JPS60112735A - Manufacture of optically active alpha-arylalkanoic acids andprecursor therefor - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of the Invention) This invention relates to a method for producing optically active α-arylalkanoic acids and a novel intermediate used therein. In particular, the present invention relates to the oxidative bonding ( The present invention relates to a method for stereoselectively producing optically active α-arylalkanoic acids by chromatography. As desired,
Concomitant or sequential hydrolysis of the resulting derivatives such as esters, amides, oxazolines, nitrites or carboxy metal salts gives the corresponding optically active α-arylalkanoic acids. The method can optionally include removal of the halogen from the aromatic group of the alpha-arylalkanoic acid and methylation of the arylhydroxy group on the aryl moiety. Additionally, the method includes a subsequent step of producing pharmaceutically acceptable salts and esters of optically active alpha-arylalkanoic acids. The product is a drug with anti-inflammatory, analgesic and antipyretic activity.

PRIOR ART A large number of monoarylalkanoic acids (i.e., 2-arylalkanoic acids) have been reported, developed, and found to be useful as pharmaceuticals exhibiting anti-inflammatory, analgesic, and antipyretic activity. For example, U.S. Pat. No. 3,385,386 describes certain 2-
Describes phenylpropionic acids. Of particular note among the compounds described therein is 2-(4-inbutylphenyl)propionic acid, commonly known by the generic name ibuprofen. US Pat. No. 3,600,437 describes 2-(3-phenoxyphenyl)-1 and 2-(3-phenylthiophenyl)alkanoic acids, among other compounds. Particularly noteworthy among these is 2-(3-phenoxyphenyl)furopionic acid, commonly known by its common name fenoprofuent acid. U.S. Pat. No. 3,624,142 describes (fluorosubstituted biphenyl)alkanoic acids,
Among them is 2-(4'-fluoro-4-biphenyl)propionic acid. U.S. Patent No. 3755 4 2
No. 7 describes other fluoro-substituted biphenylpropionic acids, among which is 2, known as flurbiprofen.
-(2-fluoro-4-biphenyl)propionic acid. U.S. Pat. No. 3,904,682 describes a compound known by the generic name naproxen, 2-(
6-methoxy-2-naphthyl)propionic acid. Related compounds are described in Belgian Patent No. 747,812. US Pat. No. 3,912,748 describes 5- and 6-benzoxazoylalkanoic acids with anti-inflammatory, antipyretic and analgesic properties. Among them, the one that attracts attention is 2-2, commonly known as benoxaprofen.
(4-chlorophenyl-5-benzoxazoyl)furopionic acid. Therefore, an extremely wide variety of useful α
- It is clear that arylalkanoic acids are known.

Other known useful α-arylalkanoic acids include 6
-Chloro-α-methyl-9H-carbazole-2-acetic acid (carprofen), α-methyl-98-fluorene-2-acetic acid (cycloprofen), 3-chloro-α-methyl-4-(2-chloro- carbonyl)benzeneacetic acid (
Cryprofen), α-methyl-3-phenyl-7-benzofuranacetic acid (Furaprofen), 4-(1,3-
Hitro-1-oxo-2H-isoindol-2-yl)benzeneacetic acid (inzoprofen), 3-hendiyl-α-methylbenzeneacetic acid (ketoprofen), 3-chloro-4-(2.5-dihydro-IH-virol-1) −
yl)benzeneacetic acid (vilprofen), α-methyl-
Examples include 4-(2-thenylcarbonyl)benzeneacetic acid (sprophene) and its related compounds.

Many methods for producing such α-arylalkanoic acids have also been reported. These methods are described in the above patents, other patents, and non-patent literature. For example, US Pat. No. 4,135,051 describes a method for making ester precursors of a number of arylalkanoic acids using trivalent thallium salts as reactants. This process has the disadvantage that the thallium salt used therein is a toxic chemical and must be removed from the final product. US Patent No. 39
No. 75431 describes a method for producing α-arylalkanoic acids from glycidonitrile via enol acylate. U.S. Patent Nos. 3,658,863, 3,663,58
No. 4, No. 3,658,858, No. 3,694,476 and No. 3,959,364 describe various coupling methods for producing arylalkanoic acids. A recent example is British Patent No. 2042543 (issued September 24, 1980, No. 8005752 filed on February 20, 1980).
No. 1) is a method for producing an arylalkanoic acid ester precursor from an α-haloalkylaryl ketone using a metal catalyst for catalytic rearrangement in an acidic alcoholic medium, comprising:
A process is described in which the catalyst is a silver(I) salt of an organic and/or inorganic anion.

In large-scale production, the high cost due to the use of metal catalysts, especially silver catalysts, is an inherent drawback of this process.

U.S. Pat. No. 3,652,683 discloses the reaction of 2-(1-haloethyl)-5-methoxynaphthylene and nickel carbonyl in the presence of an alkyl metal tertiary alkoxide in a lower tertiary alkanol solvent to form an ester, and then By hydrolyzing its ester group, 2-(
A method for producing 6-medoxy (2-naphthyl) propionic acid is described.

U.S. Pat. No. 3,651,106 discloses that an ethylnaphthalene derivative substituted with a metal at the alpha position is (a) combined with 2' carbon oxide to form the corresponding carboxylic acid, and (b) combined with orthoethyl carbonate to form the corresponding ester. , (C) combined with ethyl chloroformate, or (d) combined with paraformaldehyde to give the corresponding aldehyde, and further reacted with the corresponding 2-(6-medoxy-2-naphthyl).
The method for producing propionic acid is described.

Another related patent is U.S. Patent No. 3076016.3.
907850.4017526.4055582.41
20882.4133963.4142054.414
4259.4293502.4239914 and 43
There is No. 06086.

B r Z n -C using an unsubstituted aromatic halide
The preparation of α-arylalkanoic acids by arylation of H2CO2CH2C1-I3 was reported by Forbulk and Jutand in the Journal of Organometallics.
Chemistry Vol. 177, pp. 273-281 (1979)
has been reported.

The corresponding α-lithium substituted carboxylic acid ester and unsubstituted phenyl halide are treated in the presence of an inorganic nickel halide catalyst and a dipolar aprotic solvent to obtain the phenylalkyl carboxylic acid ester. American Chemical Society, Vol. 99, 4833-4837. (1977). The reaction of Grignard reagents with alkyl halides in the presence of catalysts has been described in the journal Hayashi et al.
Op American Chemical Fusa 4 Fufu 4104 Volume 18
0-186 (1982), Hayashi et al., Vol. 98, 3
71-819 (1976), Tamao et al., Bulletin of the Chemical Society of Japan Vol. 49, No. 7, pp. 1958-1969 (1976), and Hayashi et al., Tetrahedron Letters Vol. 21, 79- 8
2 (1980).

Wakefield discusses reverse metal-halogen exchange reactions of organolithium compounds in Chemistry of Organolithium Compounders (Pergamon Press, New York, 1974) and references cited therein. For this reaction to occur with organolithium compounds, this exchange appears to require highly active unsaturated compounds or alkyl-polyhalogen compounds, resulting in optically active acids, so this exchange is possible with the method of the present invention. I can't wait. Similarly, Beer and Kearney, Tetrahedron Letters No. 51, 4697-4700 (
(1976) in the case of Grignard reagent and lower ω-
The copper-catalyzed reaction of chloromagnesium bromo acid salts is discussed.

Despite the usefulness of the above methods in a variety of cases, there remains a need for a simple process for producing optically active alpha-alkanoic acids of the type described herein. Many α-arylalkanoic acids exist as mixtures of optical isomers.

It is often advantageous to use stereoselective methods to produce the desired optically active isomer that accounts for the predominant pharmaceutical activity of alpha-aryl carboxylic acids.

For example, d-2-(6-medoxy-2-naphthyl)propionic acid has greater pharmaceutical activity than the l-isomer. Therefore, it is desirable to use stereoselective methods to directly produce the d-isomer. Such methods eliminate the need for a dJ isomer resolution step using optically active bases such as cinchonidine, brucine, and the like. Elimination of the splitting process results in a substantial reduction in both material costs and manufacturing labor costs.

This reduction is particularly true for compounds that are presented in medicine as substantially pure optically active isomers, such as 2-(6-medoxy-2-naphthyl)propionic acid (naproxen) or precursors that can be readily converted to this acid. is important.

[Summary of the invention]

This invention is based on the formula % formula % () (where Ar is an aryl moiety, kl is lower alkyl having 1 to 8 carbon atoms (inclusive) or 3 to 8 carbon atoms (inclusive) cycloalkyl having a carboxy group, a metal salt of a carboxy group, an alkoxy group, a substituted aminocarbonyl group, a nitrile group or an oxazinonyl group). , formula % formula % () (wherein R1 and Y have the above-mentioned meanings, M means lithium, tin, tin halide, zinc, or zinc bromide). In the presence of an aryl halide represented by [) (wherein Ar means the above-mentioned meaning and According to another feature of the invention, the method further comprises: contacting a compound of formula (■) with a pharmaceutically acceptable salt thereof; 2-(5-bromo6-medoxy2
- dehalogenation of halogen-substituted naphthalene derivatives which are naproxen precursors, such as naphthyl)propionic acid;
and 2-(6-hydroxy-2 for naproxen)
- methylation of hydroxynaphthalene derivatives such as (naphthyl)propionic acid.

In this invention, the catalytic bonding of an alkyl carboxylic acid, ester, amide, nitrile, oxazoline or metal salt with an aryl halide is achieved by direct metallization or activation of the alpha carbon of the carbonyl with a metal or metal halide, i.e. -CH(M) acid, -CH(M
) ester, -CH(M)amide, -CH(M)nitrile, -CH(M)oxazoline, or carboxylic acid metal salt -CH(M)C(0)OM (M is a metal ion)
This is done by generating . 6-(methoxy-
An aryl halide such as 2-bromonaphthalene is selected as being sufficiently reactive to react with the metal derivative in the presence of a chiral (optically active) transition metal catalyst, optionally in the presence of a dipolar aprotic solvent. It will be done. The reaction mixture is held for a sufficient time to form the corresponding optically active alpha-arylalkanoic acid, ester, amide, nitrile, oxazoline or metal salt. If desired, the above compounds are hydrolyzed in parallel or in stages to obtain the corresponding α-arylalkanoic acids.

According to another feature, the invention relates to a process for the preparation of stereoisomers, in particular single stereoisomers, of α-arylalkanoic acids and their pharmaceutically acceptable salts.

