JPH06100526A - Phenoxyalkylcarboxylid acid derivative - Google Patents

Abstract

PURPOSE:To obtain a new phenoxyalkylcarboxylic acid derivative useful for preventing and treating allergic diseases such as asthma, having strongly selective leukotriene antagonism. CONSTITUTION:A compound of formula I (A and B are' carbonyl or hydroxymethylene; E is H, OH or acetoxy; G and L are ethyl, acetyl, 1- or 2-hydroxyethyl or hydroxycarbonylmethyl; (m) is 0-2; R<1> is H or lower alkyl; (m) is 1 or 2 and B is hydroxymethylene when A is carbonyl, E is H and G and L are ethyl) or its alkali salt such as 4-[6-acetyl-3-[3-[-[4-acetyl-3- hydroxy-2-(2-hydroxypropyl) phenyl]thio]propoxy]-2-propylphenoxy]butyric acid. The compound is obtained by reacting a compound of formula II with a compound of formula III in an organic solvent in the presence of an inorganic base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel phenoxyalkylcarboxylic acid derivative which has a strong selective leukotriene antagonistic activity and is useful for the prevention and treatment of allergic diseases such as asthma and a method for producing them.

[0002]

2. Description of the Related Art Leukotrienes (leukotrienes C ₄ , D ₄ and E ₄ ) which are metabolites of the 5-lipoxygenase system of arachidonic acid are considered to be major causative agents of immediate allergic diseases such as bronchial asthma. -A (sl
ow reacting substance of anaphylaxis). Therefore, drugs that antagonize leukotrienes are expected as useful antiallergic agents.

[0003]

The present inventor has previously found that some compounds of phenoxyalkylcarboxylic acid derivatives are drugs that antagonize leukotrienes (Japanese Patent Laid-Open No. 2-1459). Patent publication EP495
485), and further, the creation of a compound that is active in vivo has been desired.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies on drugs that antagonize leukotrienes, and as a result, found that a phenoxyalkylcarboxylic acid derivative represented by the following general formula (1) is potent and selective. The inventors have found that they have a leukotriene antagonism and completed the present invention. [In the formula, A and B are each independently a carbonyl group or a hydroxymethylene group, E is a hydrogen atom, a hydroxyl group or an acetoxy group, G and L are each independently an ethyl group,
An acetyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a hydroxycarbonylmethyl group or a lower alkoxycarbonylmethyl group, m represents 0, 1 or 2, and R ¹ represents a hydrogen atom or a lower alkyl group, When A is a carbonyl group, E is a hydrogen atom, and G and L are ethyl groups, m represents 1 or 2 and B represents a hydroxymethylene group.]

According to the present invention, the compound of the general formula (1) can be produced by the route described below.

(A) The compound represented by the general formula (1) can be produced by reacting the compound represented by the general formula (2) with the compound represented by the general formula (3). [In the formula, B is a carbonyl group or a hydroxymethylene group, E is a hydrogen atom, a hydroxyl group or an acetoxy group, and L is an ethyl group, an acetyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a hydroxycarbonylmethyl group or A lower alkoxycarbonylmethyl group, and R ¹ represents a hydrogen atom or a lower alkyl group] [In the formula, A is a carbonyl group or a hydroxymethylene group, G is an ethyl group, an acetyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a hydroxycarbonylmethyl group or a lower alkoxycarbonylmethyl group, and m is 0, 1 or 2, and Y represents a halogen atom]

The reaction is preferably carried out in an organic solvent such as acetone, methyl ethyl ketone, diethyl ketone or dimethylformamide at a reaction temperature of room temperature to solvent reflux temperature. It is also preferable to add an inorganic base such as potassium carbonate or sodium carbonate, and to add potassium iodide. The compound having an ester bond in the above general formula (1) can be hydrolyzed by a conventional method and converted into a corresponding carboxylic acid form and / or alcohol form.

(B) A compound represented by the general formula (1) in which m is 0 is produced by reacting a compound of the following general formula (4) with a compound of the formula (5) and, if necessary, hydrolysis. can do. The reaction is carried out according to the method of (a) above, and an organic solvent such as acetone, methyl ethyl ketone,
The reaction temperature is preferably room temperature to solvent reflux temperature in diethyl ketone or dimethylformamide. It is also preferable to add an inorganic base such as potassium carbonate or sodium carbonate, and to add potassium iodide. [In the formula, B is a carbonyl group or a hydroxymethylene group, E is a hydrogen atom, a hydroxyl group or an acetoxy group, and L is an ethyl group, an acetyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a hydroxycarbonylmethyl group or A lower alkoxycarbonylmethyl group, R ¹ represents a hydrogen atom or a lower alkyl group, and Y represents a halogen atom] [In the formula, A represents a carbonyl group or a hydroxymethylene group, and G represents an ethyl group, an acetyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a hydroxycarbonylmethyl group or a lower alkoxycarbonylmethyl group]

