JPH0162A - Phenoxyacetic acid derivative - 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 (Industrial Application Field) The present invention relates to a novel phenoxyacetic acid derivative or a salt thereof.

(Prior Art) It is known that 14-(2-benzenesulfonylaminoethyl)phenoxyacetic acid has an inhibitory effect on platelet aggregation (Japanese Patent Publication No. 57-35910).

(Structure and Effects of the Invention) The present invention is based on the general formula (wherein R1, R1, R3 and R4 each represent a lower alkyl group, and the others represent a hydrogen atom, and H% is 1 to 3 Ring A represents a phenylene group which may have 1 to 2 substituents, and the group -COOR' represents an optionally protected carboxyl group. ) or a salt thereof.

Compound (I) or a salt thereof, which is the object of the present invention, has a more excellent platelet aggregation inhibiting action than the above-mentioned known compounds, and is a useful compound as a prophylactic and therapeutic agent for thrombosis.

Examples of target compounds include -M in formula (1), R1,
Any one or two of R2, R3 and R4 is a lower alkyl group such as a methyl group, ethyl group, propyl group, or butyl group, and the others are hydrogen atoms, and R5 is a methyl group, an ethyl group,
From lower alkyl groups such as propyl, halogen atoms such as fluorine, chlorine, and bromine, lower alkoxy groups such as methoxy, ethoxy, and propoxy, trihalogenomethyl groups such as trifluoromethyl, and nitro groups. It is a phenyl group which may have 1 to 3 selected substituents, and ring A is a methyl group, a lower alkyl group such as an ethyl group, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and a methoxy group, an ethoxy group. A phenylene group which may have one or two substituents selected from lower alkoxy groups such as groups, and the group -COOR' is a free carboxyl group, or a methyl group, an ethyl group, a propyl group, a butyl group. Examples include compounds which are carboxyl groups protected by lower alkyl groups such as, substituted or unsubstituted phenyl lower alkyl groups such as benzyl group, p-methoxybenzyl group, and p-nitrobenzyl group, and benzhydryl group.

Among these, preferred compounds include -i formula (I) in which one or two of RISRl, R3 and R4 are alkyl groups having 1 to 4 carbon atoms, and the others are hydrogen atoms,
R5 is a phenyl group which may have 1 to 3 substituents selected from an alkyl group having 1 to 3 carbon atoms, a halogen atom, a lower alkoxy group having 1 to 3 carbon atoms, a trihalogenomethyl group, and a nitro group; , Ring A is a phenylene group which may have 1 to 2 substituents selected from an alkyl group having 1 to 3 carbon atoms, a halogen atom, and an alkoxy group having 1 to 3 carbon atoms, and the group -COORb is a free Examples include compounds that are a carboxyl group or a carboxyl group protected by an alkyl group having 1 to 3 carbon atoms. Further, more preferable compounds in general formula (I) include R1, R2,
Either one of R3 and R4 is an alkyl group having 1 to 4 carbon atoms, the other is a hydrogen atom, and R5 is substituted with an alkyl group having 1 to 3 carbon atoms, a halogen atom, a trihalogenomethyl group, or a nitro group; a phenyl group in which ring A may be substituted with a halogen atom, and the group -COOR' is a free carboxyl group or is protected with an alkyl group having 1 to 3 carbon atoms. It is a compound. A more preferable compound is a compound having the general formula (R1,
1! , one of R3 and R4 is a methyl group or an ethyl group, the other is a hydrogen atom, and R5 is a phenyl group which may be substituted with a methyl group, a chlorine atom, a bromine atom, a trifluoromethyl group or a nitro group. and ring A is a phenylene group optionally substituted with a fluorine atom or a chlorine atom, and the group -COOR6 is a free carboxyl group, or
Or it is a compound protected with an alkyl group having 1 to 3 carbon atoms.

The object compound (1) of the present invention has two types of optical isomers based on one asymmetric carbon atom or two types of optical isomers based on two asymmetric carbon atoms.
Although certain stereoisomers or four optical isomers may exist, the present invention encompasses any of these isomers and mixtures thereof.

According to the present invention, the target compound (I) or a salt thereof is a) a phenol compound represented by the general formula (wherein R1, R1, R3, R4, R5 and ring A have the same meanings as above); Salt and general 2 X'C
HzCOOR" (III) (wherein, Xl represents a reactive residue, and the group -COOR" represents an optionally protected carboxyl group) is subjected to a condensation reaction with an acetic acid derivative represented by b) the group -COOR When " is a protected carboxyl group, the protecting group can be removed if desired, and C) if necessary, the product can be produced by further converting the product into its salt.

In addition, the target compound (I) or a salt thereof has the general formula a) (where Y represents an optionally protected amino group or a reactive residue, R1, RII, R3, R4, ring A and the group -
(COOR" has the same meaning as above.) and a phenoxyacetic acid derivative or its salt represented by the general formula % formula % () (However, when 2 is an optionally protected amino group, 2 is a hydroxyl group or (If Y is a reactive residue, it represents a free amino group, and R5 has the same meaning as above.) is subjected to a condensation reaction with a benzenesulfonic acid compound represented by b) the group -COOR. ” is a protected carboxyl group and/or 5y is a protected amino group,
C) It can also be produced by removing the protecting group if desired and further converting the product into a salt thereof if necessary.

The protecting group (R”) for the carboxyl group in the starting compounds (III) and (IV) includes hydrolysis, acid treatment,
Any protecting group that can be easily removed by conventional treatments such as reduction can be used, such as lower alkyl groups such as methyl, ethyl, propyl, butyl, benzyl, etc. , p-methoxybenzyl group, substituted or unsubstituted phenyl lower alkyl group such as p-nitrobenzyl group, benzhydryl group, and the like.

Examples of reactive residues (X and Y or Z) include halogen atoms such as chlorine atoms, bromine atoms, and iodine atoms;
Lower alkylsulfonyloxy groups such as methanesulfonyloxy groups, substituted or unsubstituted phenylsulfonyloxy groups such as benzenesulfonyloxy groups, and P-)luenesulfonyloxy groups can be suitably used.

Phenol compound (■ or its salt and acetic acid derivative (I)
The condensation reaction with N) can be suitably carried out according to a conventional method, for example, in a solvent. As the solvent, for example, acetone, chloroform, alkanol, methylene chloride, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, or a mixed solvent thereof can be suitably used. As the salt of phenol compound (II), for example, alkali metal salts, alkaline earth metal salts, etc. can be used. This reaction is carried out using deoxidizing agents such as alkali metal carbonates, alkali metal hydroxides, alkali metal bicarbonates,
Preferably, it is carried out in the presence of an organic amine such as triethylamine. This reaction can be suitably carried out at room temperature to under heating.