According to a further feature, the invention provides for acids, esters,
An amide, nitrile, oxazoline or carboxy metal salt and an aryl halide are treated in the presence of a chiral (optically active) transition metal catalyst, optionally in the presence of a dipolar aprotic solvent, to optionally produce an ester, amide, nitrile, The present invention relates to a process for producing materials consisting essentially of a single stereoisomer of alpha-arylalkanoic acids by hydrolyzing an oxazoline or metal salt to the desired acid.

Each of the above methods comprises: (a) concomitantly or sequentially hydrolyzing the produced ester, amide, nitrile, oxazolidine, or metal salt to the corresponding α-arylalkanoic acid, optionally;
then (b) hydrolyzing the free acid of formula (I) to said free acid by treating the corresponding salt or ester with an acid; or (C) by treating the free acid of formula (1) with an alkanol. esterification, or (d) converting the free acid of formula (I) into a pharmaceutically acceptable salt without loss of optical activity by treatment with a pharmaceutically acceptable base.

According to another aspect, the invention relates to novel intermediates useful in the production of optically active α-arylalkanoic acids.

[Detailed description of the invention]

(Definition) In this specification, "alkoxycarbonyl group" is an ester group, i.e. -
COOR3 (here, R3 is a group independently selected from the same alkyl groups as R1).

"Alkyl" refers to an alkyl group having 1 to 8 carbon atoms (inclusive), including methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, S-
Examples include butyl, t-butyl, n-hexyl and n-octyl.

"Alkanol" refers to an organic alcohol containing one of the above "alkyl" groups.

"Alkoxy" refers to an alkoxide group having 1-8 carbon atoms (i.e. R30-), including methoxy, ethoxy, n-propoxy, -monopropoxy, n-butoxy, ! -butoxy, [-butoxy, n-hexoxy, n-
Examples include octoxy.

"Aryl" means 3-phenoxyphenyl, 2-fluoro-1-biphenyl, 4-isobutylphenyl, 1-fluoro-4-biphenyl, 5-bromo-6-medoxy-2-naphthyl, 5-chloro-6-medoxy-2- It refers to unsubstituted or substituted phenyl, phenoxyphenyl, naphthyl or biphenyl groups, such as naphthyl, 6-hydroxy-2-naphthyl and 6-medoxy-2-naphthyl. Optional substituents on phenyl, phenoxyphenyl, biphenyl and naphthyl groups include 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and [-butyl]. (inclusive) lower alkyl, methoxy, ethoxy, n-propoxy, impropoxy,
Examples include lower alkoxy having 1 to 4 carbon atoms (inclusive), hydroxy, hydroxy salts such as -butoxy, and halogens such as chloro, bromo or fluoro.

"Chiral" refers to a chemical structure with an asymmetric center.

"Cycloalkyl" means cyclopropyl, cyclobutyl,
It refers to a cyclic hydrocarbon group having 3 to 8 carbon atoms such as cyclopentyl, methylcyclopentyl, cyclopentylmethyl, cyclohexyl, cyclooctyl and the like.

"Dipolar aprotic solvents" include benzene, toluene, dibutyl ether, dimethoxyethane, diethyl ether, hexamethylphosphoramide, hexane, hexene,
Solvents include, but are not limited to, pentane, petroleum ether, tetrahydrofuran, N-methylpyrrolidine, and the like. Mixtures of these solvents and inert diluents, such as hydrocarbon solvents, are useful in this invention.

[Enantiomer] or "enantiomorph" refers to a molecule whose mirror image is not superimposable. A necessary and sufficient condition for exhibiting optical activity (ie, enantiomers) is that a molecule is not superimposable with its mirror image. This phenomenon usually occurs in organic chemistry when a carbon atom is bonded to four different atoms or groups. "Enantiomer" and "optical isomer" are often used interchangeably in this specification.

"Enantiomeric excess" or "eeJ" is defined as the percentage of the predominant enantiomer minus the other.

For example, a mixture of 95% (+) isomer and 5% (-) isomer has an ee of 90%.

"Grinard reagent" refers to alkyl or arylmagnesium halides such as ethylmagnesium chloride, methylmagnesium bromide, phenylmagnesium bromide, P-methylphenylmagnesium iodite, and the like. Any combination of alkyl or aryl or halogen groups can be used.

Examples of "halogen" or "X" include bromine, iodine, chlorine and fluorine. Usually, A in this invention
The preferred order of rX is aryl iodite, aryl bromide, and aryl chloride. The yield of product (I) generally decreases in the order of aryl iodite, aryl bromide, and aryl chloride in this reaction.

“Metal” or “M” refers to lithium, tin, tin halide (
chloride, bromide or iodite), zinc or zinc bromide. Metals can be introduced directly into acids, esters, amides, oxazolines or nitriles using alkyl or aryl metals or by treatment with metal or organometallic bases that have sufficient strength to remove protons under appropriate conditions. can.

"Metalized" or "metallized" refers to the formation of a metal, in some cases, a halogen-metal-carbon bond (X-■-C-).

[Metal salt of carboxy group] is -COOM group, M
may be lithium, tin, tin halides (chloride, bromide, iodite), zinc or zinc bromide]
shows.

"Nitrile" refers to an organic compound containing a cyano (-CmN) group.

"Optical yield" or "optical purity" is defined similarly to enantiomeric excess. However, strictly speaking, it indicates the measured optical rotation of the mixture, which may or may not reflect the true ratio of enantiomers. In this specification, the two terms are used more or less interchangeably.

"Optically active" refers to a functional term meaning that a system or compound rotates the plane of polarized light.

"As desired" or "as desired" means that the event or situation described thereafter may or may not occur; For example, "optionally substituted phenyl" means that phenyl may be substituted or unsubstituted, and that this description includes both unsubstituted phenyl and substituted phenyl. It means to be.

"Optionally then converting the free base to an acid addition salt" means that the conversion may or may not be performed in order for the process to be covered by this invention, and that this invention It is meant to include methods that convert into acid addition salts as well as methods that do not.

"Oxazinonyl group" has the formula -C=N-(CH2)n-
It represents a cyclic protecting group represented by 0 (n is an integer of 1-5).

The "pharmaceutically acceptable non-toxic ester" of formula (I) is defined as a compound in which the OH moiety of -COOH in formula (■) has 1-1 carbon atom.
Including those substituted with 12 alkoxy. These are discussed in more detail later in the description and in Example 35 in which an acid of formula (I) is reacted with a suitable alcohol.

[Pharmaceutical-L acceptable non-toxic salts] refers to derivatives in which -H of -c o o tr in formula (I) is replaced with a cation such as sodium or bonded with a suitable amine. . These will be explained later in the description and formula (
This is discussed in more detail in Example 33, in which the acid of I) is reacted with a suitable base.

"Protection" or "protecting group" refers to the protection of a carboxy group by conversion to a salt, ester, amide, oxazoline or nitrile from which the carboxylic acid can subsequently be regenerated.

"Substituted aminocarbonyl group has the formula -C(0)N
R4R5 (wherein R4 and 5 are independently selected from the same alkyl groups as R1 above).

"Transition metal catalyst" (eg, as used in Step B) refers to an iron, cobalt, nickel or palladium catalyst in which the phosphorus and the alkyl or aryl group are coordinated. Such optically active catalysts include chiraphos (CHIRAPHO5) and phenphos (PHE) as nickel or palladium catalysts.
NPI-105), PROPHO5 and those listed below.

(Overview of the method) The method for the direct production of optically active arylalkanoic acids according to the present invention involves converting the corresponding fatty acids into mono- or dimetal-substituted derivatives, and further converting the derivatives into mono- or dimetal-substituted derivatives in the presence of a chiral (optically active) transition metal catalyst. and optionally in the presence of a dipolar aprotic solvent, reacting with an aryl halide to give the formula (I)
and, if necessary, hydrolyzing compound (I) to the corresponding Ar-Cl-1-(R1)-COOH.

Alternatively, the carboxy group of the alkanoic acid can be converted into a derivative, i.e. using a protecting group such as an ester, amide, nitrile or oxazoline, which can be halogenated and metalized to give a metal compound, which can then be converted into a metal compound as described above. It can also be reacted with an aryl halide.

Alternatively, the carboxy groups of alkanoic acids can be directly metallated under certain conditions, and the thus protected carboxy groups are further reacted to obtain α-metalated and carboxy-protected compounds, which are then converted to aryl as described above. Can be reacted with halides.

Additionally, the carboxy group of the alkanoic acid can be protected as an ester, amide, nitrile or oxazoline and metallized to give a metalized and protected derivative, which can be further reacted with an aryl halide as described above. Conversion of the carboxylic acid, R1-CH-COOH, to the carboxylic acid dilithium dianion is currently the preferred method,
Propionic acid in which R1 is methyl will be described later in Example 3. In the subsequent reaction, arylhalai)=(A
rX) and a chiral (optically active) catalyst to produce compound (I). Here too, in the case of dilithium compounds, the reaction proceeds in high yield and the optically active Ar-C)
(-(R1)-COOM is produced, and the desired optically active arylalkanoic acid Ar-CH-(
R1)-COOH is obtained.

Lithium can be attached using an alkyl or aryl lithium such as n-butyllithium or phenyllithium in an inert solvent such as tetrahydrofuran at low temperature. As a representative example, N,N-diisopropylamine, n-butyllithium and propionic acid
Combine at °C and warm to room temperature over several hours. A preferred metal is lithium.

[Method reaction order]

The reaction order is as follows.

(Reaction order) RI KI RI PLl l Step Gl 1 x-CH-Y-nM-CH-Yg-Li-σtoY(II
c) (M) (IF) (M) (Ila) (I) Method (Steps A, R and C) In one embodiment, the compound of formula (I) is prepared directly using the carboxy group (Step A, B and C) are manufactured. Formula (Il
The starting materials for a) can be purchased commercially or prepared from the corresponding substituted carboxylic acids, i.e. l-CH2-C0OH (formula I
Ia) can be produced by a conventional method. Compound (I[a
) is treated with a strong base such as n-butyllithium or lithium diisopropylamide in step A to produce the -metal compound (■). In another example, the introduced metal “M
” may be lithium, tin or tin halide, zinc or zinc bromide. In the case of lithium, a dilithium dianion Li"CH-R'-COO-+Li is produced as a compound (IT).

Some of the aryl halides used in this invention are heavy or prepared by methods known to those skilled in the art.

Chiral (optically active) transition catalysts are known in the art, such as [(k)-bis(1,2-diphenylphosphino-1-phenylethane]nickel(II) chloride, as described by Booth and Chat, Journal Op. - Manufactured according to Chemical Society, p. 3238 (1965).

