WO2004002925A2 - Process for preparing (r)-aryloxypropionic acid ester derivatives - Google Patents

Process for preparing (r)-aryloxypropionic acid ester derivatives Download PDF

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WO2004002925A2
WO2004002925A2 PCT/KR2003/001244 KR0301244W WO2004002925A2 WO 2004002925 A2 WO2004002925 A2 WO 2004002925A2 KR 0301244 W KR0301244 W KR 0301244W WO 2004002925 A2 WO2004002925 A2 WO 2004002925A2
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group
alkyl
cyclohexane
acid ester
ester derivatives
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WO2004002925A3 (en
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Dae Whang Kim
Kun Hoe Chung
Hae Sung Chang
Young Kwan Ko
Jae Wook Ryu
Jae Chun Woo
Dong Wan Koo
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Korea Research Institute of Chemical Technology KRICT
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Priority to JP2004517376A priority patent/JP2005536484A/en
Priority to EP03736345A priority patent/EP1532097A2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a method for preparing optically active (R)- aryloxypropionic acid ester derivatives, and more particularly to a method for preparing (R)-aryloxypropionic acid ester derivatives represented by the following formula 1 with high optical purity and good yields at low cost via nulceophilic substitution reaction using phenol derivatives with various substituted functional groups and (S)-alkyl O-arylsulfonyl lactates as reactants in the presence of a proper solvent and a base at optimum temperature :
  • R 1 is a C 1-6 -alkyl or benzyl group
  • A is an aryl group selected from the group consisting of a phenyl group, a naphthyl group, quinoxazolyloxyphenly group, a benzoxazolyloxyphenyl group, a benzothiazolyloxyphenyl group, a phenyloxyphenyl group, a pyridyloxyphenyl group and a pheyloxynaphthyl group, wherein the aryl group can be substituted with 1-3 functional groups selected from the group consisting of a hydrogen atom, a halogen atom, a nitro group, a nitrile group, an acetoxy group, a C ⁇ -4 -alkyl group, a C 1- -haloalkyl group, a C 1-4 -alkoxy group, and a C -haloalkoxy group.
  • the compound represented by Formula 1 commonly called (R)-propionic acid ester, is well known as a herbicidal substance that inhibits physiological functions of plants. Among them, a few compounds including (R)-ethyl 2-[4-(6- chloro-2-benzoxazolyloxy)phenoxy]propionate have been used as agrochemicals.
  • the 2-substituted propionic acid ester derivatives as represented above have optical isomers.
  • their (R)-isomers have herbicidal activities while their (S)-isomers are of little herbicidal activities.
  • an object of the present invention is to provide a novel method for preparing optically active (R)- propionic acid ester derivatives at low cost by preventing racemization.
  • the present invention relates to a method for preparing (R)-propionic acid ester derivatives with high optical purity by reacting phenol derivatives represented by the following Formula 2 and (S)-alkyl O-arylsulfonyl lactate represented by the following Formula 3 in the presence of alkali metal carbonate base in an aliphatic or aromatic hydrocarbon solvent at 60 - 100 ° C :
  • R 1 is a G- ⁇ -alkyl or benzyl group
  • R 2 is a C ⁇ -6 -alkyl, phenyl group, or a phenyl group substituted with a C ⁇ -6 -alkyl or a C ⁇ -6 -alkoxy group
  • A is an aryl group selected from the group consisting of a phenyl group, a naphthyl group, a quinoxazolyloxyphenly group, a benzoxazolyloxyphenyl group, a benzothiazolyloxyphenyl group, a phenyloxyphenyl group, a pyridyloxyphenyl group and a pheyloxynaphthyl group, wherein said aryl group can be substituted with 1-3 functional groups selected from the group consisting of a hydrogen atom, a halogen atom, a nitro group, a nitrile group, an acetoxy group, a Cw
  • the present invention relates to a method for preparation of optically active (R)-propionic acid ester derivatives with high yield and good optical purity via nucleophilic substitution reaction using phenol derivatives and (S)-alkyl O- arylsulfonyl lactates as reactants, wherein the reactions are performed under a condition of solvent, temperature and leaving group, which are all specifically designed.