The condensation reaction between the phenoxyacetic acid derivative (IV) or its salt and the benzenesulfonic acid compound (V) can be carried out as appropriate in the presence or absence of a deoxidizing agent. As the deoxidizer, an alkali metal bicarbonate, an alkali metal carbonate, an alkaline earth metal carbonate, or an organic base such as lysine, trimethylamine or triethylamine can be suitably used. The reaction can be carried out in a solvent or without a solvent, and ether, benzene, methylene chloride, dioxane, ethanol, methanol, water, or a mixed solvent thereof can be used as appropriate. In addition, in the phenoxyacetic acid derivative (IV), when the group Y is an amino group,
It can also be subjected to the reaction in the form of a salt such as a mineral acid salt or an organic acid salt, and when the group Y is a protected amino group or -〇〇OR'l is a free carboxyl group, for example, an alkali metal salt, It can also be subjected to the reaction in the form of a salt such as an alkaline earth metal salt.

Furthermore, when the group Y is a protected amino group, it is preferable to use a lower alkanoyl group such as an acetyl group or a propionyl group, or an aryloxycarbonyl group such as a benzyloxycarbonyl group as the protecting group for the amino group. . This reaction can be suitably carried out under heating.

In the product thus obtained, when the group -COOR'' is a protected carboxyl group and/or when the group Y is a protected amino group, the protecting group may be removed if desired, and the protecting group The removal can be carried out by conventional methods such as hydrolysis, solvolysis, acid treatment, and reduction.

Incidentally, since all of the above reactions proceed without racemization, if an optically active form is used as the starting compound (n) or (IV), the target compound (I) can also be obtained as an optically active form.

The object compound (1) of the present invention can be used for pharmaceutical purposes either in its free form or in its salt form. When used for pharmaceutical purposes, the salts are preferably pharmacologically acceptable salts, such as salts with inorganic or organic bases, such as alkali metal salts such as sodium salts, potassium salts, calcium salts, etc. salts, alkaline earth metal salts such as magnesium salts, heavy metal salts such as zinc salts, and organic amine salts such as ammonium salts, triethylamine salts, pyridine salts, ethanolamine salts, and basic amino acid salts.

The target compound (1) or a salt thereof can be administered either orally or parenterally, and can be mixed with an excipient suitable for oral or parenteral administration and used as a pharmaceutical preparation.

Furthermore, pharmaceutical preparations may be solid preparations such as tablets, capsules, and suppositories, or liquid preparations such as solutions, suspensions, and emulsions. ,
It can also be used in the form of an injection.

The object compound (1) of the present invention or a salt thereof can be prepared as described above (
It has excellent platelet aggregation inhibiting effects, such as cerebral thrombosis, coronary artery thrombosis, pulmonary thrombosis, pulmonary embolism, peripheral vascular embolism,
It can be used for the treatment, mitigation, and prevention of various thromboses such as thrombovasculitis, embolism, and the like. For example, when investigating the inhibitory effect on collagen-induced aggregation of human platelets, it was found that the compound of the present invention (±)-4-(2-(4-chlorophenyl)sulfonylamino-1-methylethyl)phenoxyacetic acid 4 which is a compound described in -35910
-(2-Benzenesulfonylaminoethyl) exhibits approximately 4 times stronger platelet aggregation inhibiting action than phenoxyacetic acid. Furthermore, the target compound (1) or a salt thereof has low toxicity and exhibits high safety as a medicine.

The raw material compound (II) of the present invention has the general formula (wherein R? represents an optionally protected hydroxyl group, R
', R meaning, R3, R4 and ring A have the same meanings as above. ) and a phenylsulfonyl halide derivative represented by the general formula (%) (where 9% has the same meaning as above and x2 represents a halogen atom) in a solvent with an alkali metal carbonate or It can be prepared by reacting in the presence of an organic amine and, if necessary, removing a protecting group from the product. Alternatively, among the raw material compounds (U), compounds in which either one of R and R4 is a lower alkyl group, the other is a hydrogen atom, and R1 and R3 are hydrogen atoms may have the general formula (however, if R'l has the same meaning as above.) The compound represented by (■) is reacted with the compound (■) in the presence of an alkali metal carbonate in a solvent, and then the product is reacted with a lower alkyl magnesium halide. , a compound represented by the general formula (wherein R2, R4, 9%, ring A and R7 have the same meanings as above) is prepared, and then the compound is catalytically reduced in the presence of a palladium-carbon catalyst, and the essential steps are Then, the hydroxyl protecting group can be further removed. On the other hand, the raw material compound (m is a general formula (however, Y' is an optionally protected amino group or reactive residue, R1, R1, R2
, R4 and ring A have the same meanings as above. ) and compound (III) are reacted in a solvent in the presence of a deoxidizing agent, and if necessary, the protecting group can be removed from the product according to a conventional method.

Experimental Example 1 Human platelet aggregation inhibition (in vitro) Nine volumes of blood collected from a healthy individual were mixed with one volume of a 3.13χ (W/V) trisodium citrate aqueous solution, and then centrifuged to obtain a platelet suspension (PRP). ) was prepared. The remaining solution was further centrifuged to prepare platelet-free plasma (PPP). PRP
was diluted with PPP to adjust the platelet count to approximately 4 x 10'/mm'. Next, 25 μl of the sample and an equimolar sodium bicarbonate solution were added to PRP200 and EJ1, and after stirring at 37°C for 2 minutes, the collagen was dissolved. & (
25-29 μg/ml solution: Biochimica Kogyo Biophysica Acta, Vol. 186, p. 254 (1969)
] was added to induce platelet aggregation. Platelet aggregation ability was determined by Pawn's method [Nature, Vol. 194, p. 927 (1).
962)] to examine the platelet aggregation inhibiting effect of the sample. The platelet aggregation inhibitory effect of the test compound is tC
S. (Concentration required to suppress platelet aggregation induced by collagen by 50x). The results are shown in Table 1.