Chiral (optically active) catalysts derived from other phosphines are available from Merrill's Asymmetric Synthesis Using Chiral Phosphine Ligands (Reactor).
Design Corporation, New Chassis 072
05, Hillside, 100 Hoffman Place, Copyright 1980).

In this reaction (step B), a halogen or dihalogen chiral (optically active) transition metal catalyst is used to control the oxidation state of the metal, e.g. can be treated with excess alkyl or aryl metal to reduce from to MO.

Chiral transition metal catalysts include any optically active cyclic organic nickel or palladium phosphorus halide derivative. Cyclic derivatives having this type of structure are illustrated in Tables 1 and 2 below.

Table 1 Optically active ferrocenyl phosphorus catalyst substituents fal A B C Name Configuration 1"CI"N (51-CM2N(C)13)2-1'
Ph2IIPPEF (8) -PPh2-CH2CH
3Il These chiral (optically active) catalysts have been described by Hayashi et al.
It is described in Journal of the American Chemical Society, Vol. 104, p. 180:2186 (1982).

3. In the case of ferrocenylphosphine containing both central and planar chirality, k and S are used in the order of central chirality first and planar chirality second.

b, A r 1 is 2-methylphenyl.

c, A r 2 is 3-methylphenyl.

d, Ara is 3,5-dimethylphenyl.

e, Ar4 is 3-methoxyphenyl.

", 1 is ethyl.

g, R, 2 are isopropyl.

h, R3 is isobutyl.

i, R4 is tetramethylene (cyclic).

j, R5 is pentamethylene (cyclic).

, R6 is 3-oxopentamethylene (cyclic).

1. R7 is 3-methyl-3-azapentamethylene (cyclic).

m, the "P" atom of substituent A and the "N" atom of substituent B are
It is bonded by Pd(Cf2) to form a 6-membered ring.

n, "PJ atom to the substituent and "P" atom of substituent C are
It is bonded by Pd(C12) to form a 6-membered ring.

Table 2 Chiral (optically active) transition metal catalyst CI (1ゝ) φ φcr, t3HCH3Hφ φc2 (
C) φ φ II φ 11 Hφ φc3 + (1
) φ φ 11cII3iIII φ φa) Q is a transition metal such as palladium or nickel, T and Z
independently represents halogen, usually chloro.

b) If Q is nickel and T and 2 are chloro, C1
is CHIRAPHO5 nickel (I[) chloride, i.e. [(R)-bis-(1,2-diphenyl-phosphino)-1,2-'; methylethane]nickel (■) chloride.

C) If Q is nickel and T and Z are chloro, C2
is PHENPHO5 nickel(II) chloride, i.e. [(R)-bis(1,2-diphenyl-phosphino)-1-phenylethane]nickel (U
) chloride.

d) If Q is nickel and T and 2 are chloro, then C3
is PROPHO5 nickel(II) chloride, i.e. [(R)-bis(1,2-diphenyl-
phosphino)-1-methylethane]nickel (■) chloride.

In certain embodiments of this invention, the coupling of the aryl halide to the compound of formula (If) can optionally be carried out in the presence of said dipolar aprotic solvent.

In step C, compound (I) is hydrolyzed under acidic or basic conditions known to those skilled in the art to yield the optically active free acid Ar-CH(R')-COOH.

(Step D, Summer (, B and C)) In another aspect of this invention, the compound of formula (I) is prepared by protecting the carboxy group in some way (Step D) intermediate R1
Produced by producing -CH-Y (formula (]Tb), R1 and Y have the above meanings) and converting it into a suitable α-metal substituted derivative (Step H). Combined with ArX After (Step B), compound (I) is finally reconverted to a carboxylic acid (Step C).

These protected compounds [i.e. (I[b)] are known and include metal salts of carboxy groups, alkoxycarbonyl (ester LffiF-converted aminocarbonyl (amide)
, oxazolinyl (oxazolines) and nitriles, can be prepared by methods known in the art.

In other words, protection of the carboxy group (step D), i.e., from R1-CH2C00H to 1-c]2-Y((II
a) to (Ilb): l, for example haester R1 and nitrile RICH2C=N, where [3vk4 and R
5 is independently selected from the groups defined for R1 and aryl, and n is an integer from 1-5).\Conversion can be accomplished by methods known to those skilled in the art.

In more detail, protection of the carboxy group by conversion to an ester, amide, oxazoline, or nitrile and subsequent regeneration of the carboxy group is described in Morrison and Boyd, Organic e-chemist IJ-J 3rd edition, Allyn & Bacon, Inc. Ited, Boston, 19
Published in 1973, Wabner and Zook “Synthetic
"Organic Chemistry" John Willie & Song Incorporated, New York, 1
It is generally known from several chemical publications, including one published in 953.

Ester R1-CH2-C00R3 (R1 and 3 as defined above) includes any alkyl and aryl esters, especially esters of propionic acid.

For example, to produce a suitable ester, propionic acid is heated with butanol in the presence of an acid such as sulfuric acid or P-toluenesulfonic acid, and water is azeotropically removed using benzene.

Amide R1-CH2-C(0)NR4R5(R1,R4
and R5 as defined above) includes any dialkyl diamide, especially an amide of a carboxylic acid such as propionic acid. For example, to obtain the amide, propionic acid is converted to propionyl chloride with thionyl chloride, then treated with a dialkylamine and the amide isolated.

Oxazoline has 1-CH2-C=N(CH2)no(R
1 and n as defined above) can be prepared or purchased by treating a carboxylic acid or acid chloride with an amino alcohol followed by dehydration. After addition of the Ar group, the carboxylic acid is regenerated by treatment with water and mineral acid.

Nitriles, such as R1-CH-C-N (R1 as defined above), can be purchased commercially or made into an amide;
It can be prepared by dehydrating the resulting amide with phosphorous pentoxide or a similar dehydrating agent. After addition of the Ar group, the nitrile is reconverted to the corresponding acid by treatment with water and mineral acid. The nitrile may be any alkyl (kl) substituted acetonitrile, such as R-CH2C-N, where R1 is as defined above.

In step H, compound (IIb) is treated with a strong base, i.e. an alkyl metal such as n-butyllithium, n-butyltin, n-butylzinc, lithium-N,N-diimpropamide under conditions known in the art. Compound (II) (R', M and Y are as defined above) is obtained by treatment.

Step B [Asymmetric bonding of compound (II) and ArX] and Step C (hydrolysis to optically active arylalkanoic acid)
(wherein Ar, R', X and Y have the meanings given above) are carried out as described above.

(Steps J, B and C) In another embodiment of this invention, B and C are used in Step D%J.

The process is carried out to prepare the compound of formula (IIb) as described above.

In the step, compound (Ilb) is treated with a strong lithium base, i.e. an alkyl or aryl lithium such as n-butyllithium or phenyllithium, or lithium-N,N-diisopropylamide under conditions known in the art. to give a compound (Ild) (R1 and Y have the meanings described above, and Li represents lithium).

The thus "activated" compound (IId) can be combined with an alkyl metal such as n-butyltin or n-butylzinc or a metal halide such as tin(II) chloride or zinc(IF) chloride as known in the art. Compound (II) (R'', M and )' are as defined above).

Steps B and C (R", Ar, X and Y are as defined above) are carried out as described above.

Steps E, G, B and C In another embodiment of this invention steps E, G, B and C are used. The process is carried out as described above to prepare the formula (II
carried out to produce the compound b).

Step E includes phosphorus (H) halide, phosphorus (V
) halide, autimon (I) halide, antimony (
V) Preparation of compounds of formula (ITc) by α-halogenation of esters, amides, nitriles or oxazolines using halogenating agents such as halides and the like.

This halogenation process is known in the art and is described in the aforementioned Morrison and Boyd and Wagner and Zook publications, as well as other similar publications.

In step G, compound (IIC) is treated with a metal such as lithium, tin or zinc, or a strong base such as n-butyllithium to form a compound of formula (II). Reactions for substituting halogens with metals are described in the aforementioned Morrison and Boyd and Wagner and Zook publications, as well as other similar publications.

Step B (asymmetric bonding of (II) and ArX)] and Step C [
Hydrolysis of chiral (optically active) arylalkanoic acid ＼ (Here, Ar, R1, X and Y have the above meanings)
is performed as described above.

(Steps F, G, B and C) In another embodiment of this invention, Steps F, G, B and C
or used.

Step F is the direct halogenation of compound (Ha) (R' and Y are as defined above). In some cases, the compound (Ira) in which Y is carboxy can be converted to compound (Ira) by halogenation known in the art and described above as Step E.
'rc) is directly halogenated.

Steps a, n and C (where R', Ar, X and Y have the above meanings) are also as described above.

It will be apparent to those skilled in the art that appropriate selection of starting materials, protecting groups, metals, IJ-alhalides, catalysts, solvents, reaction times and temperatures are necessary for optimization of this invention. For example, interaction of solvents with catalysts, starting materials and metals should be avoided.

Reaction times, temperatures and material ratios in the practice of this invention are not limited. However, process B is about -100
It has been found suitable to carry out the process in the temperature range from 0.degree. C. to about 100.degree. The preferred coupling reaction temperature is about -80
℃ to room temperature.

Typical reaction times are about 0.5 to about 24 hours.

Suitable yields include metal compounds such as in the range of about 11 to 2.5 equivalents, including an excess of metal compounds such as lithium, N,N-diisopropylamide, tin(II) chloride, zinc or zinc bromide. obtained when using a range of amounts of compounds.

The generation of a carfozoic acid moiety in the molecule by hydrolytic removal of the protecting group in step C can be carried out by methods known in the art. Various combinations of time, temperature and material ratios are used.

The method of this invention also applies to the compound Ar-CH(R1)-C
dehalogenation of ool-1 (Ar is e.g. 5-bromo-6-medoxy-2-naphthinope5-chloro-6-medoxy-2-naphthyl) or of the formula Ar -(, II (R
)-COOH (Ar is, for example, 6-human.

xy-2-naphthyl, 5-bromo-6-hydroxy-2
-naphthyl, 5-chloro-6-hydroxy-2-naphthyl) and the sodium, potassium, and magnesium chloride salts of the arylhydroxy-containing compounds described above. The halogen group is then dehalogenated as described below to produce a compound where Ar is 6-medquin-2-naphthyl. The method also includes pharmaceutically acceptable salts of 2-(6-medoxy-2-naphthyl)propionic acid.

