-oxyphenyl)iso~alerate was prepared as a colorless oil from 1-(4-methoxyphenyl)-2-methanesulfonyloxy-3-methyl-1-butanone dimethyl acetal. Yield 94~.
IR (neat): 1740, 1515, 1255, 1160, 1040, 830 cm ;3~9 NMR (CDCl3): ~0.70 (3H, d, J=6Hz), l.OO (3H, d, J=6Hz), 2.0-2.6 (lH, m), 3.08 (lH, d, J=lOHz), 3.63 (3H, s), 3.78 (3H, s), 6.80 (2H, d, J=9Hz), 7.21 (2H, d, J=9Hz).
Example lll . _ To a stirred suspension of 0.65 g of sodium hydride (55% in mineral oil) in anhydrous tetrahydrofuran (10 ml) was added 2.7 ml of ethylene glycol under ice-cooling. After stirring for 40 minutes at room temperature, 2.71 g of 2-bromo-l-(4-meth-oxyphenyl)-3~methyl-I-butanone was added to the reaction mixture and the mixture was stirred for 12 hours at 60C. After addition of water (50 ml), the reaction mixture was extracted with 30 ml of methylene chloride three times. The extracts were washed with 10 ml of water, dried over magnesium sulfate, and concentrated in vacuo. The oily residue was subjected to column chromatography (Florisil, methylene chloride~ to yield 719 mg of 2-hydroxy-l-(4-met~oxyphenyl)-3-methyl-l-butanone ethylene acetal as a colorless oil, Yield 29~.
IR (neat): 3600-3400, 1620, 1520, 1255, 1175, 1040, 845 cm l NMR (CDCl3): ~0.88 (3H, d, J=6Hz), 0.90 (3H, d, J=6Hz), 1.2-1.7 (lH, m), 2.55 (lH, broad d, J=5Hz), 3.5-4.2 (5H, m), 3.77 (3H, s), 6.83 (2H, d, J-9Hz), 7.36 (2H, d, J=9Hz).

., `' 3~

Example 112 In a similar way as in Example 13, 1-~4-m~thoxyphenyl)-2-methanesulfonyloxy-3-methyl-1-butanone ethylene acetal was pre-pared as colorless crystals from 2-hydroxy-1-(4-methoxyphenyl)-3-methyl-1-butanone ethylene acetal. Yield 78%.
m.p.: 82 - 83C.
IR (~Br): 1610, 1510, 1335, 1250, 1170, 1050, 970, 940, 930, 815 cm 1.
NMR (CDC13): ~0.91 (6H, d, J=7Hz), 1.5-1.9 (lH, m), 2.99 (3H, s), 3.6-4.2 (4H, m), 3.75 (3H, s), 4.67 (lH, d, J=4Hz), 6.83 (2H, d, J=9Hz), 7.34 (2H, d, J=9Hz).
Example 113 In 5 ml of a mixture of water and methanol (3:7 by weight), 495 mg of 1-(4-methoxyphenyl)-2-methanesulfonyloxy-3-methyl-l-butanone ethylene acetal and 150 mg of calcium carbonate were heated under reflux for 148 hours. After usual work-up fol-lowed by column-chromatographic purification, 307 mg of 2-hydroxy-ethyl ~-(4-methoxyphenyl)isovalerate was obtained as a colorless oil. Yield 81~.
IR (neat): 3600-3200, 1735, 1610, 1510, 1255, 1170, 1160, 1035, 830 cm 1.
NMR (CDC13): ~0.70 ~3H, d, J=7Hz), 1.03 (3H, d, J=7Hz), 2.0-2.5 (lH, m), 2.27 (lH, broad s), 3.13 (lH, d, J=lOHz), 3.5-3.8 (2H, m), 3.76 (3H, 5), 4.0-4.3 . ~

;3~:9 (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-propan-one dimethyl acetal and 0.20 ml of trimethylsilyl trifluorometh-anesulfonate were stirred in 1 ml of orthoformic acid trimethyl ester at 65C for 9 hours~ After usual work-up, methyl alpha-phenylpropionate was found to be 50.5% yield by GLC analysis in a same way as in Example 57.
Example 115 In a similar operation as in Example 58, methyl alpha-phenylpropionate was prepared in 80% yield from 1-phenyl-2-(p-toluenesulfonyloxy)-l-propanone dimethyl acetal and ferric chloride.