Table 1 Note) Chemical name of each sample used in the experiment (Hereafter, Experimental Examples 2 to 3
): Sample No. 1: (±)-4-(2-(4-chlorophenyl)sulfonylaminopropyl)phenoxyacetic acid Sample No. 2: (±)-4-(2-(4-chlorophenyl) ) Sulfonylamino-1-methylethyl]phenoxyacetic acid sample No. 3: (±)-4-(2-(4-bromophenyl)sulfonylamino-1-methylethyl]phenoxyacetic acid pair I!1!+lC: 4- (2-Benzenesulfonylamine ethyl)phenoxyacetic acid (compound described in Example 1 of Japanese Patent Publication No. 57-35910) Experimental Example 2 Arachidonic acid-induced pulmonary embolism inhibitory effect (in vivo) -
Night-fasted mice (ddy strain, male, 5 weeks old, -group 1
0 animals), the specimen (equimolar sodium bicarbonate and 0.2
(suspended or dissolved in 5X carboxymethyl cellulose solution)
was administered orally (20 ml/kg). After 3 hours, arachidonic acid (125 mg/2.5 ml 1χNaHCOs
solution + 7.5 ml O, 9% saline/kg) was administered into the tail vein to induce pulmonary embolism. The potency of the sample compound is
The time from arachidonic acid administration to recovery of walking movement (recovery time: minutes) was measured, and 0.25χ
This was compared with that of a group to which CMC was administered but no sample was administered. The inhibitory effect of the test compound on arachidonic acid-induced pulmonary embolism was expressed as the dose that shortened the recovery time by 15% or more compared to the group to which the test compound was not administered. The results are shown in Table 2.

Table 2 Note) Chemical name of each sample used in the experiment Sample No., '4: (±)-4-(2-benzenesulfonylamino-1-methylethyl)-2-fluorophenoxyacetic acid Sample No., 5: ( ±) -4-(2-(4-chlorophenyl)sulfonylamino-1-methylethyl-2-fluorophenoxyacetic acid Experimental example 3゜Blood time corrected 乍 (in vivo) - Night-fasted mice (ddy strain, male , 5 weeks old, 10 animals in - group) were treated with specimens (equimolar sodium bicarbonate and 0.2
(suspended or dissolved in 5χ carboxymethyl cellulose solution)
After 3 hours of oral administration (201 ml, 17 kg), the tail was cut off approximately 2 ms from the tip under ether anesthesia, and the tip of the tail was immediately immersed in physiological saline kept at 37°C. The efficacy of the test compound is determined by the time it takes for bleeding to stop completely (
Bleeding time: seconds) was measured, and 0.25χC was used instead of the specimen.
This was compared with that of a group to which MC was administered but no sample was administered.

〔result〕

Compound No. 1 of the present invention showed an effect of prolonging the bleeding time by 50% or more at a dose of 3 mg/kg, and Nos. 2 and 3 at a dose of 10 mg/kg. On the other hand, in the case of the control sample, the minimum effective dose showing an effect of prolonging the bleeding time by 50% or more was 30 mg/kg.

Example 1 (1) 1-benzenesulfonylamino-2-(4-
Benzyloxyphenyl)-2-propatool 4.74
g was dissolved in a mixture of 100 ml of tetrahydrofuran and 20 ml of water, 4.29 g of oxalic acid was added to the solution, and 10 g of oxalic acid was added.
In the presence of 3.2 g of χ palladium carbon, pressurized hydrogen gas (3
After the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. Ethyl acetate is added to the residual aroma, washed with an aqueous sodium bicarbonate solution and then with saturated brine, and after drying, ethyl acetate is distilled off under reduced pressure. The residual aroma is recrystallized from a mixture of ethyl acetate and n-hexane to obtain 2.96 g of 4-(1-methyl-2-benzenesulfonylaminoethyl)phenol as colorless needles.

Yield 85χ ■, p, 162.5-164°C (2) 2.96 g of Honjima was dissolved in 25+ el of acetone, and 1.54 g of potassium carbonate and 1.5 g of ethyl bromoacetate were added.
Add 87 g and stir at room temperature for 6.5 hours. Additionally, 0.57 g of potassium carbonate and 0.68 g of ethyl bromoacetate.
After the reaction was stirred overnight, the acetone was distilled off under reduced pressure, and the residual aroma was extracted with ethyl acetate. The extract is washed with water, then with saturated saline, and then dried. Ethyl acetate was distilled off under reduced pressure, and the residual aroma was purified by relica gel column chromatography (solvent: toluene, toluene-ethyl acetate = 20:1, then 10:1).
When separated and purified using 4-(1-methyl-2-benzenesulfonylaminoethyl)phenoxyacetate ethyl
4 g are obtained as a colorless oil.

Yield: 53% Mass (ie/e) = 377 (M”) (3) Dissolve 1.55 g of Honjima in 16 liters of ethanol, add 6.21 g of normal sodium hydroxide aqueous solution, and stir at room temperature for 2 hours. The mixture was concentrated under reduced pressure, the residual fragrance was dissolved in water 61, and a nonionic adsorption resin (trade name: Diaion HP-
20, manufactured by Mitsubishi Kasei Co., Ltd.) Purify with packed column chromatography (solvent: water then 50x methanol). Both fractions containing the target product are collected and the solvent is distilled off. When the remaining residue is powdered by adding isopropyl alcohol, 4-(1-methyl-2-
1.13 g of benzenesulfonylaminoethyl) phenoxyacetic acid sodium salt are obtained as a colorless powder.

Yield 74χ m, p, 180°C or higher Mass (m/e): 394 (M”+Na), 372
(M”+H) Free carboxylic acid: Colorless caramel Mass (m/e): 349 (M”), 179 Examples
2 (1) 11.13 g of di-4-(2-aminopropyl)phenol hydrobromide was added to 3.1 g of sodium carbonate.
Add to a mixture of 8 g of ethyl acetate 100+wl and 100 ml of water. To this mixture, a solution of 9.71 g of benzenesulfonyl chloride in 50-1 ethyl acetate and a solution of 3.18 g of sodium carbonate in 30n+1 water are simultaneously added dropwise over 0.5 hours while stirring at 0-5°C. The mixture was stirred at 10° C. for 0.5 hour, neutralized with 10× hydrochloric acid, and the organic layer was separated. The aqueous layer is extracted with chloroform, combined with the previously separated organic layer, and evaporated under reduced pressure. The residue was crystallized from n-hexane to obtain 7.48 g of di-4-(2-benzenesulfonylaminopropyl)phenol as colorless prism crystals. Yield: 86χ m, p, 97-99°C Mass (-8): 291 (M (2) Add 7.4 g of Honjima and 3.51 g of potassium carbonate to 140 ml of acetone. Add a solution of 4.66 g of ethyl bromoacetate in 1 ml of acetone to the solution with stirring, and stir at room temperature for 18 hours. After the reaction. The reaction solution was concentrated under reduced pressure to about 173, and after neutralization with a 10x hydrogen chloride-ethanol solution,
Extract with chloroform. Chloroform was distilled off under reduced pressure,
By separating and purifying the residue using silica gel column chromatography (solvent: chloroform-methanol = 50:1-20:1), 8.50 g of ethyl dl-4-(2-benzenesulfonylaminopropyl)phenoxyacetate was obtained as a colorless oil. get as.