  • Phenol derivatives and (S)-alkyl O-arylsulfonyl lactates, reactants of the present invention as represented by the above Formulas 2 and 3, are known compounds and are synthesized by the known methods.
  • (6- chloro-2-benzoxazolyloxy)phenol can be prepared by a 4-step reaction using commercially available substances, such as aminophenol, urea, sulfuryl chloride, phosphorus pentachloride, and triethylamine, and solvents, such as xylene, acetic acid, chlorobenzene, and dichloroethane.
  • (S)-alkyl O-arylsulfonyl lactate can be prepared by reacting (S)-alkyl lactate and arylsulfonyl chloride in the presence of triethylamine in dichloroethane solvent.
  • reaction solvent aliphatic or aromatic hydrocarbon solvents such as xylene, toluene, benzene, cyclohexane, methylcycloheane, n-hexane, and n-heptane, etc. can be used, and cyclohexane and xylene are preferred among them.
  • the reaction temperature is also a very important factor to prevent racemization. A temperature range of 60 - 100 ° C is appropriate, but considering reaction time and convenience, reflux temperature of cyclohexane ( ⁇ 80 ° C) is particularly preferable.
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.
  • Production of metal salt of phenol as an intermediate using the alkali metal carbonate as a base can greatly reduce unnecessary side reactions.
  • the above base is preferred to be powder (400-700 mesh) rather than pellets because powder form can reduce reaction time.
  • water is generated as a byproduct while phenol-metal salt is produced as a main reaction intermediate.
  • phenol-metal salt is produced as a main reaction intermediate.
  • Table 1 shows the yield, ratio of generated optical isomers and spectral data of the compounds (1-25) performed the same as in Example 1.
  • Table 2 shows yields and ratio of optical isomers generated in the course of substitution reactions performed the same as in Example 2.
  • Table 3 shows yields and ratio of optical isomers generated in the course of substitution reactions performed the same as in Example_3.
  • Table 1 shows the yield, ratio of generated optical isomers and spectral data of the compounds (33-38) performed in Example 8.
  • Tables 6 and 7 show yields and ratio of optical isomers generated in the course of preparing (D+)-methyl-2-[4-(6-chloro-2- benzoxazolyloxy)phenoxy]propionate (compound 27) according to the known methods shown in the reaction schemes 1 and 2.
  • Table 6 shows yields and ratio of optical isomers generated in the course of preparing (D+)-methyl-2-[4-(6-chloro-2- benzoxazolyloxy)phenoxy]propionate (compound 27) according to the known methods shown in the reaction schemes 1 and 2.
  • Table 8 shows yields and ratio of optical isomers generated in the course of preparing (D+)-n-ethyl-2-[4-(3-chloro-5-trifluoromthylpyridine-2- yloxy)phenoxy]propionate (compound 29) according to the known methods shown in the reaction scheme 2.
  • the preparing method of the present invention enables production of optically pure (R)-aryloxy propionic acid ester derivatives with good yield and is thus expected to produce an enormous economic effect.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention relates to a method for preparing optically active (R)-aryloxypropionic acid ester derivatives, and more particularly to a method for preparing (R)- aryloxypropionic acid ester derivatives with high optical purity and good yield at low cost from phenol derivatives with various substituted functional groups and (S)-alkyl O-arylsulfonyl lactates.

Description

PROCESS FOR PREPARING (R)-ARYLOXYPROPIONIC ACID
ESTER DERIVATIVES
Technical Field The present invention relates to a method for preparing optically active (R)- aryloxypropionic acid ester derivatives, and more particularly to a method for preparing (R)-aryloxypropionic acid ester derivatives represented by the following formula 1 with high optical purity and good yields at low cost via nulceophilic substitution reaction using phenol derivatives with various substituted functional groups and (S)-alkyl O-arylsulfonyl lactates as reactants in the presence of a proper solvent and a base at optimum temperature :
Figure imgf000002_0001
wherein R1 is a C1-6 -alkyl or benzyl group; A is an aryl group selected from the group consisting of a phenyl group, a naphthyl group, quinoxazolyloxyphenly group, a benzoxazolyloxyphenyl group, a benzothiazolyloxyphenyl group, a phenyloxyphenyl group, a pyridyloxyphenyl group and a pheyloxynaphthyl group, wherein the aryl group can be substituted with 1-3 functional groups selected from the group consisting of a hydrogen atom, a halogen atom, a nitro group, a nitrile group, an acetoxy group, a Cι-4 -alkyl group, a C1- -haloalkyl group, a C1-4 -alkoxy group, and a C -haloalkoxy group.