More specifically, 2-(6-nodoxy-2~naphdyl)
Propionic acid precursors are represented by compounds of the formula (RT), where W is selected from the group hydrogen, chloro or pro, and R2 is hydrogen or methyl. These racemic naproxen compounds of formula (IV) are known. For example, the compound ((1,/)-2-(5-bromo-6-medoxy-2-naphthyl)propionic acid is described in German Patent No. 1934460, where R is methyl and W is propionic acid in the formula (■). Corresponds to the compound.Formula (
The compound in (2) in which R2 is methyl and W is chloro is described as a racemic mixture in Belgian Patent No. 752,627. Compounds of formula (■) in which R is hydrogen and W is hydrogen are described as racemic mixtures in German patent application no. 1793825 and Italian patent application no. 25778-A 776.

Once the 2-(6-medoxy-2-naphthyl)propionic acid precursor of formula (IV) has been obtained in optically pure or highly concentrated form, it can be converted into naproxen or its pharmaceutically acceptable salts. can.

For compounds of formula (TV) where 2 is hydrogen or methyl and W is hydrogen, conversion to naproxen involves dehalogenation of the compound of formula (■). Therefore, this method involves the replacement of halogens by hydrogen.

When k2 is hydrogen and W is I.logen, it is preferred to first methylate the compound as described below and then remove the 5-position halogen. The 2-(5-halo-6-medoxy-2-naphthyl)propionic acid precursor of naproxen can be subjected to a dehalogenation reaction that does not affect the remaining structure of the molecule during the formation of naproxen. A suitable method involves combining an unresolved or resolved 5-nolambda compound of formula (TV) with
an alkaline earth metal alcoholate such as magnesium alcoholate, e.g. magnesium methylate, and a tertiary amine such as a tri(lower)alkylamine, e.g. triethylamine, of the alcoholate or alcohol alkanol from which the alkalate was made. This includes reacting in an inert solvent such as The reaction is carried out at about 30°C to the boiling point of the solvent. For example, magnesium powder, methanol, and a 1 molar excess of triethylamine are mixed and the mixture is kept under an inert atmosphere such as nitrogen. Optical high density or split 2-(5-/\low 6-medoxy 2
Naphthyl) propionic acid is added as a solution in anhydrous methanol. After the reaction is complete, ie, after about 1 hour at reflux temperature, hydrochloric acid is added to the reaction mixture to dissolve any remaining magnesium. Naproxen is recovered from the reaction mixture by known methods.

For example, the reaction mixture containing naproxen is extracted with a suitable solvent such as water and chimethylene chloride. The organic layer is separated and washed with water to crystallize pure naproxen.

Alternatively, the naproxen precursor of formula (■) is combined with at least 2, preferably from 2 to 50 molar equivalents (calculated on aluminum) of a nickel aluminum or cobalt aluminum alloy, to at least 2, preferably from 2 to 50 molar equivalents (calculated on aluminum). The reaction is allowed to proceed in the presence of an equivalent amount of alkali metal hydroxide in an inert solvent until the 5-halo group is removed.

Preferred nickel aluminum or nickel cobalt alloys have particle sizes of 1 millimeter or less and require an aluminum concentration of at least 10% of the alloy weight. Suitable alkali metal hydroxides are sodium hydroxide, potassium hydroxide and lithium hydroxide. The reaction is carried out in an inert solvent, preferably methanol, ethanol, propatool, impropatol, tertiary butanol, tetrahydrofuran, or dioxane. The reaction temperature is about 0°C to about the reflux temperature of the solvent, preferably at least 40°C. Reaction time is about 15 minutes to about 12 hours.

The undivided or divided 5-halo compound of formula (VV) may also contain magnesium (preferably as a powder with a particle size of 1 mm or less), lower alkanols and optionally 1
It can be reacted directly with a molar excess of aliphatic amine until naproxen is formed. The reaction is carried out from about 0°C to the reflux temperature of the reaction mixture, preferably at least 20°C.
The process is carried out in an inert atmosphere, such as nitrogen, at a temperature of 10°C. The time required to reduce the 5-halo group varies depending on the reaction temperature. Usually about 10 minutes to about 12 hours are sufficient for this reaction. At reflux temperature, the reaction is complete within 1 hour.

Alternatively, the 5-halo compound of formula (IV) is a combination of Raney nickel and an inert compound such as a lower alkanol, an ester having up to 6 carbon atoms such as ethyl acetate, or a lower alkanoic acid such as acetic acid, propionic acid, etc. Treated in an organic solvent, optionally under a hydrogen atmosphere. This reaction is carried out at a temperature of at least 0°C, preferably 20°C or higher, for about 10 minutes to about 24 hours. Reflux temperature is preferred.

In yet another method, a 5-halo compound of formula (■) is treated with palladium on carbon, platinum or platinum oxide and hydrogen in an inert organic solvent as described for nickel. This reaction is carried out at about 0° C. to the reflux temperature of the solvent, preferably at room temperature, for about 10 minutes to 12 hours.

The crude naproxen precursor of formula (IV) where R2 is hydrogen can be directly converted to naproxen. Similarly, the raw material can be purified to the desired optical rotation by crystallization and then converted to naproxen. Conversion to naproxen is carried out by treating the naproxen precursor with a suitable methylating agent.

Methylation involves the reaction of a naproxen precursor of formula (IV), a 6-hydroxy compound, with dimethyl sulfate, dimethyl carbonate or methyl halide in an alkaline medium. Water or a lower aliphatic alcohol can be used as a suitable solvent.

To create the alkaline medium, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate can be used. The reaction is carried out at a temperature range of about 40° C. to the reflux temperature of the reaction mixture. The optimum reaction temperature is about 40-70°C.

The reaction time varies depending on the reaction, but generally the reaction is complete in about 1 to about 10 hours. Isolation of naproxen is carried out by adding a strong organic or inorganic acid to the cooled reaction mixture to acidify the mixture and filtering.

The recovered precipitate is washed and dried at a temperature such that the naproxen is not affected by the drying operation. The naproxen precursor of Formula 2 (IV) in which R2 is hydrogen and W is halogen is methylated by the method described above, and then dehalogenated as described above.

Dehalogenation of 5-halo compounds of formula (IV) or
The naproxen obtained by methylation of the r-hydroxy compound in IV) can be further split and/or recrystallized to obtain a product with extremely high optical rotation, that is, [a′JD is +62 to
67'' (chloroform). Additionally, the acid can be converted to a pharmaceutically acceptable salt, preferably the sodium salt.

The method of this invention uses the formula % formula % as a starting material (wherein R1 is 1 to 8 sl carbon atoms (including numbers at both ends)
or cycloalkyl having 3 to 8 carbon atoms (inclusive), M is lithium, tin, tin halide, zinc or zinc bromide, Y' is a metal salt of a carboxy group -C ( O) OM, alkoxycarbonyl group -C(0)OR3, substituted aminocarbonyl group -C(0)
NR4R5, or nitrile group -CE:N, oxazinonyl group -C=N(CH2)nO,M has the above meaning, R3
, R4 and k are independently defined as k, n
means an integer of 1-5).

In this invention, 75 novel compounds containing structure (II) are generated. More specifically, the novel intermediate has the formula (II
), k is lower alkyl such as methyl, M is L
i and Y' include those having the above structure.

Particularly preferred ones are k = methyl and Y = 10mN.

M is lithium. The novel compound of formula (I) is
Ar is 6-1) xy-2-1-7thyl, R1 is methyl, and Y' includes the above. More specifically, formula (I)
A new structure with (S)-configuration in Ar is 6-
Medoxy-2-naphthyl, kl is methyl, Y' is -;
1 stone beggar 57 included, n is 2.

Isolation and purification of the compounds and intermediates described herein may be carried out, if desired, by appropriate separation or purification methods, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, or thick layer chromatography; This is done by a combination of these methods. Specific explanations of appropriate separation/isolation methods are provided in the Examples below. However, of course other equivalent separation and isolation methods can also be used.

If desired, the compounds of formula (I) can be further purified with high optical properties by fractional crystallization or conventional resolution methods, e.g. separation of diastereomeric salts obtained by reaction of these compounds with optically active bases (e.g. fractional crystallization). Optical antipodes with purity can be obtained. Examples of optically active bases are optically active forms of cinchonidine, brucine, N-methylglucamine, α-phenethylamine, and the like. The separated pure diastereomeric salts are then cleaved using standard methods to lead to each optical isomer of the compound of formula (I). For example, optically active 2-(
6-medoxy2-naphthyl)propionic acid and its precursors are optionally further described in U.S. Pat. No. 4,246,164.
No. 4,246,193, and U.S. Patent Application No. 382
It is purified by the method described in No. 499.

Pharmaceutically acceptable non-toxic salt derivatives of compounds of formula (I) are prepared by treating the free acid with a suitable amount of a pharmaceutically acceptable base. Representative pharmaceutically acceptable bases include sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, manganous hydroxide. , aluminum hydroxide, ferric hydroxide, manganese hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, caffeine.

Procaine, hydranolamine, choline, betaine, ethylenediamine, curcosamine, methyl chloramine, theobromine, purines, piperazine, piperidine, N-
These include ethylpiperidine, poly-IJ amine resin, and the like. The reaction is carried out in water alone or in admixture with an inert water-miscible organic solvent at a temperature of about 0°C to about 100°C, preferably at room temperature.

Typical inert, water-miscible organic soluble hinges include methanol, ethanol, isoprono-ol, butanol, acetone, dioxane, and even C-matitrahydrofuran. The molar ratio of the compound of formula (I) to the base is chosen to provide the required ratio of salts. For example, in the preparation of calcium or magnesium salts, a free acid starting material of formula (I) is reacted with at least one-half molar equivalent of a pharmaceutically acceptable base to form a neutral salt. .

When preparing the aluminum salt of the compound of formula (I), at least one third molar equivalent of a pharmaceutically acceptable base is used to obtain a neutral salt. Preferred salts of the invention are alkali IJ metal salts of compounds of formula (I), especially
It is a compound of and sodium salt. More preferred salts include formula (I) in which the aryl group Ar is 6-medoxy 2
- Solu-IJium salt of the compound naphthyl. The most preferred salt is the sodium salt of 2-(6-medoxy-2-naphthyl)propionic acid, especially the d-isomer having the S-configuration.

Salts of compounds of formula (I) are prepared by combining the salt with an acid, preferably an inorganic acid,
For example, using hydrochloric acid, sulfuric acid, etc., from about 0°C to about 50°C,
It can be reconverted to the corresponding free acid by acidification, preferably at room temperature.