(C) The compound represented by the general formula (1) in which m is 1 or 2 can be produced by oxidizing the compound of the general formula (1a) and, if necessary, hydrolyzing the compound. Typically, an equimolar amount or excess of a mild oxidizing agent such as m-chloroperbenzoic acid or hydrogen peroxide is added to the compound represented by the general formula (1a) in a suitable solvent such as methylene chloride or alcohol. It is produced by reacting with ice-cooling to room temperature. [Wherein A, B, E, G, L and R ¹ are as described above, but when A is a carbonyl group, E is a hydrogen atom and G and L are ethyl groups, B is a hydroxymethylene group. Represent]

(D) In the compound represented by the general formula (1) in which E is a hydroxyl group or an acetoxy group, the compound represented by the general formula (6) is an alkali salt of acetic acid, for example, an inorganic salt such as sodium, potassium or magnesium. , An organic salt such as triethylamine, trimethylbenzylammonium, pyridine and a suitable solvent such as acetic acid, alcohol, acetonitrile,
A compound in which E is an acetoxy group can be produced by reacting in dimethylformamide or the like at room temperature to the boiling point of the solvent. This compound can be hydrolyzed according to a conventional method to induce a compound having E as a hydroxyl group. [In the formula, A and B each independently represent a carbonyl group or a hydroxymethylene group, and G and L each independently represent an ethyl group, an acetyl group, a 1-hydroxyethyl group, 2-
A hydroxyethyl group, a hydroxycarbonylmethyl group or a lower alkoxycarbonylmethyl group, R ¹ represents a hydrogen atom or a lower alkyl group, and X represents a halogen atom]

Some of the compounds represented by the general formula (1) have 1 to 5 asymmetric centers, and optical isomers based on the asymmetric centers exist. Any of these mixtures are included in the present invention.

These optical isomers are produced by using an optically active raw material, and a salt with the optically active substance, for example, a base such as (S)-(-)-1- (1-naphthyl) ethylamine. It can also be produced by forming a diastereomeric salt with the corresponding carboxylic acid derivative or by performing optical resolution by preparative separation using an optically active column.

Further, among the compounds represented by the general formula (1),
If desired, the compound having a carboxyl group can be converted into its salt by a conventional method. Examples of the salt include salts of sodium, potassium, calcium, aluminum and the like.

[0014]

The present invention will now be described with reference to specific examples, but the invention is not limited to these examples.

Example 1 3'-allyl-2 ', 4'-bis (benzyloxy) acetophenone

After dissolving 31 g (0.161 mol) of 3-allyl-2,4-dihydroxyacetophenone in 150 ml of dimethylformamide (DMF), 7 g (0.160 mol) of 55% sodium hydride was added under ice-cooling, and after the foaming subsided. 28 g (0.164 mol) of benzyl bromide was added. After stirring for 15 minutes, add 7.5 g (0.172 mol) of 55% sodium hydride again in the same manner as above, and add benzyl bromide.
An additional 30 g (0.175 mol) was added. Keep the internal temperature at 45-50 ° C,
Stir for 30 minutes. The reaction mixture was poured into ice water and extracted twice with benzene. The benzene layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and benzene was distilled off. The residue was subjected to silica gel column chromatography (benzene) to obtain 25 g of the target fraction as an oil. 42% yield

Example 2 2 ', 4'-bis (benzyloxy) -3'-(2-hydroxypropyl) acetophenone

23 g (72.2 mmol) of mercuric acetate 120
Dissolve in water (ml) and with stirring, tetrahydrofuran (THF)
A solution prepared by dissolving 25 g (67.1 mmol) of the compound of Example 1 in 200 ml of THF was added all at once, and stirring was continued at room temperature for 1 hour. Add 150 ml of THF and add 30
Stirring was continued at ~ 35 ° C for 6 hours and then left for 3 nights. Cool with a freezing agent, add 80 ml of 3N sodium hydroxide with stirring,
50 ml of 0.5 M sodium borohydride 3N sodium hydroxide solution was added dropwise at 5 ° C or lower. Stirring was continued for 30 minutes at the same temperature, and the upper organic layer was separated. The aqueous layer was extracted twice with ether, the organic layers were combined, washed 3 times with water, washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
The residual oily substance was subjected to silica gel column chromatography (chloroform → chloroform: ethyl acetate = 19: 1).
Then, 13 g (49.6%) of the desired product was obtained as an oily substance.