Background Art
The compound represented by Formula 1, commonly called (R)-propionic acid ester, is well known as a herbicidal substance that inhibits physiological functions of plants. Among them, a few compounds including (R)-ethyl 2-[4-(6- chloro-2-benzoxazolyloxy)phenoxy]propionate have been used as agrochemicals.
Due to the presence of a single chiral carbon, the 2-substituted propionic acid ester derivatives as represented above have optical isomers. In particular, it is known that their (R)-isomers have herbicidal activities while their (S)-isomers are of little herbicidal activities.
Preparation of propionic acid derivatives and their herbicidal activities have been disclosed in literatures [European Patent Nos. 157,225, 62,905, and 44,497; German Patent Nos. 3,409,201, 3,236,730, and 2,640,730] .
The conventional methods of preparing propionic acid derivatives are well represented by the following two reaction schemes 1 and 2. Scheme 1
Figure imgf000003_0001
(S)-form ( )-form
Scheme 2
Figure imgf000003_0002
In the above methods of scheme 1, wherein substituted phenol and (S)-alkyl
O-sulfonyl lactate are reacted, and scheme 2, wherein 2,6-dichlorobenzoxazole and (R)-ethyl 2-(4-hydroxyphenoxy)propionate are reacted, the reactions are performed in a polar solvent including acetonitrile to obtain (R)-fenoxaprop ethyl [yield = 70- 80%; optical purity = 60-90%].
However, these methods generate about 5-20% of (S)-isomers as by-products, which are not easily removed, and thus a rather complex process such as recrystallization is required to obtain pure (R)-fenoxaprop ethyl, thus increasing cost in preparation. Further, it is also a burden that starting materials, (R)-alkyl 2-(4- hydroxyphenoxy)propionates used in the reactions are to maintain high optical activity.
The inventors of the present invention focused on developing a novel method for preparing (R)-propionic acid ester derivatives, which have high optical purity with good yield. In doing so, the inventors of the present invention realized that it is important to find an appropriate condition for nucleophilic substitution reaction that prevents racemization of propionic acid ester derivatives. Accordingly, an object of the present invention is to provide a novel method for preparing optically active (R)- propionic acid ester derivatives at low cost by preventing racemization.
Disclosure of Invention
The present invention relates to a method for preparing (R)-propionic acid ester derivatives with high optical purity by reacting phenol derivatives represented by the following Formula 2 and (S)-alkyl O-arylsulfonyl lactate represented by the following Formula 3 in the presence of alkali metal carbonate base in an aliphatic or aromatic hydrocarbon solvent at 60 - 100 °C :
Figure imgf000004_0001
wherein R1 is a G-β -alkyl or benzyl group; R2 is a Cι-6 -alkyl, phenyl group, or a phenyl group substituted with a Cι-6 -alkyl or a Cι-6 -alkoxy group; A is an aryl group selected from the group consisting of a phenyl group, a naphthyl group, a quinoxazolyloxyphenly group, a benzoxazolyloxyphenyl group, a benzothiazolyloxyphenyl group, a phenyloxyphenyl group, a pyridyloxyphenyl group and a pheyloxynaphthyl group, wherein said aryl group can be substituted with 1-3 functional groups selected from the group consisting of a hydrogen atom, a halogen atom, a nitro group, a nitrile group, an acetoxy group, a Cw -alkyl group, a C -haloalkyl group, a CM -alkoxy group, and a C -haloalkoxy group. Hereinafter, the present invention is described in more detail.
The present invention relates to a method for preparation of optically active (R)-propionic acid ester derivatives with high yield and good optical purity via nucleophilic substitution reaction using phenol derivatives and (S)-alkyl O- arylsulfonyl lactates as reactants, wherein the reactions are performed under a condition of solvent, temperature and leaving group, which are all specifically designed.