Pharmaceutically acceptable non-toxic esters of compounds of formula (I) are prepared by esterifying the corresponding free acid with the alcohol corresponding to the desired ester, ie, an alkanol having up to 8 carbon atoms. This reaction is
Trifluorination is carried out in the presence of strong acids such as boronic acid, hydrogen chloride, sulfuric acid, and p-toluenesulfonic acid. Since the alcohol reagent used for esterification is liquid at the reaction temperature, the alcohol can also serve as a solvent. Optionally, the reaction is carried out in a hydrocarbon solvent such as hexane, isooctane, decane, cyclohexane, benzene, toluene or xylene, a halogenated hydrocarbon solvent such as methylene chloride, chloroform or dichloroethane, or example solvents such as diethyl ether, dibutyl ether, It is carried out in an inert organic solvent that dissolves the free acid and alcohol, such as dioxane or tetrahydrofuran. The reaction is carried out at a temperature of about 0° C. to the reflux temperature of the reaction mixture;
Preferably using hydrogen chloride as a catalyst at a temperature of about 15°C to about 3°C.
Performed at 5°C.

The product theal, Ar-CH(R1)-COOH, is a compound in which Ar and R1 have the above meanings by diluting the reaction mixture with water and dissolving the resulting aqueous mixture with water such as diethyl ether, benzene, methylene chloride, etc. It is isolated by a conventional method such as extraction with an immiscible inert organic solvent, combined extracts, washing with water until neutral, and then concentration under reduced pressure.

A r -CH(R”) -COOH Kara Production Sarel Typical non-toxic esters include methyl alcohol, ethyl alcohol, propyl alcohol, inpropyl alcohol, butyl alcohol, 2-butyl alcohol, 2-
Pentyl alcohol, impentyl alcohol, 2-hexyl alcohol, and other alcohols are produced separately.

Alternatively, alkyl esters of Ar-CH(R")-COOH can be prepared by transesterification by methods known in the art. In the production of esters by transesterification, higher esters are produced from lower esters. It is preferred to prepare e.g. isoamyl esters from e.g. methyl esters. However, higher esters can be transesterified to lower esters by using a substantial excess of lower alcohol. For example, by using a substantial excess of ethanol. This allows transesterification of hexyl esters to ethyl esters.

As yet another method, A r -CH(R") -
Esters of COOH can be prepared by reacting the free acid with a suitable diazoalkane such as diazomethane, diazo-n-hexane or diazo-1-propane in an aprotic organic solvent at low temperature.

[Description of preferred embodiments]

A preferred method of the invention for preparing optically active compounds of formula (I) is a method using steps A, B and C, in particular when Ar is substituted naphthyl, kl is alkyl, Y
is t-butyl and M is lithium.

Embodiments of this method include substitution of Ar with naphthyl such as 5-bromo-6-medoxy-2-naphthyl or 5-chloro-6-
There is a method using steps A, B and C, which is medoxy 2-naphthyl, and then removing the halogen to produce naproxen.

Embodiments of this method also include Ar-substituted naphthylate
- There is a method using steps A, B and C which are bromo-6-hydroxy-2-naphthyl or 6-hydroxy-2-naphthyl, then methylating the hydroxy and removing the halogen if present to give naproxen. .

A more preferred method is that R1 is alkyl, Ar is substituted naphthyl, Y is -COOLi, M is lithium, the chiral (optically active) transition metal catalyst is an organopalladium (or nickel) phosphorus compound, and the dipolar aprotic solvent is tetrahydrofuran. This is a method using steps A, B and C described above.

The most preferred method is that R1 is methyl, Ar is 6-medoxy-2-naphthyl, and Y is -COOLi.

M is lithium, and the chiral (optically active) transition metal catalyst is [(
R)-bis(1,2-diphenylphosphino)-1-phenylethane]nickel(II) chloride, the step A wherein the dipolar aprotic solvent is tetrahydrofuran;
This is a method using B and C.

Preferred compounds produced by this method include optically active substituted naphthylalkanoic acids. Particularly preferred are substituted naphthylpropionic acids of the formula having the C3)-configuration, and their pharmaceutically acceptable salts, preferably the sodium salts.

That is, in formula (I), Ar is 6-medoxy2
-Naphthyl R1 is methyl, Y or carboxy group.

A preferred ester R1-CHCOOR3 (R1 and 3 are as defined above) is [-butyl propionate].

Preferred amides R1-CH2C(0)NR4R5(R1
, k and R5 as defined above) is a dialkylamide, especially dimethylpropionamide.

A preferred nitrile R-CH2-C:E'N (R1 has the above meaning) is propionitrile.

Preferred oxazolines are unsubstituted and alkyl substituted oxazolines R1-CH-C=N-(CJ,,12)n-
0 (R1 and n have the meanings given above), especially 2-ethyloxazoline (n is 2).

Preferred chiral (optically active) transition metal catalysts are the aforementioned cyclic organic nickel or palladium phosphorus halides. Examples of preferred chiral (optically active) transition metal catalysts include ((R)
-bis(1,2-diphenylphosphino)-1,2-dimethylethane]nickel (If) chloride and [(
R)-bis(1,2-diphenylphosphino)-1-methylethane]nickel (TI) chloride.

Preferred solvents include toluene, tetrahydrofuran, dimethoxymethane, diethyl ether and mixtures thereof. A particularly preferred solvent is tetrahydrofuran.

Individual compounds within the scope of this invention can be produced by selecting appropriate starting materials, such as those mentioned above, and selecting reaction steps, for example, as described above, to obtain the target compound. From the above disclosure, it will be apparent to those skilled in the art how to make individual compounds, including those that fall within the scope of this invention but are not individually described.

Examples of the compounds of this invention represented by the above formula CI) are the compounds shown below.

(S)-2-(4-isobutylphenyl)furopionic acid, (S)-2-(3-phenoxyphenyl)furopionic acid, (S)-2-(4-fluoro-4-biphenyl)propionic acid, (S) )-2-(2-fluoro-4-biphenyl)propionic acid, (S)-2-(6-medoxy-2-naphthyl)propionic acid.

Other compounds within the scope of this invention include:

(S)-2-(phenyl)propionic acid, (S)-2-
(4-Methylphenyl)propionic acid, (S)-2-(3-methoxyphenyl)propionic acid, (S)-2-(2,4-dimethylphenyl)propionic acid, (S)-2-(6- methylnaphthyl)propionic acid, (S), -2-(6,7-dimethylnaphthyl)propionic acid, (S)-2-(6,7-simethoxynaphthyl)propionic acid, (S)-2-( 4-Biphenyl)propionic acid, (S)
-4-(3-methyl-4-biphenyl)propionic acid, (S)-4-(3-methoxy-4-biphenyl)propionic acid, (S)-4-(3-methyl-4-biphenyl)propionic acid , (S)-4-(3-methoxy-4-biphenylpropionic acid.

These have varying degrees of anti-inflammatory activity. handle(
The above compound of R)-configuration is suitable for chiral (optically active)
Can be produced using a catalyst.

[Description of specific aspects]

The following description of the embodiments is provided to enable those skilled in the art to more clearly understand and easily carry out the invention, and is intended to be illustrative of the invention and not to limit it.

Example 1 Preparation of compounds of formula (I) via esters.

In a dry 100+nj23 neck flask equipped with a magnetic stir bar, nitrogen inlet tube and isobaric dropping funnel, add 1,2 ig of N,N-diisopropylamine and 7 ig of tetrahydropropylamine.
Add Run(T)IF)20-. The flask was cooled to 0°C, and n-butyllithium 6°56+n, ((10,
5 mmol, 1.6 M solution) is added from silyzine. The resulting solution is stirred for 10 minutes and cooled to -78°C. 1.36 g of t-butyl propionate and T) IF 10 m!
! solution into the flask over a period of 5 minutes. The resulting solution is stirred at -78°C for 1 hour.

In the second 100 m, Q3 neck 7 rasf, equipped with a magnetic stirring bar, a nitrogen inlet tube and an isobaric dropping tube, [(R
)-bis(1,2-diphenylphosphino)-1-phenylethane 18g of nickel (Kawa Chlorai 1'2°) and 25ml of THF are added. The mixture is heated to 78"C.
Cool and add 1.25 m Q of n-butyllithium (2 mmol, 1.6 M solution). The resulting solution is 17
Stir for 5 minutes at 8° C. and then add a solution of 1.9 g of 2-bromo-6-methoxynaphthalene and 10 ml of THF. Stir the resulting solution for 15 minutes. The solution of t-butyl lithiopropionate was then transferred to a 100 m (47 flask) using a double-tipped needle. The resulting solution was stirred at -78 °C for 2.5 h and allowed to warm to room temperature. The solution was stirred for an additional 14 h. The reaction is terminated by pouring into 5% aqueous hydrochloric acid solution (150ml).The aqueous layer is extracted three times with 75J of dichloromethane and the solvent is removed using a rotary evaporator. Potassium oxide? Dissolve in Smi. Reflux the solution for 24 hours and remove methanol using a rotary evaporator. Acidify the remaining aqueous solution and add 75 m of dichloromethane.
Extract 3 times with e. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2-( having the (S)-configuration.
0.33g of 6-medoxy (2-su7tyl)propionic acid
(yield 18%).

In place of 2-bromo-6-methoxynaphthalene, the following compounds 2-su7tyl bromide, 2-iodo-6-methoxynaphthalene, 2-chloro-6
゛-Methoxynaphthalene, 7enyl bromide, 4-inbutylphenyl bromide, 3-phenoxyphenyl bromide, 4-bromobiphenyl, 4-(4'-fluorophenyl)phenyl bromide, 4-(2-fluorophenyl)phenyl bromide The above operation is repeated using chemical equivalents of (S
)-configuration 2-(2-su7tyl)propionic acid, 2-(6-medoxy2-naphthyl)propionic acid, 2-(6-7toxy2-su7tyl)propionic acid, 2- (phenyl)propionic acid, 2-(4-inbutylphenyl)propionic acid, 2-(
3-phenoxyphenyl)propionic acid, 2-(4-biphenyl)propionic acid, 2(4'-fluoro-4-biphenyl)propionic acid, and 2-(2-fluoro-4-biphenyl)propionic acid are obtained.

The following compounds, isopropyl propionate, N,N-dimethylpropionamide, and 2-ethylimidacillin propionitrile were used in place of t-butyl propionate and hydrolyzed to give 2-( having the (S)-configuration). 6-medoxy-2-su7tyl)propionic acid is obtained.

Example 2 Preparation of 2-(6-medoxy-2-su7tyl)propionic acid using an optically active catalyst.