Yield 88.5χ Mass (m/e): 377 (M") IRν, -=
(cs+-'): 3270.1745 (3) Main island 8
．． 5g to 10χ aqueous sodium hydroxide solution 100II11
After stirring at 100° C. for 5 minutes and at room temperature for 0.5 hour, the pH was adjusted to 3 with concentrated hydrochloric acid. After chloroform extraction and drying of the extract, chloroform was distilled off under reduced pressure to obtain 6.88 g of dt-4-(2-benzenesulfonylaminopropyl)phenoxyacetic acid as a colorless powder.

Yield 87'& m, p, 131-132°C (recrystallized from a mixture of acetone-11-hexane) Mass (m/e): 349 (M sodium salt: colorless powder (recrystallized from ethanol) s, p , 192-194℃ Mass (ge/e): 394 (M”+Na)+3
72(M”+H) Example 3 (1) (R)-1-(4-methoxyphenyl)-2
- Add 5.043 g of aminopropane and 8.40 g of sodium bicarbonate to a mixture of 50 ml of methylene chloride and 50 ml of water. A solution of 4.86 g of benzenesulfonyl chloride in methylene chloride is added dropwise to the mixture while stirring at 5-10°C, and the mixture is stirred at room temperature for 2 hours. After the reaction is completed, the methylene chloride layer is separated. Furthermore, the aqueous layer was extracted with methylene chloride,
The methylene chloride layer was combined with the previous methylene chloride layer, and after drying, the methylene chloride was distilled off under reduced pressure. The remaining residue was purified by silica gel column chromatography (solvent: chloroform, then chloroform-methanol/
50:1), recrystallized and crystallized from isopropyl ether-methanol mixture, (R)-1
6.76 g of -(4-methoxyphenyl)-2-benzenesulfonylaminopropane is obtained as colorless prismatic crystals.

Yield 88.6χ s, p, 75-75.50 °C [α) -18,84° (C・1.072.methanol) (2) 120 m of methylene chloride with 6.10 g of ice crystals
A solution of 14.3 g of boron tribromide in 20 m+1 methylene chloride is added dropwise to the solution at −78° C. under an argon atmosphere. The reaction solution is returned to room temperature over 1.5 hours. After the reaction is completed, cooled sewage water 201 is added. The methylene chloride layer is separated, washed with saturated brine and dried, and then the methylene chloride is distilled off under reduced pressure. (R)-4-(2-
Benzenesulfonylaminopropyl) phenol 5.5
9 g are obtained as colorless platelets.

Yield 96.1χ m, p, 92-92.50°C [α) -22,50° (C=1.00.methanol) (3) Ice crystals 5.24g, ethyl bromoacetate 3.
31g and 2.49g of potassium carbonate in 150ml of acetone
1 and stirred at room temperature for 19 hours. Furthermore, 0.6 g of ethyl bromoacetate was added, and after stirring for 8 hours, the inorganic substances were removed by filtration, and the filtrate was concentrated under reduced pressure. Remove the residual fragrance by silica gel column chromatography (solvent: chloroform-methanol, 100%
:1) and recrystallized from a mixture of chloroform-isopropyl ether to obtain (R)-
5.05 g of ethyl 4-(2-benzenesulfonylaminopropyl)phenoxyacetate are obtained as colorless needles.

Yield 74.3χ P, 108.5-109℃ [α) -11,03° (c=t, ots, methanol) Mass (s8)=377CP) (4) Add 4.68g of ice crystals to water Dissolve sodium oxide Ig in a mixture of 80% of tetrahydrofuran and 10% of water,
After the reaction was completed by stirring at room temperature for 1.5 hours, tetrahydrofuran was distilled off under reduced pressure, acidified with 10x hydrochloric acid, and extracted with chloroform. After washing with saturated brine and drying, chloroform is distilled off under reduced pressure. By recrystallizing the residual aroma from a mixture of isopropyl ether and methylene chloride, and further recrystallizing it from a mixture of chloroform and hexane, (
R)-4-(2-benzenesulfonylaminopropyl)
4.204 g of phenoxyacetic acid was obtained as colorless needles.

Yield 97χ Theory, p, 92-93℃ [α) -12,01° (C=1.074.methanol) Mass of ice crystals, NMR are consistent with that of the target product obtained in Example 2-(31) did.

Sodium salt Colorless powder (recrystallized from ethanol) Clear,
p, 193-196°C [α) -15,41@((,,1,012,methanol)Example 4 (1) (S)-1-(4-methoxyphenyl)-2
- By treating aminopropane in the same manner as in Example 3-(1), (S)-1-(4-methoxyphenyl)-2
- Obtain benzenesulfonylaminopropane.

Yield 94.2χ Kabura, p, 74.5-76°C [α] +18.60° (C = 1.00.methanol) (2) By treating ice crystals in the same manner as in Example 3-(21) (S) -4-(2-benzenesulfonylaminopropyl)phenol is obtained.

Yield 90.2χ Garden, ρ, 92-94℃ [α) +22.00° (C・1.00.methanol) (3) By treating ice crystals in the same manner as in Example 3-(3), Ethyl S)-4-(2-benzenesulfonylaminopropyl)phenoxyacetate is obtained.

Yield 75X, p, 109-110.5°C [α) +10.50' (C=1.00.methanol) (4) By treating ice crystals in the same manner as in Example 3-(4). all) (S)-4-(2-benzenesulfonylaminopropyl)phenoxyacetic acid is obtained.

Yield: 99x, ρ, 89-91°C [α] +11.90' (C = 1.008. Methanol) Mass of the main island, NMR was consistent with that of the target product obtained in Example 2-<3) .

Sodium salt colorless powder (recrystallized from ethanol m, p
, 192-195°C [α) +15.13° (C, 1,004, methanol) Example 5 (l) (±) -4-(2-aminopropyl)phenol hydrobromide 2.32 g, carbonic acid Sodium hydrogen 4.2g
, 50 ml of water A mixture of 100 ml of ethyl acetate and 2.06 g of 4-methoxyphenylsulfonyl chloride was stirred at room temperature for 3 hours. After the reaction, the ethyl acetate layer was separated, and after drying, the solvent was distilled off under reduced pressure (± )-4-(
2.4 g of 2-(4-methoxyphenyl)sulfonylaminopropyl]phenol are obtained as a brown oil.