8~;319 1~ Example_116 In the same way as in Example 80, 1-(6-methoxy-2-naphthyl)-2-(Q-10-camphorsulfonyloxy)-1-propanone dimethyl acetal as a mixture of two diastereomers was produced from Q-10-camphorsulfonyl chloride and 1-(6-methoxy-2-naphthyl)-2-hydroxy-1-propanone dimethyl acetal. The mixture was recrystallized twice from methanol to give one of the diastereomers ~mp. 93 - 96C; (~)23 -32.2 (c=0.801, chloroform~) as colorless plate-like crystals. This product completely agreed wi~h one of the diastereomers of 1-(6-methoxy-2-naphthyl)-2-~d-10-camphorsulfonyloxy)-1-propanone dimethyl acetal which was obtained in Example 80 ~ 25 l32.5 (c=l, chloroform)) in IR and NMR spectral data. ~ ~
The starting Q-10-camphorsulfonyl was prepared from commercial ammonium Q-10-camphorsulfonate ((~)D2 -18.4 ~c_5.3, water)) and thionyl chloride by the method described in H. Sutherland, and R. L. Shriner, J. Am. Chem. Soc~, 58, 62 (1936).
t~)D6 -32.3 (c-1.36, chloroform) m.p.: 58 - 64 . .
Example 117 `~ ~ - 555 mg of the diastereomer of 1-(6-methoxy-2-naphthyl)-2-(Q-10-camphorsulfonyloxy)-1-propanone dimethyl acetal, which was isolated in Example 116, was reacted in the same way as in Example 56 to give 249 mg of methyl (+)-~-(6-methoxy-2-naphthyl)propionate. Yield 90 %.
(~)D5 +75 0 (c=0.949, chloroform). The IR and ~]~IR spectral ~ .. . ~
~ .. _ ... _ .. . _ _ ... . . . ... . . .. . . . . . . . .

" 11863~9 7q data of the product agreed with those of the product obtained in Example 56.
Example_118 _ __ 799 mg of 1-(6-methoxy-2-naphthyl)-2-hydroxy-1- -propanone dimethyl acetal ~as dissolved in 3 ml of anhydrous pyridine, and the solution was stirred at room temperature. To the solution was added 833 mg of p-toluenesulfonyl chloride, and the mixture was stirred at room temperature for 3 days. Water ~30 ml) was added, and the mixture was extracted with three successive 10 ml lots of methylene chloride. The extracts were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily re-sidue was purified by column chromato-graphy ~silica gel, methylene chloride) to give 1.019 g of 1-~6-methoxy-2-naphthyl)-2-(p-toluenesulfonyloxy)-1-propanone dimethyl acetal as a colorless oil.
Yield: 81.9 %
IR ~neat): 1612, 1489, 1360, 1278, 1192, 1178, 899, 560 cm~l.
NMR tCDC13): -~1.13 (3H, d, J=7 Hz-), 2.40 t3H, s), 3.13 (3H, s), 3.21 (3H, s), 3.88 (3H, s) 9 5.04 tlH, q, J-7 Hz), 7.0 - 7.9 ~lOH, m).
Example 119 To a solution of 132 mg of metallic sodium in 5 ml of anhydrous methanol was added 879 mg of 1-~6-methoxy-2-naphthyl)-2-bromo-1-propanone. The mixture was stirred at room temperature for 7 hours. Water ~20 ml) was added, ~ 863~19 ,~o and the mixture was extracted with three successive 10 ml lots of methylene chloride. Two drops of pyridine was added to the extracts, and the mixture was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give crude 1-~6-methoxy-2-naphthyl)-2-hydroxy-l-propanone dimethyl acetal. Without purification, the crude product was dissolved in 2 ml of anhydrous pyridine, and the solution was stirred at room temperature.
~ To the solution was added 0.60 ml of benzenesulfonyl chloride, and the mixture was stirred for 20 hours. Water (10 ml) was added, and the mixture was extracted with three successive 10 ml lots of methylene chloride. The ; extracts were washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromato-Ç'- graphy (silica gel, methylene chloride) to give 1.024 g of 6-methoxy-2-naphthyl)-2-benzenesulfonyloxy-1--propanone dimethyl acetal as a colorless oil. The yield of the ,",;~ , ~, . . .
product was 82.0 % based on 1-(6-methoxy-2-naphthyl)-2-~Z0 bromo-l-propanone. ~

; IR ~neat): 1637, 1612, 1488, 1456, 1365, 1278, 1190, 925, 900, 761, 598 cm~l.
, ~., , ~ ., .
NMR (CDC13): ~1.15 (3H, d, J-7 Hz), ; ~ ~3.10 (3H, s), 3.18 (3H, s), ~5.08 (lH, q, J-7 Hz), 7.0 - 8.1 (llH, m).

Example 120 Iodotrimethylsilane (0~53 ml; 0.75 g) was added , 111~6319 _~1 to 10 ml of methylene chloride in an argon atmosphere and stirred at room temperature. An anhydrous methylene chloride solution (10 ml) of 1.074 g of 1-~6-methoxy-2-naphthyl)-2-(p toluenesulfonyloxy)-l-propanone dimethyl acetal was added to the solution over 20 minutes, and the mixture was stirred at the same temperature for 40 minutes, Twenty milliliters of a 20 % aqueous solution of sodium thiosulfate was added, and the mixture was stirred . .; ,.
overnight. The organic layer was washed with five succes-sive 20 ml lots of the same sodium thisulfate solution as mentioned above, dried over anhydrous magnesium sulfate ?