In Example 2, [(R)-bis(1,2-diphenylphosphino/)-f-phenyl ether nickel ([(R)-bis(1,2-diphenylphosphino/)-f-phenyl ether] was used in place of 2.18 g of chloride. )-1-phenylethane 1 nickel (11
) Bromide 3. Using Og, 2-(6-medoxy-2-7-tinoliprobionic acid having a 6(S)-configuration) was obtained in a yield of about 50% in the same manner as in Example 1.

Example 3 Preparation of (S)-2-(6-medoxy-2-su7tyl)propionic acid using dilithiopropionate.

In a dry 100mj 23-neck flask equipped with a magnetic stir bar, reflux condenser, nitrogen inlet tube and isobaric addition funnel,
1.40 g of N,N-diisopropylamine and 30 ml of anhydrous tetrahydro 7 run are added. Bring the flask to 0℃
Cooled to n-butyllithium 9.13m, e(12,
6 mmol, 1.38 M solution) is added via syringe.

The resulting solution was stirred for 15 minutes and then
A solution of 0.469 g of o- and propionic acid is added to the flask over a period of 5 minutes. Return the solution to room temperature and then heat to 45°C.
The dilithium dianion of propionic acid is obtained by heating for 1.5 hours.

Add ((R)-1,2-diphenylphosphine/)-1-7 to a second 100 m, c 3-necked flask equipped with a magnetic stir bar, reflux condenser, nitrogen inlet tube and isobaric addition funnel.
! Nilethane 1 Nickel(II) chloride 0.24g
and anhydrous Tetrahydro7ran 201111 are added. 7 Raphs were cooled to -78°C, and n-butyllithium 0
．． Add 59 J (0.82 mmol, 1.38 M solution). The solution was stirred for 15 minutes and then added with 10 J of tetrahydro7ran.
and 1.42 g of 2-bromo-6-medoxynaphthalene. Stir the resulting solution for 15 minutes.

Transfer the dilithium propionate dianion from the 50 m17 flask to the addition funnel attached to the second flask. The dianine is added dropwise to the reaction mixture over a period of 30 minutes at -78°C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours until 10%
Pour into 175 J of aqueous hydrochloric acid. The aqueous layer was extracted three times with 75 dichloromethane, the extract was dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator to obtain 1.79 g of a solid material. Analysis of the solid substance by gas-liquid phase chromatography revealed that the target product (S)-2-(6-medoxy-2-su7tyl)propionic acid (MNPA1 naproxen) (yield 45%) was
It contained 8%.

In place of 2-bromo-6-methoxynaphthalene, the following compounds 2-su7tyl bromide, 2-iodo-6-methoxynaphthalene, 2-oo-6
-Medoxina 7talepephenyl bromide, 4-isobutylphenyl bromide, 3-phenoxyphenyl bromide, 4-bromobiphenyl, 4-(4'-fluorophenyl)phenyl bromide, 4-(2-fluorophenyl)phenyl bromide chemistry m9 Repeat the above operation using (S
)-configuration 2-(2-su7tyl)propionic acid, 2-(6-medoxy2-naphthyl)propionic acid, 2-(6-medoxy2-su7tyl)propionic acid, 2-phenylpropionic acid ionic acid, 2-(4-isobutylphenyl)propionic acid, 2-(
3-phenoxyphenyl)propionic acid, 2-(4“-
biphenyl)propionic acid, 2-'(4'-fluoro-
4-biphenyl)7'propionic acid and 2-(2-fluoro-4-4-biphenyl)propionic acid are obtained.

Example 4-12 Preparation of 2-(6-medoxy-2-naphthyl)propionic acid using dilithiopropionate.

Examples 4-12 were conducted in the same manner as Example 3. The results are shown in Table 3 below. In all examples, nuclear magnetic resonance spectroscopy using optically active shift reagents, acid isolation and optical rotation measurement using a polarimeter, production of derivatives and high performance liquid chromatography
R- or S as determined by PLC)
- The configurational isomers are present in greater than 70% enantiomeric excess.

These techniques are described in Kenoshita et al., [7 Yarn Off Chromatography] Vol. 202, pp. 375-9, 19
Published in 1980 and Volume 210, Pages 77-81, 198
It is detailed in the annual issue.

Table 3 Coupling of solitiopropionate and 6-methoxy-2-bromonaphthalene MNI''A Example Solvent I!MN (g) Dlr^ (g) Catalyst (g) Removal % (d) 4 THF 1 , 5 .52 Kiraphosation 3) 35+'
0.2 eq. n-butyllithium (e) 5THFl, 4. 5] Kira Boss 45 (0,25
) (e) 6 Noethyl ],, II, 61 7 Enphos 36
Aetherno (0,25) TIIF (50750) (e) 7 n/)* 1.4. 52 7 Enpho X 30 Noethane (0,22+ (e) 8 THF 1.4 .51 7 Enpho
25) (f) 9 THF 2.4. 837 Enhos 31 (0,4
0) (f) 10 TIIF 2.3. 80 Fuho X 34(0
, 45) (4) II THF 1,4. 52 Provos 28 (0,
23) (e) 12 T II F' 1.4. 51 Prohos 2
8(0,24) xx Quilahos, 7enphos and prophos exist as nickel(II) chloride compounds.

(a) r3MN+, which is bromo6-me1xinaphthalene.

(b) 1) IPA is the dilithium salt of propionic acid.

(c) MNPA is 2-(6-medoxy-2-naphthyl)propionic acid.

(d) THF is tetrahydroctane.

(e) Organophosphorus nickel (14) in which 2 equivalents of cyclic agent ethylmagnesium chloride were added to the catalyst concentration in the second row of Example 3? Immediately after adding the catalyst and tetrahydro7ran to the Lorai.

(f) Ring agent n-7 telluritiuno, 2 vs. catalyst concentration
An equivalent amount is added immediately after the addition of the nickel(II) chloride catalyst and tetrahydrofuran described in the second column of Example 3.

Example 13 Anhydrous tin (1
1) Add chlorides i, 4e, 3 and 20 J of anhydrous tetrahydro-7rane (THF). Lithium aluminum hydride (0.25 g, 0.5 mmol) is then added over the tin chloride cap. The resulting slurry was stirred for 5 minutes and then diluted with 1. ethyl 2-bromopropionate. rilp, and tetrahydro7ranSin
Then, 1.89 g of 2-bromo-6-methoxy-naphthalene and 10 mρ of tetrahydro7rane were added dropwise. 1(R)-(1-Phenylphosphino)-2-(dimethylamino)-[-butylethane nickel(II) chloride (0,371?) was added to the flask and the reaction was stirred at room temperature for 24 hours. The reaction is then terminated by pouring into 5% aqueous hydrochloric acid solution IS OJ. The aqueous layer was extracted three times with 75 ml of dichloromethane (g), and the solvent was distilled off under reduced pressure.

Dissolve the residue in 150 J of methanol and 0.1N potassium hydroxide. The solution is refluxed for 24 hours and methanol is removed using a rotary evaporator. The remaining aqueous solution is acidified and extracted three times with 75 In Q dichloromethane. Dry the extract with sodium sulfate* and remove the solvent using a rotary evaporator. Thin layer chromatography analysis shows the presence of the desired product 2-(6-medoxy-2-su7tyl)propionic acid. It has an (S)-configuration as analyzed by magnetic resonance spectroscopy in the presence of an optically active shift reagent.

Example 14. -19 Production of 2-(5-)\Rho〇-haxy2-su7tyl)propionic acid using dilithiopropionate.

Examples 14-19 were conducted in the same manner as Example 3. The results are shown in Table 4 below.

Table 4 Norithiopropionate and 5-halo 6-medoxy 2
-Coupling of bromonaphthalene (,) (SHXN) (DLPA) ■ (c) (MHNPA) (f) (g) 15 THF 1.4. 50 Kirahos (0,22)
39 Sietane 18 □8F 1. ? , 51 7. +7-0°, 2'r): (9(f) (ll) +9 THF 2.37 .83 Prophos (0,40
) 29xx quilahos, 7enphos and prophos are
Exists as a nickel(II) chloride compound.

(a) SHXN is 5-substituted-6-medoxy 2-bromonaphthalene.

(b) D I-P A is dilithium propionate salt.

(c) MHNPA is 2(5-hao-G-7 toxic 2
-su7tyl) propionic acid.

(cl)THF is tetrahydro7rane.

(e) W is bromo.

(') W is chloro.

(g) 2 equivalents of reducing agent ethylmacenium chloride per 1 concentration of catalyst is written in the second stage of Example 3, llk L
Immediately after the addition of the chloride catalyst and the t) Rahi F Roaran.

(h) Add 2 equivalents of the reducing agent n-butyllithium to the catalyst concentration and add the organophosphorous nickel (
11) After addition of chloride catalyst and tetrahydrofuran,
Add immediately.

Except for Examples 17I and 15, where quilafos produces M HN P A with the (R)-configuration, excess (S
)-enantiomer-containing MHNPA.

Example 2rl-25 2-(5-substituted-6 using dilithiopropionate)
-Production of hydroxynaphthyl)-propionic acid.

Table 5 Dilithiopropionate and 5-substituted-6-hydroxy-
Coupling of 2-bromonaphthalene (a) (b) (SHBN) (DLPA) (c) (HNPA) 21 iH? ' 1+4, ri U Kirahos (υ, li
) 4! :1m (i) 2'7/notki 1,4. 51 7 Enphos (0,
22) 32/Ecun (g) (i) 24 TIIF 1.4. 51 7 Enphos (0,2
5) 33xx Quirahos, 7 Enphos and Prophos exist as nickel(11) chloride compounds.

(a) SIlriN is 5-substituted-6-humanroxy2
- Bromonaphthalene.

(b) D I-, l-' A is propionic acid nolithium salt.

((·)IINT'A is 2-(5-substituted-6-hydroxy-2-naphthyl)propionic acid.

((+)TIIP is tetrahydro7rane.

((・)W is 70 mo and arylhydroxy is sodium 1
, protected as a salt, 1INr'j\ is a 5-bromo compound.

([)~V is chloro, arylhydroxy is protected as potassium salt, HNP, \1. t, 5-rigol.

It is a compound.

(8) W is hydrogen, the arylhydroxy is protected as a magnesium chloride salt, and HN PA is a 5-hydrogen compound.

(11) Reducing agent ethyl magnesil, relative to catalyst concentration;
Two equivalents of chloride l' were added to the second stage of Example 3 [4('
Immediately after adding the nickel (II) chloride catalyst and the tetrahydrofuran, add 1↓.