Example 3 2 ', 4'-dihydroxy-3'-(2-hydroxypropyl) acetophenone

8 g of the compound of Example 2 was dissolved in 80 ml of ethanol, 7% palladium carbon was added, and catalytic reduction was carried out at room temperature and atmospheric pressure. When hydrogen absorption was no longer observed, the reaction was stopped, the catalyst was filtered off, and the filtrate was concentrated. Ether was added to the residue to make a uniform solution, and then a small amount of n-hexane was added for crystallization. 3.8 g (88.2 g) of the target white crystal
%)Obtained. mp 112-114 ℃

Example 4 O- [4-acetyl-3-hydroxy-2- (2-hydroxypropyl) phenyl] N, N-dimethylcarbamothioate

4.2 g (20.0 mmol) of the compound of Example 3
Was dissolved in 20 ml of acetone, 2.9 g (21.0 mmol) of potassium carbonate was added, and the mixture was stirred for 10 minutes. 2.8 g (22.7 mmol) of N, N-dimethylthiocarbamoyl chloride was added, and the mixture was stirred at room temperature for 3.5 hours. After leaving it for 2 nights, add water,
Extracted with benzene. The benzene layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography (chloroform), the target product fractions were collected, and crystallized from ether to obtain 4.0 g (67.3%) of white crystals of the target product. mp 126-127 ℃

Example 5 S- [4-acetyl-3-hydroxy-2- (2-hydroxypropyl) phenyl] N, N-dimethylcarbamothioate

While stirring 4.0 g of the compound of Example 4
After heating in an oil bath with an external temperature of 195 ° C for 1 hour, increase the temperature to 195-200 ° C.
I kept it for 1.5 hours. After cooling, it is dissolved in chloroform and purified by silica gel column chromatography (chloroform → chloroform: ethyl acetate = 100: 3) to give 1.1 g.
(28%) of the desired product was obtained as an oil.

Example 6 2'-Hydroxy-3 '-(2-hydroxypropyl)
-4'-mercaptoacetophenone

1.3 g (4.37 mmol) of the compound of Example 5
Was dissolved in 2 ml of ethanol, a solution of 1.5 g of potassium hydroxide in 15 ml of water was added, and the mixture was heated under reflux for 3 hours under a nitrogen stream. After adding ice and washing the aqueous solution with ethyl acetate,
It was acidified with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Dissolve the residue in benzene, evaporate the solvent again,
It was dissolved in ether and crystallized by adding a small amount of n-hexane. 418 mg (42%) of the desired product was obtained. mp74-75 ℃

Example 7 4- [6-acetyl-3- [3-[[4-acetyl-3
-Hydroxy-2- (2-hydroxypropyl) phenyl] thio] propoxy] -2-propylphenoxy] ethyl butyrate

1.1 g (2.56 mmol) of ethyl 4- [6-acetyl-3- (3-bromopropoxy) -2-propylphenoxy] butyrate (compound of Example 11) was dissolved in 4 ml of dimethylformamide to give 0.5 g of potassium carbonate. Then, 485 mg (2.14 mol) of the compound of Example 6 was added, and the mixture was stirred at room temperature for 2 hours. Ice water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Silica gel chromatography of the residual oil (chloroform: ethyl acetate = 100: 3)
The desired product fraction was collected and crystallized from ether. 950 mg (77.1%) of the desired product was obtained as white crystals.
mp 104-105 ℃

Example 8 4- [6-acetyl-3- [3-[[4-acetyl-3
-Hydroxy-2- (2-hydroxypropyl) phenyl] thio] propoxy] -2-propylphenoxy] butyric acid

930 mg (1.62 mmol) of the compound of Example 7 was dissolved in 8 ml of a 50% (v / v) ethanol aqueous solution containing 0.4 g of sodium hydroxide, and the mixture was allowed to stand at room temperature for 1 hour. Ice water was added to the reaction solution, which was acidified with concentrated hydrochloric acid, and then extracted twice with ethyl acetate. After washing the organic layer with water and saturated saline,
It was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was subjected to silica gel column chromatography (chloroform: ethanol = 100: 1 → 100: 2), the target fractions were collected and crystallized from a mixed solvent of acetonitrile / isopropyl ether / n-hexane. Precipitated crystals are collected by filtration, washed with ether, and air-dried to give the desired product (650 mg)
(73.5%) white crystals were obtained. mp 107-110 ℃

[0031]