Phenol derivatives and (S)-alkyl O-arylsulfonyl lactates, reactants of the present invention as represented by the above Formulas 2 and 3, are known compounds and are synthesized by the known methods. For example, (6- chloro-2-benzoxazolyloxy)phenol can be prepared by a 4-step reaction using commercially available substances, such as aminophenol, urea, sulfuryl chloride, phosphorus pentachloride, and triethylamine, and solvents, such as xylene, acetic acid, chlorobenzene, and dichloroethane. And, (S)-alkyl O-arylsulfonyl lactate can be prepared by reacting (S)-alkyl lactate and arylsulfonyl chloride in the presence of triethylamine in dichloroethane solvent.
In the nucleophilic substitution reaction of the present invention, selection of the reaction solvent plays a crucial role in preventing racemization. As a reaction solvent, aliphatic or aromatic hydrocarbon solvents such as xylene, toluene, benzene, cyclohexane, methylcycloheane, n-hexane, and n-heptane, etc. can be used, and cyclohexane and xylene are preferred among them. The reaction temperature is also a very important factor to prevent racemization. A temperature range of 60 - 100 °C is appropriate, but considering reaction time and convenience, reflux temperature of cyclohexane ( ~80°C) is particularly preferable.
As a base of the present invention, alkali metal carbonates such as sodium carbonate, potassium carbonate, etc., can be used. Production of metal salt of phenol as an intermediate using the alkali metal carbonate as a base can greatly reduce unnecessary side reactions. Further, the above base is preferred to be powder (400-700 mesh) rather than pellets because powder form can reduce reaction time. In the nucleophilic substitution reaction according to the present invention, water is generated as a byproduct while phenol-metal salt is produced as a main reaction intermediate. Thus generated water is removed by use of a specifically selected solvent in the present invention and this leads to a more effective prevention of racemization of products as well as hydrolysis of ester. Upon completion of the nucleophilic substitution reaction, the sulfonic acid salt is filtered without cooling, and the filtrate is condensed to obtain (R)-propionic acid ester derivatives represented by Formula 1, the target compound of the present invention with high yields and good optical purity.
This invention is further illustrated by the following examples, however, these examples should not be construed as limiting the scope of this invention in any manner. Best Mode for Carrying Out the Invention
Example 1
Preparation of (D+)-ethyl-2-(4-chloro-2-methylphenoxy)propionate (compound 1)
30mL of cyclohexane, 1.43g (lOmmol) of 4-chloro-2-methylphenol, 2.86g (10.5mmol) of (S)-ethyl 0-/?-toluenesulfonyl lactate, and 2.76g (20mmol) of powdery K C03 were put in a 50mL flask equipped with a cooling condenser-attached Dean- Stock and reacted for 17 hours while refluxing. The reaction mixture was filtered without cooling and the solid cake was washed with 20mL of warm cyclohexane. The cyclohexane layer, the filtrate, was condensed to obtain 2.26g of the target compound (yield = 93%; purity = 98%; optical purity = 99.4%).
Rf=0.68(EA:Hx=l:4); IH NMR(CDC13, 200MHz) δ 1.24(t, /=7.2Hz, 3H), 1.62(d, /=6.8Hz, 3H), 2.25(s, 3H), 4.20(q, /=7.2Hz, 2H), 4.69(q, /=6.8Hz, IH), 6.58 ~ 7.13(m, 3H); MS(70eV) m/z 244(M+), 242(M+), 169, 142, 125, 107, 89, 77
The following Table 1 shows the yield, ratio of generated optical isomers and spectral data of the compounds (1-25) performed the same as in Example 1.
Table 1
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Example 2 Preparation of (D+)-ethyl-2-[4-(6-chloro-2-benzoxazolyloxy)-phenoxy]-propionate (Compound 26, Commercial Name: Fenoxaprop-p-ethyl)
50mL of cyclohexane, 2.61g (lOmmol) of (6-chloro-2-benzoxazolyloxy)phenol, 2.86g (10.5mmol) of (S)-ethyl O-p-toluenesulfonyl lactate, and 2.76g (20mmol) of powdery K2C03 were put in a lOOmL flask equipped with a cooling condenser- attached Dean-Stock and reacted for 12 hours while refluxing. The reaction mixture was filtered without cooling and the solid cake was washed with 20mL of warm cyclohexane. The cyclohexane layer, the filtrate, was condensed to obtain 3.20g of the target compound (yield = 89%; purity = 98%; optical purity = 99.9%). mp 82 ~ 84 °C (observed); Rf=0.52(hexane/ethylacetate=3/l); 1H-NMR(CDC13, 200MHz) δ 1.13(t, 7=7.1Hz, 3H), 1.81(d, /=6.9Hz, 3H), 4.22(q, /=7.1Hz, 2H), 4.72(q, /=6.9Hz, IH), 6.99 ~ 7.42(m, 7H); MS(70 eV) m/z 363(M+), 361(M+), 291, 288, 263, 261, 182, 144, 119, 91.