(1) Two equivalents of the reducing agent n-7 chill lithium were added to the catalyst concentration in the Niakel (11
) Add immediately after addition of chloride catalyst and tetrahydrofuran.

After completion of the reaction, if any alkali metal salts protecting the 'fJh group hydroxyl groups remain, the alkali metal salts are hydrolyzed to free hydroxyl groups by methods well known in the art.

Except for Examples 20 and 21, which use quilaphos to produce l-I N F' A with the (R)-configuration, examples that produce l-I N r·,8 containing an excess of the (S)-enanteomer. 26 Production of (S)-2-(0-methoxy-2-naphthyl)propionic acid.

(Manufacturing from one bromo precursor using nickel-aluminum) 3 g of nickel-aluminum alloy was mixed with (S)-2-(5
-Chloro-6-medoxy-2-su7tyl) propionic acid (1 g) and 10% Ylium hydroxide (2 fi m z) are added in small portions at 90°C. After stirring the mixture for 2 hours, it is filtered, diluted with excess dilute hydrochloric acid, and extracted with methylene chloride. The organic layer is dried and the residue is recrystallized from methylene chloride/hexane to give (S)-2-(6-medoxy-2-su7tyl)propionic acid.

Example 27 Preparation of (S)-6-(methoxy-2-su7tyl)propionic acid.

(Preparation from bromo precursor using magnesium) To a 250 mC7 flask equipped with a reflux condenser and a nitrogen inlet tube, add 6 powdered magnesium (IB), as well as 50 J of anhydrous methanol and 10 g of ethylamine. Vent the flask with nitrogen and maintain a nitrogen atmosphere during the reaction.

A solution of (S)-5-bromo-6-medoxy-2-su7tyl)propionic acid (0.1 mol) and 15 g of methanol is added and the mixture is cooled under reflux after the addition of the 5-promonaproxen precursor has ended. Heat for 1 hour. Add 6N to the cooled mixture until no magnesium remains.
Mix with hydrochloric acid. Pour water into the mixture and extract with methylene chloride. The organic layer is separated, washed with water, the solution is concentrated, and hexane is added to precipitate crystals. After recrystallization, (S)-2-(6-medoxy-2-su7tyl)propionic acid is obtained.

Example 28 Preparation of 2-(6-medoxy-2-naphthyl)propionic acid.

(1 g of Raney nickel made from hydrogen precursor using Raney nickel, 1 g of 5-chloro-naproxen precursor)
and 10 J of anhydrous methanol. Filter the mixture and dilute the solution with water.

The precipitate is dried and then recrystallized from acetone/hexane to yield (S)-2-(6-medoxy-2-su7tyl)propionic acid.

Example 29 Preparation of (S)-2-(6-medoxy-2-su7tyl)propionic acid.

(Production from hydrogen precursor by methylation) (S)-2
-(6-hydroxy-2-su7tyl)propionic acid 28
into a 1N F hydroxide aqueous solution; add 368 g of dimethyl sulfate to this solution.

The solution is heated at 60° C. for 2 hours, cooled to room temperature, and then dilute hydrochloric acid is added to acidify the reaction mixture. The obtained precipitate is filtered, washed with water until it becomes neutral, and crystallized to obtain 2-(6-medoxy-2-naphthyl)propionic acid.

(S)-2-(6-hydroxy-5-
Bromo-2-su7tyl)propionic acid was methylated and dehalogenated according to the method of Example 27 to give (S)-2-
(6-medoxy-2-su7tyl)propionic acid is obtained.

Example 30 In a dry 50+n (!3-necked round-bottomed flask equipped with a magnetic stir bar, reflux condenser, argon inlet tube, and isobaric addition funnel), 1.40 g of diisopropylamine and 35 μm of anhydrous tetrahydro7rane (THE)! The flask is cooled to 0 °C and n-butyllithium (12.6 mmol) is added via silinol. The resulting solution is stirred for 10 minutes and a solution of 47 g of propion IIQ and 5 IIl of tetrahydrofuran is added to Add dropwise to the flask over a period of 1 minute.The solution is allowed to come to room temperature and then stirred at 45°C for 1.5 hours.

Second 100 m, equipped with magnetic stirring bar, reflux condenser, argon inlet tube and isobaric dropping funnel, (73 neck 7 ras: +[(R)-bis(1,2-diphenylphosphino)-1- Phenylethane J Nickel (++>chloride (7 enphosnickel(II) chloride) 0.25.
and 20 IJ of anhydrous tetrahydro7ran. Cool the plastic to -78°C and add 0.8 n-butyllithium.
Add 4 mmol.

The solution was stirred for 15 minutes, then 1.42 g of 2-bromo-6-medoxynaphthalene and 10 m of tetrahydrofuran,
Add solution d dropwise. Stir the resulting solution for 15 minutes.

Add propionic acid dianion from 50mJ27 lasco to the second
Transfer to a dropping funnel attached to the 7th rasp.

Add the dianion dropwise to the solution over 30 minutes. The reaction mixture was warmed to room temperature, stirred for 14 hours, and diluted with 10% hydrochloric acid 250
Inject into i. The aqueous layer is 0.1N potassium hydroxide 7SJ
Extract 3 times. The basic extract is acidified and extracted three times with dichloromethane 75-. The extract was dried over anhydrous sodium sulfate and concentrated to $1 0.75 g of naproxen.
42 g of 6proxene ffO (yield 30.4%)
obtained, this figure indicates that the ratio of (S)-enantiomer to (R)-enantiomer is 90:1 ('l).

The arylpropionic acid methyl ester is obtained by refluxing the acid in methanol containing a catalytic amount of sulfuric acid.

Splitting analysis of the methyl ester singlet in proton nuclear magnetic resonance performed in the presence of the chiral citrate reagent i.e. tris[3-hebutafluoropropyl)hydroxymethylene-d-camphorate 1 europium (Ill) The ratio of the enantiomers is ( The ratio of (S) to R)-configuration is 90:10.

Example 31 Example 3 with 7-enphosnickel (11) chloride
In the procedure of 0, when one equivalent of [(R)-bis(1,2-diphenylphosphino)-1,2-:)methylethane 1 nickel (II) chloride (quilaphos nickel (II) chloride) is used as a substitute, (R)-2-(6-medoxy-2-naphthyl)propionic acid is obtained.

Example 32 Example 3 with 7-enphosnickel(II) chloride
In the procedure of 0, [(R)-bis(1,2-diphenylphosphino)-1-methylethane 1 nickel(II)
When one equivalent of chloride (prophosnickel chloride) is used as a substitute, (S)-2-(6-medoxy-2-su7tyl)propionic acid is obtained.

Example 33 This example illustrates the conversion of the free carboxylic acids of Examples 1-32 to various salts.

One molar equivalent of sodium shim hydroxide was added to 0. Add as an IN solution to a solution of 300 II g of (S)-2-(6-haxy-2-naphthyl)propionic acid and 5 ml of methanol. The solvent was concentrated under reduced pressure and the residue was dissolved in methanol 2- and then precipitated with ether to give the crude (S)-2-
Sodium (6-medoxy-2-su7tyl)propionate is obtained.

Similarly, by substituting ammonium hydroxide or potassium hydroxide for sodium hydroxide, pond salt,
For example (S)-2-(6-medoxy-2-naphthyl)
Ammonium propionate or potassium (S)-2-(6-medoxy-2-su7tyl)propionate is obtained.

Example 34 Direct interconversion of acid addition salts of acids of formula I.

This example illustrates the interconversion of the carboxylic acid salt of a compound of formula I into various salts.

(S)-2-(6-medoxy-2-su7tyl)propionyl acetate) 1.0 g in 50% sulfuric acid aqueous solution
is added and after dissolution, the solution is concentrated to obtain an oil. The product was suspended in ethanol, filtered, air-dried, and dissolved in methanol/
Recrystallization from acetone yielded (S)-2-(6-medoxy-2-su7tyl)propionyl sulfate.

Example 35 This example illustrates the conversion of the free carboxylic acids of Examples 1-33 to various esters.

A solution of 3Q O mg of (S)-2-(6-medoxy-2-naphthyl)propionic acid and 5 m of isobutyl alcohol is saturated with hydrogen chloride. After 24 hours, the excess alcohol is evaporated and the residue is mixed with an alumina substrate. Purification by chromatography using chromatography to obtain isobutyl (S)-2-(6-medoxy-2-su7tyl)propionate.

Similarly, isobutyl alcohol is replaced with the corresponding alcohol,
For example, pentyl, isoamyl, hexyl, octyl,
By substituting nonyl, decyl, dodecyl alcohol, etc., other esters such as pentyl, isoamyl, hexyl, octyl, nonyl, decyl, dodecyl, etc. are obtained.

Although this invention has been described with respect to particular embodiments, it will be apparent to those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of this invention. That is clear.

Additionally, without departing from the spirit of this invention, certain circumstances,
Changes may be made in the employment of raw materials or compositions, methods, steps, or objects.