Example 9 4- (6-acetyl-3-hydroxy-2-propylphenoxy) butyric acid

15 g (40.5 mmol) 4- (6-acetyl-3-benzyloxy-2-propylphenoxy) butyric acid
And palladium carbon (about 7%) 3g ethanol 100ml
The mixture was suspended in, and catalytically reduced with hydrogen at room temperature for 3 hours. The catalyst was filtered and the solvent was distilled off. The residue was recrystallized from acetonitrile to obtain 8.7 g of the desired product. mp 121-123 ° C From the mother liquor, 1.7 g of the desired product was obtained. Total amount 10.4g (yield
91.6%)

Example 10 Ethyl 4- (6-acetyl-3-hydroxy-2-propylphenoxy) butyrate

10.4 g (37.1 mmol) of the compound of Example 9
Was dissolved in 60 ml of ethanol, 0.4 ml of sulfuric acid was added, and the mixture was refluxed for 4 hours. The solvent was evaporated, ice water and ethyl acetate were added to the residue, and the layers were separated. The organic layer was washed successively with cooled aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. Evaporate the solvent,
11 g (yield 96.1%) of the target substance of reddish brown oily substance was obtained.

Example 11 4- [6-acetyl-3- (3-bromopropoxy)-
2-propylphenoxy] ethyl butyrate

Example in which 36 g (178 mmol) of 1,3-dibromopropane and 4.9 g (35.5 mmol) of potassium carbonate were suspended in 60 ml of acetone and dissolved in 25 ml of acetone with stirring.
11 g (35.7 mmol) of the compound of 10 were added. After refluxing for 2 hours, 1 g (7.2 mmol) of potassium carbonate was added,
Reflux was continued for 1 hour. After cooling, the insoluble matter was filtered and the solvent was distilled off. The residue was subjected to silica gel column chromatography (hexane / benzene mixture (1: 1) → benzene and chloroform), and the fractions containing the desired product were combined. The solvent was distilled off to obtain 5.4 g of the desired product as an oily substance. In addition, 9 g of a mixture containing the desired product was obtained. The mixture was purified again by silica gel column chromatography (chloroform) to obtain 6.9 g of the desired product. Total amount 12.3g (yield 80.3
%)

Example 12 2'-acetoxy-3'-allyl-4'-benzyloxyacetophenone

3'-allyl-4'-benzyloxy-
2'-Hydroxyacetophenone (Example 27) 20 g (7
0.8 mmol), 14.5 g (142 mmol) acetic anhydride and 60 ml of pyridine were refluxed for 3 hours. After the solvent was distilled off, it was extracted with chloroform. 2N-hydrochloric acid obtained by cooling the organic layer,
It was washed successively with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixed solution of benzene and hexane to obtain 20 g of the desired product. mp69-70 ° C From the mother liquor, 1.7 g of the desired product was obtained. Total amount 21.7g (yield
94.4%)

Example 13 4'-benzyloxy-2'-hydroxy-3 '-(3
-Hydroxypropyl) acetophenone

15 g (46.2 mmol) of the compound of Example 12 was dissolved in 150 ml of tetrahydrofuran, and 30 ml of borane / tetrahydrofuran solution (organic reaction 13 prepared by the method of page 32) was added dropwise with stirring at 5 to 10 ° C. After continuing the reaction at the same temperature for 10 minutes, water was added dropwise (excessive hydride was decomposed), and then 6 ml of 6N-sodium hydroxide solution was added dropwise. Hydrogen peroxide water (31%) 6ml 0-5 ℃
After the dropping, the stirring was continued for 20 minutes. 2 ml of dilute sodium sulfite solution was added, stirred for 10 minutes, and then poured into 800 ml of ice water. The reaction solution was acidified with hydrochloric acid and extracted twice with ether. The organic layer was washed twice with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (chloroform / ether mixture (9:
1)), and the fractions containing the desired product were combined. The solvent was distilled off, and the residue was recrystallized from benzene-hexane to give 2 '.
5.8 g of -acetoxy-4'-benzyloxy-3 '-(3-hydroxypropyl) acetophenone (yield 36.6
%)Obtained. mp96-97 ° C

5.8 g of this compound was dissolved in 60 ml of ethanol, and 4 ml of 6N sodium hydroxide solution was added. After heating at 50 ° C. for 1 hour, the solvent was distilled off. The residue was dissolved in chloroform, washed successively with cooled dilute hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the desired product as a brown oily substance. This compound was purified without purification
Used as raw material for 14.