Yield 75% a+, p, 119-120.5°C (recrystallized from 1-hexane) (2) 2.37 g of main island, 1.21 g of methyl bromoacetate, 1 g of hydrium carbonate, and 30 ml of acetone
The mixture was reacted at room temperature for 24 hours, and after the reaction, acetone was distilled off. Water is added to the residual aroma and extracted with ethyl acetate, and ethyl acetate is distilled off from the extract under reduced pressure.

The crude methyl (±)-4-(2-(4-methoxyphenyl)sulfonylaminopropyl)phenoxyacetate thus obtained was dissolved in 30 ml of methanol, 15 ml of 1O% aqueous sodium hydroxide solution was added, and the mixture was left at room temperature for 1 hour. Acidified with 10% hydrochloric acid, extracted with chloroform, and after drying, the solvent was distilled off. The residual aroma was separated and purified using silica gel column chromatography (solvent: chloroform, then developed with chloroform:methanol = 19 = 1).
)-4-[2-(4-methoxyphenyl)sulfonylaminopropyl]phenoxyacetic acid2. Olg is obtained as an oil.

Yield: 77% Mass (s+/e): 379
= Add 5 ml of aqueous sodium hydroxide solution and evaporate the solvent under reduced pressure. The residual fragrance was dissolved in 10 ml of water, subjected to M'JI using a column chromatography packed with a nonionic adsorption resin (product name: Diaion HP-20, manufactured by Mitsubishi Chemical Corporation), and recrystallized from an isopropyl alcohol-water mixture (± )-4-
1.43 g of (2-(4-methoxyphenyl)sulfonylaminopropyl) phenoxyacetic acid sodium salt are obtained as colorless granules.

m, p, 177-179°C Mass (m/e): 424 (M”+Na), 40
2(M”+Il) Example 6 (1) (±)-1-(4-methoxyphenyl)-2-amitubukun 2.69 g, sodium hydrogen carbonate 6.3 g,
Water 60ml1. A mixture of 120 ml of ethyl acetate and 2.65 g (7) of benzenesulfonyl chloride was reacted at room temperature for 3 hours. After the reaction, the ethyl acetate layer was separated, and after drying,
The solvent was distilled off under reduced pressure, and the resulting oil was diluted with 50% methylene chloride.
Dissolve in m1. Boron tribromide (9.02 g) and methylene chloride (10 ml) were cooled to -50 to -60°C and stirred.
Slowly add the solution dropwise and then stir for 2 hours to room temperature. After the reaction, cool down and decompose excess boron tribromide with water. Add 50 ml of chloroform and separate the organic layer and dry. Remove the solvent under reduced pressure. After distillation, the residual aroma was removed by silica gel column chromatography (solvent: ethyl acetate: n-hexane = 1 = 9
(±)-4-
(2-benzenesulfonylaminobutyl)phenol 3
70 g of a pale yellow oil was obtained.

Yield: 81% Mass (m/e): 305 (M) (2) By treating ice crystals in the same manner as in Example 5-(2), (±)-4-(2-benzenesulfonylaminobutyl ) Phenoxyacetic acid is obtained as an oil.

Yield 68% Examples 7 to 20 (1) The corresponding raw material compounds were converted to Examples 5-(1) or 6-
By treating in the same manner as in (1), the compounds listed in Table 3 below are obtained. In the table, (+) and (-) each represent the optical activity of the obtained compound (the same applies hereinafter).

(Part 2) (R'-1f, R'JCHs, cyclic tophenylene group) (2) The corresponding raw material compound was added to Example 5-(2
) or by processing in the same manner as 6-(2), the following 4th
The compounds listed in the table are obtained.

Physical properties of sodium salt: Example No. 9: m, p, 187-188°C
Example 21 (1) A mixture of 4.72 g of (±)-4-(2-benzyloxycarbonylamino-1-methylethyl)phenol, 2.53 g of methyl bromoacetate, 50 ml of acetone and 3.43 g of potassium carbonate was brought to room temperature. After the reaction, the acetone was distilled off, water was added to the residual aroma, extracted with chloroform, and after drying, the solvent was distilled off under reduced pressure (±).
5.68 g of methyl -4-(2-benzyloxycarbonylamino-1-methylethyl)phenoxyacetate are obtained as a pale yellow oil.

Yield 96% Mass (m/e): 357 (M”) IRv,,,
(cm-'): 3200-3500.1755.1
Dissolve 5.36 g of 712 (2) Honjima in 60 ml of methanol, add 2 ml of concentrated hydrochloric acid, and perform catalytic reduction at room temperature and pressure in the presence of 0.6 g of 10% palladium on carbon. After 3 hours, the catalyst was removed by filtration and the methanol layer was condensed under pressure. The residual aroma is recrystallized from a mixture of isopropyl alcohol and ether to obtain 3.06 g of methyl (±)-4-(2-amino-1-methylethyl)phenoxyacetate hydrochloride as colorless crystals.

Yield 79% 10ρ, 99-104°C Mass (m/e): 223 (M (3) main island 1.
82 g, ethyl acetate 50 ml. Sodium bicarbonate 1.
A mixture of 76 g, 30 ml of water and 1.53 g of 2.4.6-)limethylphenylsulfonyl chloride was heated at 5-10°C.
After stirring for 2.5 hours, the ethyl acetate layer was separated and dried, and the ethyl acetate was distilled off under reduced pressure. Dissolve the crude (±)-4-(2-(2,4,6-)limethylphenyl)sulfonylamino-1-methylethyl]phenoxyacetate in methanol'l Q m 1. ,
IN = 8 liters of aqueous sodium hydroxide solution and left for 1 hour. After methanol is distilled off, the mixture is neutralized with 5% hydrochloric acid and extracted with chloroform. By distilling off the solvent after drying (±
) -4-(2(2,4,6-trimethylphenyl)sulfoniamino-1-methylethyl]phenoxyacetic acid 16
g as a sticky oil.

Yield 59% Mass (a+/e): 391 (M examples
22-24 +1) The corresponding raw material compounds were converted into Example 2l-(1) and (
2) (By treating in the same manner, the compounds listed in Table 5 below are obtained.