Continuation of page 1

Claims (1)

[Claims] (1) Formula % Formula % () (wherein Ar is an aryl moiety, R1 is lower alkyl having 1 to 8 carbon atoms (including the numbers at both ends) or 3 to 8 carbon atoms (Y means a carboxy group, a metal salt of a carboxy group, an alkoxycarbonyl group, a substituted amine 7 carbonyl group, a nitrile group or an oxazinonyl group) In the production method, a compound represented by the formula (1 % formula % () (where tti and Y have the above meanings, and M means lithium, tin, tin halide, zinc, or zinc bromide), an aryl halide represented by the formula % formula % () (wherein Ar means the above-mentioned meaning and X means a halogen) and a chiral (optically active) transition metal catalyst, and optionally a dipolar aprotic solvent. (2) Ar is substituted naphthyl, R1 is lower alkyl, Y
2. The method according to claim 1, wherein is a metal salt of a carboxy group and M is lithium. (3) The method according to claim 2, wherein Ar is 6-medoxy-2-naphthyl, R1 is methyl, and Y is a lithium salt of a carboxy group. (4) Formula % Formula % () (where Ar is an aryl moiety, R1 is lower alkyl having 1 to 8 carbon atoms (including the numbers at both ends) or 3 to 8 carbon atoms (including the numbers at both ends) ), Y means a carboxy group, a metal salt of a carboxy group, an alkoxycarbonyl group, a substituted aminocarbonyl group, a nitrile group or an oxazinonyl group) In the formula % formula % () (wherein R1 and Y have the above-mentioned meanings, M means lithium, tin, tin halide, zinc, or zinc bromide), a compound represented by the formula % formula % In the presence of an aryl halide represented by () (wherein Ar means the above-mentioned meaning and X means a halogen), a chiral (optically active) transition metal catalyst, and optionally a dipolar aprotic solvent, A method comprising contacting to obtain a compound represented by formula (1). (5) The method according to claim 4, wherein Ar is substituted naphthyl, kl is lower alkyl, Y is a metal salt of a carboxy group, and M is lithium. (5) The method according to claim 5, wherein Ar is 6-medoxy-2-naphthyl, R1 is methyl, and Y is a lithium salt of a carboxy group. (7) Formula % Formula % () (where Ar is an aryl moiety, kl is lower alkyl having 1 to 8 carbon atoms (including the numbers at both ends) or 3 to 8 carbon atoms (including the numbers at both ends) ), Y means a carboxy group, a metal salt of a carboxy group, an alkoxycarbonyl group, a substituted aminocarbonyl group, a nitrile group or an oxazinonyl group)
A compound represented by the formula % formula % () (wherein k and Y have the above-mentioned meanings, and M means lithium, tin, tin halide, zinc, or zinc bromide) can be converted into a compound represented by the formula % formula % () (In the formula, Ar has the above meaning and X means halogen) in the presence of a chiral (optically active) transition metal catalyst and optionally in the presence of a dipolar aprotic solvent. to obtain a compound represented by formula (■). (8) The method according to claim 7, wherein Ar is substituted naphthyl, R1 is lower alkyl, Y is a metal salt of a carboxy group, and M is lithium. (9) Ar is 6-medki'/-2-f 7 chill, k
9. The method according to claim 8, wherein l is methyl and Y is a lithium salt of a carboxy group. (10) Formula % Formula % (1) (where Ar is an aryl moiety, R1 is a lower alkyl having 1 to 8 carbon atoms (including the number at both ends) or 3 to 8 carbon atoms (including the number at both ends) cycloalkyl having a carboxy group, a metal salt of a carboxy group, an alkoxycarbonyl group, a substituted aminocarbonyl group, a nitrile group or an oxazinonyl group). In the manufacturing method of the material constituted, a compound represented by the formula % (wherein R1 and Y have the above meanings, and M means lithium, tin, tin halide, zinc, or zinc bromide) in the presence of an aryl halide of the formula %() (wherein Ar is as defined above and X is a halogen), a chiral (optically active) transition metal catalyst, and optionally a dipolar non- A method comprising contacting in the presence of a protic solvent to obtain a compound represented by formula (1). (11) The method according to claim 10, wherein Ar is substituted aryl and R1 is alkyl. (12) Ar is 3-phenoxyphenyl, R1 is methyl, Y is a metal salt of a carboxy group, M is lithium,
A method according to claim 11. (13) Ar is 41-fluoro-4-biphenyl, R
12. The method according to claim 11, wherein 1 is methyl, Y is a metal salt of a carboxy group, and M is lithium. (14) Ar is 2-fluoro-4-biphenyl, R1
12. The method according to claim 11, wherein is methyl, Y is a metal salt of a carboxy group, and M is lithium. (15) Ar is 4-inbutylphenyl, kl is methyl, Y is a metal salt of a carboxy group, M is lithium,
A method according to claim 11. (15) Ar is substituted naphthyl, R1 is lower alkyl,
11. The method according to claim 10, wherein Y is a metal salt of a carboxy group and M is lithium. (17) The method according to claim 6, wherein Ar is methoxy-substituted naphthyl, R1 is methyl, and the transition metal catalyst is a chiral (optically active) organophosphorous nickel compound. (18) Ar is 6-medoxy-2-naphthyl,
18. The method of claim 17, wherein the compound of formula (I) has the (S)-configuration. (19) Ar is substituted naphthyl, R1 is lower alkyl, Y
11. The method according to claim 10, wherein is an alkoxycarbonyl group, ~I is lithium. (20) The method according to claim 19, wherein Ar is 6-medoxy-2-naphthyl, k1camethyl, and Y is a tertiary-butoxycarbonyl group. (21) (a) The resulting ester, amide, oxazolidine, nitrile, or metal salt of the carboxy group is hydrolyzed concomitantly or sequentially to the corresponding α-arylalkanoic acid, optionally followed by +b1 formula (I ) hydrolyzing the corresponding salt or ester of the free acid of formula (I) to said free acid by treating with an acid; or (C) esterifying the free acid of formula (I) by treating with an alkanol; or (d) 11. The method of claim 10, comprising converting the free acid of formula (I) into a pharmaceutically acceptable salt by treatment with a pharmaceutically acceptable base. (22) AI or substituted naphthyl, R1 is lower alkyl,
22. The method according to claim 21, wherein Y is a metal salt of a carboxy group and M is lithium. (23) Ar is 6-Medoxy 2-fVf Ru R1
23. The method according to claim 22, wherein is methyl and Y is a lithium salt of a carboxy group. (24) the pharmaceutically acceptable salt is an alkali metal salt;
The method according to claim 23. (25) The method according to claim 24, wherein the pharmaceutically acceptable salt is an IJ salt. (26) Chiral (optically active) transition metal catalyst [(R)-
11. The method of claim 10, wherein the nickel(II) chloride is bis(1,2-diphenylphosphino)-1<2-dimethylethane]nickel(II) chloride. (27) Chiral (optically active) transition metal catalyst [(R)-
11. The method of claim 10, wherein the nickel(II) chloride is bis(1,2-diphenylphosphino)-1-phenylethane]nickel(II) chloride. (28) Chiral (optically active) transition metal catalyst [(R)-
11. The method of claim 10, wherein the nickel(II) chloride is bis(1,2-diphenylphosphino)-1-methylethane]nickel(II) chloride. (29) In the method for producing an optically active compound represented by the formula (in the formula, Y means a metal salt of a carboxy group, an alkoxycarbonyl group, a substituted aminocarbonyl group, an oxazinonyl group, or a nitrile group), , Y means the above-mentioned meaning) is brought into contact with an aryl halide represented by the formula (wherein, X means halogen) in the presence of a chiral (optically active) transition metal catalyst to form a compound represented by the formula (b) Optionally, the compound of formula (■) (wherein Y is as defined above) is hydrolyzed concomitantly or sequentially. , (S
)-2-(6-medoxy-2-naphthyl)propionic acid. (30) A chiral (optically active) transition metal catalyst [(R)
-bis(1,2-diphenylphosphino)-1-phenylethane]nickel(II) chloride. (31) The method according to claim 30, wherein X is bromo and Y is a lithium salt of a carboxy group. (32) Formula % Formula % (1) (where Ar is an aryl moiety, R1 is lower alkyl having 1 to 8 carbon atoms (including the number at both ends) or 3 to 8 carbon atoms (including the number at both ends) ), Y means a carboxy group, a metal salt of a carboxy group, an alkoxycarbonyl group, a substituted aminocarbonyl group, a nitrile group or an oxazinonyl group) (a) Formula %) (wherein kl and Y have the above-mentioned meanings, M means lithium, tin, tin halide, zinc, or zinc bromide), a compound represented by the formula % an aryl halide represented by the formula % () (wherein Ar has the above meaning and X means a halogen), in the presence of a chiral (optically active) transition metal catalyst, and optionally in the presence of a dipolar aprotic solvent. (b) Optionally, the compound represented by formula (1) (wherein ■ is a carboxyl group, a metal salt of a carboxyl group, an alkoxycarbonyl group,
substituted ami7carbonyl group, oxazinonyl group or nitrile group) is concomitantly or sequentially hydrolyzed to the corresponding α-arylalkanoic acid, optionally followed by (C) of formula (1). (d) the free acid of formula (I) is esterified by treatment with an alkanol; or (e) the free acid of formula (I) is esterified by treatment with an alkanol; A process comprising converting the free acid of I) into a pharmaceutically acceptable salt by treatment with a pharmaceutically acceptable base. (33) Ar is substituted aryl, R1 is alkyl,
A method according to claim 32. (34) Ar is 3-phenoxyphenyl, R1 is methyl, Y is a metal salt of a carboxy group, M is lithium,
The method according to claim 33. (35) Ar is 4'-fluoro-4-biphenyl, k
34. The method according to claim 33, wherein l is methyl, Y is a metal salt of a carboxy group, and M is lithium. (36) Arka2-fluoro-4-biphenyl, R1
34. The method according to claim 33, wherein is methyl, Y is a metal salt of a carboxy group, and M is lithium. (37) The method according to claim 32, wherein Ar is substituted naphthyl, R1 is methyl, Y is a metal salt of a carboxy group, and M is lithium. (38) Ar is 6-medoxy 2-s7-1-le,
38. The method of claim 37, wherein kl is methyl. (39) The method according to claim 38, wherein in step (e), the pharmaceutically acceptable salt is a sodium salt. (40) The process comprises (a) producing a compound of formula (IV) in which when W is selected from the group of hydrogen, bromo and chloro, R2 means hydrogen or methyl; (b) producing 2- (6-medoxy 2-naphthyl)
(S) comprising converting the propionic acid precursor to 2-(6-medoxy-2-naphthylpropionic acid); (C) optionally converting the acid product of part (b) into a pharmaceutically acceptable salt; -2-(6-Medoxy-2-naphthyl)propionic acid or a pharmaceutically acceptable salt thereof The method according to claim 1 for the production of a pharmaceutically acceptable salt thereof. 41. The method according to claim 40, wherein the salt is IJum salt. (42) The method according to claim 40, wherein in step (a), R2 is methyl and W is bromo, and in step (b), bromine is removed by dehalogenation. (43) The method according to claim 40, wherein in step (a), R2 is hydrogen and W is hydrogen, and in step (b), the hydroxy group is methylated. (44) In step (a), R2 is hydrogen and W is bromo, and in step (b), the hydroxy group is methylated and bromine is removed by dehalogenation. the method of. (45) Formula % Formula % (wherein R1 is lower alkyl having 1 to 8 carbon atoms (inclusive) or cycloalkyl having 3 to 8 carbon atoms (inclusive), Y ' means a metal salt of a carboxy group, an oxazinonyl group or a nitrile group, and M means lithium, zinc, zinc bromide, tin or tin halide). (46) The compound according to claim 45, wherein R' is methyl, Y' is a nitrile group, and M is lithium. (47) A compound represented by the formula (% formula % means a nitrile group, -03N). (48) Ar is 6-medoxy-2-naphthyl, kl is methyl, V' is oxazinonyl group, -C=N-(CH2
)n-0, where n is 2.