- : - . :. -: -and concentrated under reduced pressure.- The residue was purified by column chromatography (silica gel, chloroform) to give 495 mg of methyl ~-(6-methoxy-2-naphthyl)propionate.
.. . . . .
~ 15 Yield 81 %. The NMR spectral data of the product com- -., " ~ .
~ pletely agreed with those of the product obtained in ~., ~ Example 54.

.
~, :

~ ' '~ ' . ' - , . .

, , . , :,, :~., "
,.: - ;, .. . .. ~ ~ . . ..
' ' ', ~'' ~ " , - . , . ' ,, . .:

,., ., , ~ - .
.. ~., . , :

~ -- ., ~ , .
:

Claims (15)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the general formula II

wherein Ar represents an aromatic group and R1 represents a hydrogen atom or a saturated aliphatic group, or Ar and R1 may form a condensed ring together with the carbon atom to which they are bonded; R3 and R4, independently from each other, represent an alkyl group, or taken together, represent an alkylene group; and R5 represents a substituted or unsubstituted alkyl group or an aromatic group, which comprises (a) reacting a compound of the formula V

wherein X represents a halogen atom, Ar and R1 are as defined above, with an alkali metal alkoxide of the formula wherein M represents an alkali metal and R3 is as defined above, in the presence of an alcohol of the formula wherein R3 is as defined above, or reacting the compound of formula V with an alkali metal alkoxide of the formula wherein R3 and M are as defined above, to form an apoxy compound of the formula VII

wherein Ar, R1 and R3 are as defined above, and then reacting the epoxy compound with an alcohol of the formula wherein R4 is as defined above, in the presence of an alkali metal alkoxide of the formula wherein R4 is as defined above and M represents an alkali metal, or reacting the compound of formula V with an alkylene glycol, and (b) reacting the resulting compound of the formula VI

wherein Ar, R1, R3 and R4 are as defined above, with a compound of the formula R5 - SO2 - Hal or (R5-SO2)2O
wherein R5 is as defined above and Hal represents a halogen atom.

2. The process of claim 1 wherein Ar represents the group R6-Ar1- or a thienyl group, in which Ar1 represents a phenylene or naphthylene group and R6 represents a hydrogen atom, a hlaogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkoxy group, a lower alkanoylamino group, an oxo-isoindolinyl group, or a phenyl group.

3. The process of claim 1 wherein R1 is a hydrogen atom or a lower alkyl group.

4. The process of claim 1 wherein R3 and R4, independently from each other, represent a lower alkyl group, or taken together, represent a lower alkylene group.

5. The process of claim 1 wherein R5 represents alower alkyl group, a lower haloalkyl group, a d- or ?-10-camphoryl group, or a group of the formula in which R7 represents a hydrogen atom, a halogen atom, a nitro group or a lower alkyl group.

6. The process of claim 1 for preparing a compound of the general formula II-1 wherein Ar2 represents the group R6-Ar1- or a thienyl group, Ar1 represents a phenylene or naphthylene group; R1' represents a hydrogen atom or a lower alkyl group; R3' and R4?, independently from each other, represent a lower alkyl group, or taken together, represent a lower alkylene group; R5' represents a lower alkyl group, a haloalkyl group, a d- or ?-10-camphoryl group, or a gruup of the formula ; R6 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkoxy group, a lower alkanoylamino group, an oxo-isoindolinyl group, or a phenyl group; and R7 represents a hydrogen atom, a halogen atom, a nitro group or a lower alkyl group.

7. The process of claim 6 wherein Ar2 represents a 6-methoxy-2-naphthyl group.

8. A compound of formula II as defined in claim 1 when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.

9. A compound of formula II-1 as defined in claim 6 when prepared by a process according to claim 6 or an obvious chemical equivalent thereof.

10. The process of claim 1 for preparing a compound of the following general formula wherein R1, R3 and R4 are as defined in claim 1, and Ar3 represents a 6-methoxy-2-naphthyl group, a 4-isobutylphenyl group, a 4-lower alkoxyphenyl group, a 4-difluoromethoxyphenyl group, a 2-thienyl group, a 4-(1-oxo-2-iso-indolinyl)phenyl group, a 4-biphenylyl group and a 4-(tert-butyl)phenyl group.

11. A compound of formula VI-1 as defined in claim 10 when prepared by a process according to claim 10 or an obvious chemical equivalent thereof.

12. The process of claim 10 wherein R1 represents a hydrogen atom or a lower alkyl group; R3 and R4, independently from each other, represent a lower alkyl group, or taken together, represent a lower alkylene group.

13. The process of claim 10 wherein Ar3 is a 6-methoxy-2-naphthyl group and R1, R3 and R4 are each methyl groups.

14. The process of claim 6 wherein Ar2 is a 6-methoxy-2-naphthyl group and R1', R3' , R4' and R5' are each methyl groups.

15. The process of claim 6 wherein Ar2 is a 6-methoxy-2-naphthyl group, R1 , R3 and R4 are each methyl groups and R5' is a .delta.-10-camphonyl group.