Example 14 4'-benzyloxy-2'-hydroxy-3'-
[[3- (3,4,5,6-Tetrahydro-2H-pyran-2-yl) oxy] propyl] acetophenone

6.2 g (20.6 mmol) of the compound of Example 13
Further, 0.3 g of p-toluenesulfonic acid monohydrate was dissolved in 60 ml of methylene chloride, and 3 g (35.7 mmol) of 2,3-dihydropyran was added under stirring with ice cooling, and the reaction was carried out for 1 hour.
The reaction mixture was washed successively with cooled aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (chloroform), and 6.5 g (yield 81.9%) of the desired product was obtained as an oil.

Example 15 2 ', 4'-dihydroxy-3'-[[3- (3,4,
5,6-Tetrahydro-2H-pyran-2-yl) oxy] propyl] acetophenone

6.5 g (16.9 mmol) of the compound of Example 14
And 1 g of palladium on carbon (about 7%) were suspended in 50 ml of ethanol, and the catalytic reduction was carried out under atmospheric pressure with hydrogen under stirring at room temperature to 1.5
I went on time. Furthermore, 1.0 g of a catalyst was added, and the reaction was continued for 2.5 hours under the same conditions. The catalyst was filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform) and then recrystallized from ether to obtain 3.95 g of the desired product (yield 79.4%). mp 110-111 ° C

Example 16 O- [4-acetyl-3-hydroxy-2- (3-hydroxypropyl) phenyl] N, N-dimethylcarbamothioate

3.95 g (13.4 mmol) of the compound of Example 15, 2.04 g (14.8 mmol) of potassium carbonate and N, N
1.8 g (14.6 mmol) of dimethylthiocarbamoyl chloride was suspended in 40 ml of acetone and stirred at room temperature for 2 hours. Furthermore, 1.6 g (11.6 mmol) of potassium carbonate and 0.8 g (6.3 mmol) of the above chloride were added, and the mixture was stirred and refluxed for 1 hour. After cooling, 0.2 ml of water was added and the mixture was stirred for 20 minutes, then the insoluble matter was filtered off. The solvent was distilled off, the residue was dissolved in chloroform, and the solution was washed successively with aqueous sodium hydrogen carbonate, water and saturated brine.
It was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ether mixture (19: 1)) and recrystallized from ethanol to obtain 2.4 g of the desired product (yield 60.1%). mp 126-12
7 ° C

Example 17 O-[[[4-acetyl-3-hydroxy-2- (3,
4,5,6-Tetrahydro-2H-pyran-2-yl)
[Oxy] propyl] phenyl] N, N-dimethylcarbamothioate

2.4 g (8.07 mmol) of the compound of Example 16
And p-toluenesulfonic acid monohydrate (0.24 g) were dissolved in chloroform, and the solvent was distilled off. The residue was dissolved in 30 ml of chloroform and then stirred under ice-cooling with 2,3-dihydropyran.
1.4 g (16.6 mmol) was added and the reaction was carried out for 15 minutes. The reaction solution was washed successively with cooled aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (chloroform), and recrystallized from ether / hexane to give 2.6
g was obtained. mp 82-83 ° C 0.2 g of the desired product was obtained from the mother liquor. Total amount 2.8g (yield 9
0.9%)

Example 18 S- [4-Acetyl-3-hydroxy-2- (3-hydroxypropyl) phenyl] N, N-dimethylcarbamothioate

2.7 g (7.08 mmol) of the compound of Example 17
Was heated and stirred under a nitrogen stream at 190 to 195 ° C. (oil bath temperature) for 3 hours. After cooling, it was dissolved in 20 ml of isopropyl alcohol, 5 ml of water and 2 ml of hydrochloric acid were added, and the mixture was left at room temperature for 30 minutes.
The solvent was distilled off, the residue was dissolved in chloroform, and washed successively with water, aqueous sodium hydrogen carbonate, water and saturated brine. It was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was subjected to silica gel column chromatography (chloroform / ether mixture (9:
After purification in 1)), recrystallize from ether to give the desired product.
1.4 g (yield 66.5%) was obtained. mp87-88 ° C

Example 19 2'-Hydroxy-3 '-(3-hydroxypropyl)
-4'-mercaptoacetophenone

Potassium hydroxide solution (KOH 1.3 g (23.5
(1.4 mmol), water (10.8 ml), and ethanol (1.2 ml) were added with 1.4 g (4.71 mmol) of the compound of Example 18 under a nitrogen stream.
Refluxed for 2.5 hours. It was poured into ice water and the reaction solution aqueous layer was washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid under stirring with ice cooling, and extracted with ethyl acetate. The organic layer was washed 3 times with saturated saline,
It was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ether / hexane to obtain 0.8 g of the desired product. mp6
4.5-66.0 ° C 0.1 g of the desired product was obtained from the mother liquor. Total amount 0.9g (84.5
%)