Y=NH! , Item 8 = By treating the raw material compound corresponding to fennel (2) in the same manner as in Example 2l-(31), the compounds listed in Table 6 below can be obtained.
Example positive 22: +m, p, 216-219.5°C Examples 25 to 33 The corresponding starting compounds were treated in the same manner as in Example 21 to obtain the compounds listed in Table 7 below.

Sodium: Example 43 (±')-4-(2-Aminopropyl)phenoxyacetate methyl hydrochloride 1.56 g, ethyl acetate 48 ml, potassium carbonate 2.07 g, water 15 ml and 4-nitrophenylsulfonyl chloride 1. Stir 6 g of the mixture at room temperature overnight. The ethyl acetate layer was separated, and after drying, the solvent was distilled off under reduced pressure, and the residual aroma was recrystallized from a mixture of ethyl acetate and n-hexane to obtain (±)-4-(2-(4-nitrophenyl)sulfonylaminopropyl). 2.14 g of methyl phenoxyacetate is obtained as pale yellow prismatic crystals.

Yield 87% m, p, 127.5-128°C Mass (s/e): 408 (M”) Example 44-
51 The corresponding starting compounds were treated in the same manner as in Example 43 to obtain the compounds listed in Table 8 below.

(R'=H, R"=H, Rh=CH5, R"=CH5,
Y=NIIz, Ring A/Phenylene) Example 52 (1) (±)-4-(2-acetylamino-1-methylethyl) 23.1 g of phenol was dissolved in 400 ml of acetone, and 19.9 g of methyl bromoacetate and Add 18 g of potassium carbonate and stir overnight. Furthermore, 7.96 g of methyl bromoacetate and 7.2 g of potassium carbonate are added and stirred for 3 days. After the reaction, the acetone is distilled off under reduced pressure, water is added to the residual aroma, and the mixture is extracted with ethyl acetate. After washing with saturated saline and drying,
The solvent and excess methyl bromoacetate were distilled off under reduced pressure to obtain 31.6 g of methyl (±'')-4-(2-acetylamino-1-methylethyl)phenoxyacetate as a yellow oil.

Mass (m/e): 265 (M”) (2) Add ice crystals to 200 ml of 6N-hydrochloric acid and heat under reflux for 7° for 5 hours. After the reaction, the solvent is distilled off and the residual aroma is crystallized from tetrahydrofuran. (±)-4-(2-Amino-1-methylethyl)phenoxyacetic acid hydrochloride 19g
obtained as a colorless solid.

m, p, 220.5-223℃ (decomposition) Mass (
m/e): 209(M”), 179IRνmam (
C1l-li: 1730(3) A mixture of 2.95 g of ice crystals, 3.65 g of potassium carbonate, 30 ml of water and 2.45 g of 4-fluorophenylsulfonyl chloride was heated to 80°C.
Stir for 2 hours. After cooling, the pH was adjusted to 1 with 6N hydrochloric acid and extracted with ethyl acetate. After distilling off the solvent under reduced pressure, the thus obtained (±)-4-(2-(4-fluorophenyl)sulfonylamino-1-methylethyl]phenoxyacetic acid was converted into a sodium salt with an IN-sodium hydroxide aqueous solution. After that, (±)-4-(2-(4-fluorophenyl)sulfonylamino-1 -Methylethyl phenoxyacetic acid sodium salt 2.82 g is obtained as a powder.

Yield 60% m, p, 213-214.5°C (colorless prismatic crystals,
(4) Dissolve 1.95 g of ice crystals in 30 ml of water,
Adjust the pH to 1 with % hydrochloric acid and extract with chloroform. After drying, the solvent was distilled off, and the residual aroma crystals were recrystallized from a mixture of ethyl acetate and n-hexane to obtain (±)-4-(2-
1.65 g of (4-fluorophenyl)sulfonylamino-1-methylethyl]phenoxyacetic acid is obtained as colorless prism crystals.

Yield: 90% The corresponding starting compounds were treated in the same manner as in Example 52 to obtain the compounds listed in Table 9 below.

(: [ Example 56 (±)-4-(2-amino-1-methylethyl)phenoxyacetic acid hydrochloride 2.95 g, sodium carbonate 3.82 g
, 30 ml of water and 3.1 g of 2,5-dichlorophenylsulfonyl chloride are stirred at 80° C. for 3 hours. Hereinafter, by processing in the same manner as in Example 43 (±)
-4-(2-(2,5-dichlorophenyl)sulfonylamino-1-methylethyl)phenoxyacetic acid is obtained.

m, p, 111.5-116.5°C (decomposition, ethyl acetate-n-hexane) IRl'max (cm-'): 3320117
40,1710 Example 57 (1) 1.98 g of (±)-4-(2-amino-2-methylpropyl)phenol oxalate was dissolved in chloroform 4
0 ml, 76.27 g of triethylamine and 4
- Add 6.5 g of chlorophenylsulfonyl chloride and heat under reflux for 5 hours.

After the reaction, the solvent was distilled off, dissolved in 50 ml of methanol, and 35 ml of 10% sodium hydroxide aqueous solution was added.
Heat to reflux for minutes. The solvent was distilled off, acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The extract is washed with water, aqueous sodium bicarbonate solution, and saturated brine, dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent: chloroform, then chloroform:methanol-50:1), and recrystallized from a mixture of ethyl acetate-n- and xane to give (±)-4-(2-(4- 1.40 g of chlorophenyl)sulfonylamino-2-methylpropylphenol is obtained as pale yellow prismatic crystals.

Yield 53% M, L 131.5-133.5℃ Mass axis/e): 339 (M") (2) Dissolve 1.50 g of Honjima in 20 ml of acetone, add 0.91 g of potassium carbonate, and stir , a solution of 0.84 g of methyl bromoacetate in 20 ml of acetone was added dropwise at room temperature,
After the reaction was stirred for 24 hours, the solvent was distilled off and the residue was dissolved in ethyl acetate-water. After washing the ethyl acetate layer with water and saturated brine and drying, the solvent was distilled off and recrystallized from a mixture of ethyl acetate and n-hexane to obtain (±)-4-(2-
1.70 g of methyl (4-chlorophenyl)sulfonylamino-2-methylpropyl phenoxyacetate is obtained as pale yellow prism crystals.

Yield 94% Sho, p, 133-135°C Mass (m/e): 41101'') (3) By treating the main island in the same manner as in Example 21, (±)-4
-(2-(4-chlorophenyl)sulfonylamino-2
-Methylpropyl]phenoxyacetic acid is obtained.