The following Table 2 shows yields and ratio of optical isomers generated in the course of substitution reactions performed the same as in Example 2.
Table 2
Figure imgf000012_0001
Figure imgf000013_0002
Example 3
Preparation of (D+)-methyl- 2-[4-(6-chloro-2-benzoxazolyloxy)-phenoxy]- propionate (Compound 27) 50mL of cyclohexane, 2.61g (lOmmol) of (6-chloro-2-benzoxazolyloxy)phenol,
2.35g (10.5mmol) of (S)-methyl 0-(p-methoxy benzene) sulfonyl lactate, and 2.12g (20mmol) of powdery Na2C03 were put in a lOOmL flask equipped with a cooling condenser-attached Dean-Stock and reacted for 12 hours while refluxing. The reaction mixture was filtered without cooling and the solid cake was washed with 20mL of warm cyclohexane. The cyclohexane layer, the filtrate, was condensed to obtain 3.10g of the target compound (yield = 89%; purity = 98%; optical purity = 99.9%). mp 97 °C (observed); Rf=0.50(hexane/ethylacetate=3/l); 1H-NMR(CDC13, 200MHz) δ 1.51(d, /=6.4Hz, 3H), 3.70(s,3H), 4.55(q, /=6.4Hz, IH), 6.84 ~ 7.40(m, 7H); MS(70 eV) m/z 349(M+), 347(M+), 291, 288, 263, 261, 182, 144, 119, 91.
The following Table 3 shows yields and ratio of optical isomers generated in the course of substitution reactions performed the same as in Example_3. Table 3
Figure imgf000013_0001
Reaction Ratio of
Reaction Reactio Yields
R2 Temperatu (R)/(S) Solvent n Time (& %)
-re Isomers*(%)
Figure imgf000014_0001
Example 4
Preparation of (D+)-«-butyl- 2-[4-(6-chloro-2-benzoxazolyloxy)-phenoxy]- propionate (Compound 28)
50mL of cyclohexane, 2.61g (lOmmol) of (6-chloro-2-benzoxazolyloxy)phenol, 3.15g (10.5mmol) of (S)-n-butyl O-p-toluenesulfonyl lactate, and 2.76g (20mmol) of powdery K2C03 were put in a lOOmL flask equipped with a cooling condenser- attached Dean-Stock and reacted for 12 hours while refluxing. The reaction mixture was filtered without cooling and the solid cake was washed with 20mL of warm cyclohexane. The cyclohexane layer, the filtrate, was condensed to obtain 3.60g of the target compound (yield = 92.3%; purity = 98%; optical purity = 99.9%). mp 48 ~ 50 °C (observed); Rf=0.59(hexane/ethylacetate=3/l); 1H-NMR(CDC13, 200MHz) δ 0.91(t, /=7.1Hz, 3H), 1.48 ~ 1.58(m, 4H), 1.51(d, 7=6.9Hz, 3H), 4.26(q, 7=7.1Hz, 2H), 4.45(q, /=6.9Hz, IH), 6.84 ~ 7.40(m, 7H); MS(70 eV) m/z 391(M+), 389(M+), 291, 288, 263, 261, 182, 144, 119, 91.
The following Table 4 shows yields and ratio of optical isomers generated in the course of substitution reactions performed in Example 4.