Example 20 4- [6-acetyl-3- [3-[[4-acetyl-3
-Hydroxy-2- (3-hydroxypropyl) phenyl] thio] propoxy] -2-propylphenoxy] ethyl butyrate

0.9 g (3.98 mmol) of the compound of Example 19
And 1.1 g (7.96 mmol) of potassium carbonate were suspended in 7 ml of dimethylformamide to prepare the compound of Example 11 under a nitrogen stream.
1.7 g (3.98 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Furthermore, 0.34 g (0.80 mmol) of the compound of Example 11 was added, and the reaction was continued for 30 minutes. It was poured into ice water, extracted with ethyl acetate (twice), and washed successively with water and saturated brine (twice). After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (chloroform.
After purification with an ether mixture (9: 1)), ethanol-
Recrystallization from hexane gave 1.95 g of the desired product. mp87−
Further, 0.1 g of the desired product was obtained from the 88 ° C. mother liquor. Total amount 2.05g (Yield 8
9.7%)

Example 21 4- [6-acetyl-3- [3-[[4-acetyl-3
-Hydroxy-2- (3-hydroxypropyl) phenyl] thio] propoxy] -2-propylphenoxy] butyric acid

1.95 g (3.39 mmol) of the compound of Example 20
Is dissolved in 4 ml of ethanol and sodium hydroxide solution (N
0.36 g (9.0 mmol) of aOH and 5 ml of water were added, and the mixture was left at room temperature for 1 hour. Ice water was added, and the reaction solution was washed with ether. Ethyl acetate was added to the aqueous layer, which was cooled with ice and acidified with hydrochloric acid with stirring. After liquid separation, the mixture was extracted again with ethyl acetate, the organic layers were combined, washed twice with saturated brine, and dried over anhydrous sodium sulfate.
The solvent was distilled off, and the residue was recrystallized from acetonitrile to obtain 1.5 g of the desired product. mp 84-87 ° C From the mother liquor, 0.3 g of the desired product was obtained. Total amount 1.8g (yield
97.0%), mp87-89 ° C

Elemental analysis value C H C ₂₉ H ₃₈ O ₈ S Calculated value (%) 63.72 7.01 Measured value (%) 63.59 7.01

Example 22 4- [6-acetyl-3- (3-chloropropoxy)-
2-propylphenoxy] ethyl butyrate

62 g of the compound of Example 10 and 1-bromo-3
-Dissolve 37 g of chloropropane in 200 ml of acetone and add 31 g.
Of potassium carbonate was added, and the mixture was heated under reflux for 1.5 hours. 5 g of 1-bromo-3-chloropropane and 7 g of potassium carbonate were added, and heating under reflux was continued for a total of 22 hours. The insoluble material was filtered off, and the filtrate was concentrated to obtain 82 g (theoretical value: 76.9 g) of the desired product. This was used as it was as a raw material for the next step.

Example 23 Ethyl 4- [3- (3-chloropropoxy) -6- (1-hydroxyethyl) -2-propylphenoxy] butyrate

72 g of the compound of Example 22 was added to 500 ml of methanol.
The resulting mixture was dissolved in water and cooled to -10 ° C, 7 g of sodium borohydride was added, and the mixture was stirred at -10 to -5 ° C for 15 minutes. Then, the mixture was stirred at 0 to 7 ° C for 1 hour, cooled to 0 ° C or lower again, 3.5 g of sodium borohydride was added, and the mixture was further stirred at about 0 ° C for 1.5 hours. After adding 200 g of ice, 10 ml of concentrated hydrochloric acid and 5 ml of acetic acid were added, and methanol was distilled off. The concentrate was extracted twice with ethyl acetate, washed with cold water, cold sodium hydroxide solution, and saturated saline solution (twice) in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off to give 66 g (theoretical value 67.9 g). I got the object. This was used as it was as a raw material for the next step.

Example 24 4- [3- (3-chloropropoxy) -6- (1-hydroxyethyl) -2-propylphenoxy] butyric acid

52 g of the compound of Example 23 was added to 200 ml of ethanol.
A solution of 9 g of sodium hydroxide in 50 ml of water was added, and the mixture was allowed to stand at room temperature for 1 hour, 10 ml of concentrated hydrochloric acid was added, and the solvent was distilled off. Ice water was added to the residue to make a uniform solution, 20 ml of concentrated hydrochloric acid was added, and the mixture was extracted with 300 ml of ethyl acetate. The extract was washed with water and saturated saline (twice) in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 49 g (theoretical value: 48.2 g) of the desired product.