Il, p, 177-178°C (recrystallized from ethyl acetate-Q-hexane) Mass (s/e): 397 (M ”) Example
58-60 The corresponding raw material compounds were treated in the same manner as in Example 52-(1) and (2), the obtained carboxylic acid compound was reacted with methanol, and the corresponding methyl ester compound was dissolved in Qml, and weL-10 % palladium-carbon 3g (moisture 6
4%) at room temperature and pressure. After reduction,
The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the yellow oil with residual odor was dissolved in 60 ml of acetone, and 3.61 g of potassium carbonate was added.
A solution of 2.66 g of methyl bromoacetate in 60 ml of acetone was added, and the mixture was stirred overnight. After the reaction, acetone is distilled off,
Add water and extract with ethyl acetate. After washing with saturated brine and drying, ethyl acetate was distilled off under reduced pressure.

Dissolve the pale yellow oily substance with a residual odor in 35 ml of methanol,
Add 35 ml of N-sodium hydroxide aqueous solution and stir for 1 hour. After the reaction, methanol is distilled off under reduced pressure, acidified with dilute hydrochloric acid, and extracted with chloroform. After drying, chloroform was distilled off under reduced pressure, and the residual aroma was separated and purified using silica gel column chromatography (solvent: chloroform, then chloroform:methanol = 1000:1, 100:1.10:1) to obtain 2-methoxy-4-( 4.06 g of 2-benzenesulfonylaminopropyl)phenoxyacetic acid are obtained as an oil.

Yield 62% Mass (a+/e): 379 (M”) Example 62 (1) 1-(4-methoxy-3-methylphenyl)-2
-Aminopropane and benzenesulfonyl chloride were treated in the same manner as in Example 52-(1) to produce (±)-1-(4-
Methoxy-3-methylphenyl)-2-benzenesulfonylaminopropane is obtained.

(2) Dissolve 16.48 g of the main island in 300+td of methylene chloride and cool to -60°C. While stirring, 29.7 g of boron tribromide is added dropwise, the reaction temperature is slowly raised, and the mixture is stirred at room temperature for 1 hour.

After the reaction, it is cooled again, decomposed with water, and extracted with chloroform. After drying, the solvent is distilled off, the brown oily substance with a residual odor is dissolved in 320 ml of acetone, 10.7 g of potassium carbonate and 7.89 g of methyl bromoacetate are added, and the mixture is stirred overnight. After the reaction, acetone is distilled off, water is added, and the mixture is extracted with ethyl acetate. After washing with saturated brine and drying, the solvent is distilled off. Dissolve the residual aroma in methanol, add IN-sodium hydroxide aqueous solution, and stir for 1 hour. After the reaction, methanol is distilled off under reduced pressure, and the residual aroma is purified by silica gel column chromatography (solvent: chloroform, then chloroform:methanol = 1000: 1
, 100:1.10:1) to obtain 13.5 g of 2-methyl-4-(2-benzenesulfonylaminopropyl)phenoxyacetic acid as an oil.

Examples 63 to 67 The corresponding starting compounds were treated in the same manner as in Example 62 to obtain the compounds listed in Table 11 below.

[Synthesis of raw material compounds]
(Reference example 1 (1) 1-(4-benzyloxyphenyl)-2-
78 g of chloroethanone and 63 g of hexamine are dissolved in chloroform and stirred at room temperature overnight. concentrate the mixture
After that, stir and reflux. After cooling, wash and dry the precipitated crystals.
Then, add it to a mixture of ethanol and concentrated hydrochloric acid and reflux.
-After cooling, the precipitated crystals are washed and dried to produce 2-amino-1-
(4-benzyloxyphenyl)ethanone 55.
Obtained as 6 g colorless crystals.

Yield 67χ
1 tank, p, 225℃ (decomposition)
(2) 1.11 g of the main island is dissolved in a tetrahydrofuran solution at water temperature, and an aqueous solution of 1.11 g of potassium carbonate and a solution of 1.41 g of benzenesulfonyl chloride in tetrahydrofuran are simultaneously added dropwise to the solution at 40°C. The mixture was then stirred at room temperature and extracted with ethyl acetate. Extraction After washing and drying the solution, the solvent was distilled off, and the residual aroma was recrystallized from ethyl acetate to obtain 1.34 g of 2-benzenesulfonylamino-1-(4-benzyloxyphenyl)ethanone 4 [as colorless needle crystals]. obtain.

Yield 89χ ■, p, 148-149℃ (3) 4.37g of magnesium was suspended in dry ether, 4 drops of 1,2-dibromoethane was added, and after stirring at room temperature, 18.3g of methyl iodide was suspended. Add the ether solution dropwise.

Then, a solution of 7.6 g of 2-benze/sulfonylamino-1-(4-benzyloxyphenyl)ethanone in tetrahydrofuran was added dropwise to the mixture while stirring and cooling with ice water, and the mixture was stirred at room temperature and further under reflux. After the reaction, an aqueous ammonium monochloride solution was added, followed by extraction with ethylene acetate. After washing and drying the extract, dityl acetate was distilled off, the residual aroma was purified by silica gel column chromatography, and 1-benzenesulfonylamino-2 was crystallized from a mixture of ethyl acetate and n-hexane.
4.92 g of -(4-be/zyloxyphenyl)-2-propatool are obtained as dark colored crystals.

Yield 62% 1,p, 150-151°C Reference Example 2 To a suspension of 2.15 g of lithium aluminum hydride in tetrahydrofuran, 6.78 g of 3-(4-benzyloxy-3-methoxyphenyl)-1-nitropropene was added. A solution of tetrahydrofuran was added dropwise while stirring. Then, the mixture was stirred at room temperature and then refluxed. After decomposing the reacted lithium aluminum hydride with ice water, inorganic substances were filtered off, washed, and dried.
By distilling off the solvent, 1-(4-benzyloxy-
6 g of 3-methoxyphenyl)-2-aminopropane are obtained as a pale yellow sticky oil.

Reference example 3 (1) 2-fluoro-4-methoxyacetophenone 3.
Potassium ter
Add 5.25 g of t-butoxide solution dropwise at 10°C or below,
After the reaction, the mixture was poured into ice water and extracted with ether. After washing and drying the extract, the ether is distilled off, and the residual aroma is purified by silica gel column chromatography to obtain 3.83 g of 2-(2-fluoro-4-methoxyphenyl)-2-methylethanenitrile as a colorless oil. .

Yield: 83% (2) Add Rane to an ethanol solution containing 5.05 g of ice crystals.
15 ml of nickel was added, and 30 g of hydrazine heptadinate was added dropwise at 40°C to 50°C.