Table 4
Figure imgf000015_0001
Example 5
Preparation of (D+)-n-ethyl-2-[4-(3-chloro-5-trifluoromethylpyridine-yloxy)- phenoxyj-propionate (Compound 29)
30mL of cyclohexane, 2.90g (lOmmol) of 4-(3-chloro-5- trifluoromethylpyridinyloxy)phenol, 2.86g (10.5mmol) of (S)-ethyl O-p- toluenesulfonyl lactate, and 2.76g (20mmol) of powdery K2C03 were put in a 50mL flask equipped with a cooling condenser-attached Dean-Stock and reacted for 18 hours while refluxing. The reaction mixture was filtered without cooling and the solid cake was washed with 20mL of warm cyclohexane. The cyclohexane layer, the filtrate, was condensed to obtain 3.51g of the target compound (yield = 90%; purity = 98%; optical purity = 97.0%).
Rf=0.56(EA:Hx=l:4); IH NMR(CDC13, 200MHz) δ 1.27(t, /=7.2Hz, 3H), 1.63(d, /=6.6Hz, 3H), 4.24(q, /=7.2Hz, 2H), 4.73(q, /=6.90Hz, IH), 6.89 ~ 8.27(m, 6H); MS(70eV) m/z 389(M+), 370, 316, 288, 272, 261, 226, 209, 180, 160, 119, 109, 91, 76, 63.
Example 6
Preparation of (D+)-n-ethyl-2-[4-(2,4-dichlorophenoxy)-phenoxy]-propionate
(Compound 30)
30mL of cyclohexane, 2.55g (lOmmol) of 4-(2,4-dichlorophenoxy)phenol, 2.86g (10.5mmol) of (S)-ethyl O-p-toluenesulfonyl lactate, and 2.76g (20mmol) of powdery K2C03 were put in a 50mL flask equipped with a cooling condenser- attached Dean-Stock and reacted for 17 hours while refluxing. The reaction mixture was filtered without cooling and the solid cake was washed with 20mL of warm cyclohexane. The cyclohexane layer, the filtrate, was condensed to obtain 2.74g of the target compound (yield = 77%; purity - 98%; optical purity = 94.6%).
Rf=0.77(EA:Hx=l:2); IH NMR(CDC13, 300MHz) δ 1.26(t, /=7.2Hz, 3H), 1.62(d, /=6.9Hz, 3H), 4.23(q, /=7.1Hz, 2H), 4.69(q, /=6.7Hz, IH), 6.78 ~ 7.44(m, 7H); MS(70eV) m/z 355(M+), 354(M+), 281, 253, 202, 184, 173, 162, 139, 120, 109, 91.
Example 7 Preparation of (D+)-«-ethyl-2-[7-(2-chloro-4-trifluoromethylphenoxy)- naphthalene-2-yloxy]propionate (Compound 31))
30mL of cyclohexane, 3.39g (lOmmol of 7-(2-chloro-4- trifluoromethylphenoxy)-2-naphthalenol, 2.86g (10.5mmol) of (S)-ethyl O-p- toluenesulfonyl lactate, and 2.76g (20mmol) of powdery K2C03 were put in a 50mL flask equipped with a cooling condenser-attached Dean-Stock and reacted for 19 hours while refluxing. The reaction mixture was filtered without cooling and the solid cake was washed with 20mL of warm cyclohexane. The cyclohexane layer, the filtrate, was condensed to obtain 4.08g of the target compound (yield = 93%; purity = 98%; optical purity = 92.8%). Rf=0.60(EA:Hx=l:4); IH NMR(CDC13, 300MHz) δ 1.24(t, 7=7.2Hz, 3H), 1.67(d, 7=6.9Hz, 3H), 4.23(q, 7=5.7Hz, 2H), 4.86(q, J=6.9Hz, IH), 6.94 ~ 7.81(m, 9H); MS(70eV) m/z 438(M+), 365, 338, 321, 303, 286, 275, 170, 142, 126, 114, 102.