Example 25 (-)-4- [3- (3-chloropropoxy) -6-
(1-Hydroxyethyl) -2-propylphenoxy]
Butyric acid

49 g of the compound of Example 24 was dissolved in 150 ml of ethyl acetate to give (R) -1-naphthylethylamine (23.5 g).
Was added and left in the freezer overnight. The precipitated crystals were filtered and washed with cold ethyl acetate to obtain 9.3 g of crude diastereomeric salt. The crude crystals were dissolved by heating in 40 ml of ethyl acetate and left at room temperature for recrystallization. The precipitated crystals were filtered and washed with ethyl acetate to give 6.2 g of purified diastereomeric salt.
(8.6%) obtained. _{mp 123.5-125 ℃, [α] D} 19 - 4.8
° (c = 3.0, ethanol)

4.0 g of the diastereomeric salt obtained here
Cold water containing 2 ml of concentrated hydrochloric acid and ethyl acetate were added to (7.55 mmol) and the layers were separated, and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with diluted hydrochloric acid, water and saturated brine (twice) in this order, and dried over anhydrous sodium sulfate. A half amount of this solution was taken and the solvent was distilled off to obtain 1.5 g (theoretical value: 1.35 g) of the desired product.

Example 26 (-)-4- [3-[[3- [4-acetyl-3-hydroxy-2- (2-hydroxypropyl) phenyl] thio] propoxy] -6- (1-hydroxyethyl) ) -2
-Propylphenoxy] butyric acid

Optically active carboxylic acid obtained in Example 25
1.5 g (corresponding to 2 g (3.77 mmol) of diastereomeric salt) was dissolved in 20 ml of dimethylformamide, and 1.1 g (4.86 mmol) of the compound of Example 6 and potassium carbonate were dissolved.
1.4 g was added and stirred at room temperature for 3.5 hours. The reaction mixture was poured into ice water, 2 ml of concentrated hydrochloric acid was added, and the mixture was extracted twice with ethyl acetate. The mixture was washed with water and saturated brine (twice) in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified twice by silica gel column chromatography (chloroform / ethanol mixed solution (100: 3)) to obtain 0.6 g (29%) of the desired product as a pale yellow oil. Optical rotation: [α] _D ²¹
−9.4 ° (0.10g, ethanol 10ml, 100mm)

IR (liquid film method): 1713 cm ^-1 (ν _co ketone), 1626 cm ^-1 (ν _co ketone) MS (m / z): 530 (M ⁺ -H ₂ O), 512, 486, 267
223 (100%)

NMR (CDCl ₃ , δ value): 0.97 (3
H, t), 1.29 (3H, d), 1.50 (3H, d), 1.57
(2H, m), around 2.2 (2H × 2, m), 2.6 (3
H, s), about 2.6 (2H × 2, m), 3.00 (2H,
m), 3.21 (2H, t), 3.88 (2H, m), 4.07 (2
H, t), 4.14 (1H, m), 5.14 (1H, q), 6.66
(1H, d), 6.82 (1H, d), 7.24 (1H, d),
7.56 (1H, d), 12.97 (1H, s)

Example 27 3'-allyl-4 '-(benzyloxy) -2'-hydroxyacetophenone

45 g (0.234 mol) of 2,4-dihydroxy-3-allylacetophenone and 43 g of benzyl bromide
(0.251 mol) was dissolved in 300 ml of acetone, 38 g (0.275 mol) of potassium carbonate was added, and the mixture was heated under reflux for 3 hours with stirring. The insoluble matter was collected by filtration, washed with a small amount of acetone, and the solution after concentration was concentrated under reduced pressure. The residue was dissolved in benzene (500 ml), washed with saturated brine and dried over anhydrous sodium sulfate. The benzene layer was concentrated under reduced pressure until crystals began to precipitate, dissolved by heating, and then n-hexane was added to crystallize. 56 g of the desired product was obtained. mp 106-109 ℃ Concentrate the mother liquor and remove from small amount of benzene and n-hexane to 5
g of the desired product was obtained. Total yield 61g (92.3%)

Example 28 4- [6-acetyl-3- (benzyloxy) -2-
(2-Propenyl) phenoxy] ethyl butyrate

20 g (70.8 mmol) of the compound of Example 27 was dissolved in 100 ml of dimethylformamide, 3.1 g (71 mmol) of 55% sodium hydride was added, and the mixture was stirred for 5 minutes. 15.2 g (77.9 mmol) of ethyl γ-bromobutyrate was added and reacted at 50 to 55 ° C for 2 hours and at 55 to 60 ° C for 1 hour. It was poured into 200 ml of ice water and extracted twice with ether. After washing three times with water, wash with cold sodium hydroxide and wash with water 2
The extract was washed once with saturated brine and dried over anhydrous Glauber's salt, and ether was distilled off. The residue was subjected to silica gel chromatography (benzene → benzene: ethyl acetate = 20: 1) to obtain 22 g of the desired product as an oil. Yield 78.3%