After the reaction, the catalyst is filtered off and the filtrate is concentrated. After treating the residual aroma with a 15% methanol solution of hydrogen chloride, the solvent was distilled off and recrystallized from a methanol-isolobyl ether mixture to obtain l-amino-2-(2-fluoro-4-methoxyphenyl)propane hydrochloride 4. 23 g are obtained as colorless crystals.

Yield 75% m, p, 147-149°C Reference Example 4 The corresponding raw material compound was treated in the same manner as in Reference Example 3 to obtain 1-amino-2-(3-fluoro-4-methoxyphenyl)propane hydrochloride.

Yield: 99% Reference Example 5 (1) Add 504 mg of 60% sodium hydride to tetrahydrofuran, add a solution of 2.47 g of triethyl phosphonoacetate under an argon atmosphere, and stir at room temperature. Then 1.85 g of 3-chloro-4-methoxyacetophenone
Add a tetrahydrofuran solution of 0 and react at room temperature.
After the reaction, water is added, the organic layer is separated, and the aqueous layer is extracted with ethyl acetate. The organic layers were combined, the solvent was distilled off, and the residual aroma was purified using silica gel column chromatography to obtain 3-(3-chloro-4-
1.47 g of methoxyphenyl)isocrotonic acid and 3-
(3-chloro-4-methoxyphenyl)crotonic acid 0.
Obtain 18g.

(2) 10% palladium in an acetic acid solution of 1.41 g of 3-(3-chloro-4-methoxyphenyl)isocrotonic acid.
Add 0.3 g of carbon and perform catalytic reduction at room temperature and pressure. After the reaction, the catalyst is filtered off, and after concentration, methanol and an aqueous sodium hydroxide solution are added to the residual aroma and stirred. Then, the solvent was distilled off, acidified with hydrochloric acid, and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off, the residual aroma was purified by silica gel column chromatography, and recrystallized from n-hexane to obtain 3-
(3-chloro-4-methoxyphenyl)butyric acid 807mg
is obtained as colorless crystals.

Yield 64% s+, p, 73.5-75, "c (3) This product 12°23g, triethylamine 6°49g
A toluene solution of 17.66 g of 1 diphenylphosphoryl azide is stirred at room temperature and under reflux.

Then, benzyl alcohol 11. s a gtl
11O,t, and heat to reflux. Ethyl acetate was added to the reaction solution, washed, dried, and then the solvent was distilled off to obtain 17.85 g of 1-benzyloxycarbonylamino-2-(3-chloro-4-methoxyphenyl)propane as an oil.

(4) 33 ml of a 25% hydrogen bromide-acetic acid solution is added dropwise to an acetic acid solution containing 16.42 g of ice crystals, followed by stirring.

After the reaction, ether is added and the precipitate is collected by filtration to obtain 10.33 g of 1-amino-2-(3-chloro-4-methoxyphenyl)propane hydrobromide.

Yield 78% m, p, 163.5-165°C Reference example 6 (±)-4-(2-amino-1-methylethyl)phenol hydrobromide 4.64g, potassium carbonate 6.92g
After stirring an aqueous solution of ethyl acetate containing 3.75 g of benzyloxycarbonyl chloride at room temperature, the ethyl acetate layer was separated, washed and dried, and the solvent was distilled off to give (±)-4-(2-benzyloxycarbonylamino- 4.82 g of phenol (1-methylethyl) are obtained as a pale yellow oil.

Yield: 85% Mass (m/e): 285 (M'') Reference Examples 7 to 9 The corresponding starting compounds were treated in the same manner as in Reference Example 6 to obtain the compounds listed in Table 12 below.

Reference Example 10 (l) 4.19 g of 1-amino-2-(2-fluoro-4-methoxyphenyl)propane hydrochloride was dissolved in chloroform.
Treat with aqueous sodium bicarbonate solution and concentrate the chloroform layer. Hydrobromic acid is added to the residual aroma, and after heating to reflux, the solvent is distilled off. The residual aroma was recrystallized from a mixture of isopropyl alcohol and isopropyl ether to give 3-fluoro-4
4.53 g of -(2-amino-1-methylethyl)phenol hydrobromide are obtained.

Yield: 95% m, p, 182-183.5°C (2) Add 7.52 g of sodium hydrogen carbonate to a mixture of ethyl acetate and water containing 4.47 g of ice crystals, and after stirring, add 2.9 g of benzyloxycarbonyl chloride. , stir for 1 hour. After the reaction, the ethyl acetate layer is separated, washed and dried.

Then, ethyl acetate was distilled off to give 3-fluoro-4-(2
5.82 g of -benzyloxycarbonylamino-1-methylethyl)phenol are obtained as an oil.

Yield 100% Reference Example 11 1-Amino-2-(3-fluoro-4-methoxyphenyl)propane hydrochloride was treated in the same manner as in Reference Example 1O to produce 2-fluoro-4-(2-benzyloxycarbonylamino -1-methylethyl)phenol is obtained as an oil.

Yield: 100% Reference Example 12 (l)(±)-1-Amino-2-(4-methoxyphenyl)propane (19.8 g) and an ethyl acetate-aqueous solution of 84 g of sodium bicarbonate were mixed with 18.0 g of acetyl chloride under cooling.
8 g of ethyl acetate solution are added dropwise. After the reaction, the ethyl acetate layer was separated, washed and dried, and the solvent was distilled off to give (±)-1-
24.8 g of acetylamino-2-(4-methoxyphenyl)propane are obtained as an oil.

Mass (m/e): 207 (M”) (2) Add boron tribromide 6 to a methylene chloride solution of ice crystals under cooling and stirring.
9 g of methylene chloride solution is added dropwise. After reaction under cooling,
Digest with water and add chloroform. The organic layer was then separated, washed, dried, and the solvent was distilled off to give (±)-4-(2
-acetylamino-1-methylethyl)phenol 23
．． 1 g is obtained as an oil.

Yield 100% Mass (m/e): 193 (M”)IRνmaX(
cm-'): 329 (LaO2 (L1655 reference example)
13-15 The corresponding starting compounds were treated in the same manner as in Reference Example 12 to obtain the compounds listed in Table 13 below.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (However, one or two of R^1, R^2, R^3 and R^4 are lower alkyl groups. , the others are hydrogen atoms, R^5 represents a phenyl group that may have 1 to 3 substituents, and Ring A represents a phenylene group that may have 1 to 2 substituents. and the group -COOR^6 represents an optionally protected carboxyl group.) A phenoxyacetic acid derivative or a salt thereof.