Example 8 Preparation of (D+)-«-ethyl-2-[4-(6-chloroquinoxalin-2-yloxy)phenoxy]propionate (Compound 32)
30mL of cyclohexane, 2.73g (lOmmol) of 4-(6-chloroquinoxalin-2- yloxy)phenol, 2.86g (10.5mmol) of (S)-ethyl O-p-toluenesulfonyl lactate, and 2.76g
(20mmol) of powdery K2C03 were put in a 50mL flask equipped with a cooling condenser-attached Dean-Stock and reacted for 18 hours while refluxing. The reaction mixture was filtered without cooling and the solid cake was washed with 20mL of warm cyclohexane. The cyclohexane layer, the filtrate, was condensed to obtain 3.39g of the target compound (yield = 91%; purity = 98%; optical purity =
99.8%). mp=60 ~ 61 °C (R observed), mp=83 ~ 84 °C (R,S observed), Rf=0.63(EA:Hx=l:2); IH
NMR(CDC13, 500MHz) δ 1.29(t, /=7.1Hz, 3H), 1.65(d, /=6.8Hz, 3H), 4.26(m, 2H),
4.76(q, /=6.8Hz, IH), 6.95 ~ 8.67(m, 7H); MS(70eV) m/z 372(M+), 299, 272, 255, 244,
212, 199, 163, 155, 136, 110, 100, 91, 65.
The following Table 1 shows the yield, ratio of generated optical isomers and spectral data of the compounds (33-38) performed in Example 8.
Table 5
Figure imgf000018_0001
Figure imgf000019_0001
Comparative Example 1
The following Tables 6 and 7 show yields and ratio of optical isomers generated in the course of preparing (D+)-methyl-2-[4-(6-chloro-2- benzoxazolyloxy)phenoxy]propionate (compound 27) according to the known methods shown in the reaction schemes 1 and 2. Table 6
Figure imgf000020_0001
Table 7
Figure imgf000020_0002
ketone
*Ratio of (R)/(S) isomers: Identified by LC
Comparative Example 2
The following Table 8 shows yields and ratio of optical isomers generated in the course of preparing (D+)-n-ethyl-2-[4-(3-chloro-5-trifluoromthylpyridine-2- yloxy)phenoxy]propionate (compound 29) according to the known methods shown in the reaction scheme 2.
Table 8
Figure imgf000021_0001
Comparative Example 3 The following Table 9 shows yields and ratio of optical isomers generated in the course of preparing (D+)-n-ethyl-2-[4-(6-chloroquinoxalin-2- yloxy)phenoxy]propionate (compound 32) according to the known methods shown in the reaction scheme 2. Table 9
Figure imgf000022_0001
Industrial Applicability
As described above, the preparing method of the present invention enables production of optically pure (R)-aryloxy propionic acid ester derivatives with good yield and is thus expected to produce an enormous economic effect.
While the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art will appreciate that various modifications and substitutions can be made thereto without departing from the spirit and scope of the present invention as set forth in the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A method for preparing optically active (R)-aryloxypropionic acid ester derivatives represented by the following Formula 1 by reacting phenol derivatives represented by the following Formula 2 and (S)-alkyl O-arylsulfonyl lactate represented by the following Formula 3 in the presence of alkali metal carbonate in an aliphatic or aromatic hydrocarbon solvent under the temperature range of 60 to 100 °C :
A-OH (2)
Figure imgf000023_0001
wherein R1 is a Cι-6 -alkyl or benzyl group; R2 is a C -6 -alkyl, phenyl group, or a phenyl group substituted with a Cι-6 -alkyl or a G-β -alkoxy group; A is an aryl group selected from the group consisting of a phenyl group, a naphthyl group, a quinoxazolyloxyphenly group, a benzoxazolyloxyphenyl group, a benzothiazolyloxyphenyl group, a phenyloxyphenyl group, a pyridyloxyphenyl group and a pheyloxynaphthyl group, wherein said aryl group can be substituted with 1-3 functional groups selected from the group consisting of a hydrogen atom, a halogen atom, a nitro group, a nitrile group, an acetoxy group, a C1-4 -alkyl group, a Cι-4 -haloalkyl group, a Cι-4 -alkoxy group, and a C1- -haloalkoxy group.
2. In Claim 1, said hydrocarbon solvent is selected from the group consisting of toluene, xylene, cyclopentane, cyclohexane, methylcyclohexane, cycloheptane, n- hexane, and n-heptane.
3. In Claim 1, said solvent is cyclohexane or xylene.
4. In Claim 1, said method for preparing optically active (R)- aryloxypropionic acid ester derivatives is performed using potassium carbonate as a base in cyclohexane as a solvent at 80 °C .
PCT/KR2003/001244 2002-06-26 2003-06-25 Process for preparing (r)-aryloxypropionic acid ester derivatives Ceased WO2004002925A2 (en)

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