Example 29 4- [6-acetyl-2- (2-hydroxypropyl)
Ethyl-3- (benzyloxy) phenoxy] butyrate

A solution of 3.8 g of the compound of Example 28 in 25 ml of tetrahydrofuran was added to 3 g of mercuric acetate in 10 ml.
Was dissolved in water and stirred at room temperature (25 ° C) for 2.5 hours. After cooling to -5 ° C with a freezing agent, adding 15 ml of tetrahydrofuran and adding 10 ml of 3N sodium hydroxide,
8 ml of 0.5M sodium borohydride / 3N sodium hydroxide solution was added dropwise, and the mixture was stirred at the same temperature for 25 minutes. The organic layer was separated, and the aqueous layer was extracted with ether. The organic layer and the ether layer were combined, washed with water 5 times, dried over anhydrous Glauber's salt, and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform → 2% acetic acid / chloroform → 5% acetic acid / chloroform) to obtain 2.4 g (57.9%) of the desired product as an oil.

Example 30 Ethyl 4- [6-acetyl-3-hydroxy-2- (2-hydroxypropyl) phenoxy] butyrate

2.2 g (5.3 mmol) of the compound of Example 29
Dissolve in 50 ml of ethanol, 800 mg of 7% palladium on carbon
Was added and catalytically reduced at room temperature and atmospheric pressure for 1.5 hours. The catalyst was filtered off and ethanol was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / chloroform), and 1.3 g (75.5
%)Obtained.

Example 31 4- [6-acetyl-3- [3-[(4-acetyl-3
-Hydroxy-2-propylphenyl) thio] propoxy] -2- (2-hydroxypropyl) phenoxy] ethyl butyrate

1.3 g (4.0 mmol) of the compound of Example 30 and 1.4 g (4.2 mmol) of the compound of Example 35 were mixed with acetone 13
1.3 g (9.4 mmol) of potassium carbonate was added to the solution, and the mixture was heated to reflux with stirring for 3 hours. Insoluble matter is filtered off,
After washing with acetone, acetone was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained crude oil of the target substance was subjected to silica gel column chromatography (chloroform → chloroform: ethyl acetate = 20: 1) to obtain 2.4 g of the purified target substance.

Example 32 4- [6-acetyl-3- [3-[(4-acetyl-3
-Hydroxy-2-propylphenyl) thio] propoxy] -2- (2-hydroxypropyl) phenoxy] butyric acid

2.4 g of the compound of Example 31 was added to 5 ml of ethanol.
And add 6 ml of 2N aqueous sodium hydroxide solution to 60
Warmed to 0 ° C for 10 minutes. The mixture was diluted with ice water, washed with ether, acidified by adding concentrated hydrochloric acid, and extracted with ethyl acetate.
The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate, and the solvent was distilled off. Silica gel column chromatography of the residue (chloroform: ethanol = 100: 1)
After purification by means of recrystallization from acetonitrile / n-hexane, 474 mg of the desired crystal was obtained (total yield from Example 32: 2
1.6%) was obtained. mp41-50 ° C

Elemental analysis value C H C ₂₉ H ₃₈ O ₈ S Calculated value (%) 63.72 7.01 Actual value (%) 63.44 7.14

Example 33 4- [6-acetyl-3-benzyloxy-2- (3-
Hydroxypropyl) phenoxy] butyric acid

6 g (15.1 mmol) of the compound of Example 28 was dissolved in 60 ml of tetrahydrofuran, and 10 ml of a borane-tetrahydrofuran solution (organic reaction 13 prepared by the method of page 32) was added dropwise at 0 to 5 ° C. with stirring. After stirring at the same temperature for 30 minutes, water was added dropwise, and then 2.4 ml of 3N sodium hydroxide solution was added dropwise. Hydrogen peroxide water (31%) 3.
3 ml was added dropwise at the same temperature, and the reaction was continued for 30 minutes. It was poured into ice water, a dilute sodium sulfite solution was added, and the mixture was extracted with ether. The ether layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (chloroform) to obtain 1.8 g of the oily target product (yield 28.7%).

Example 34 Ethyl 4- [6-acetyl-3-hydroxy-2- (3-hydroxypropyl) phenoxy] butyrate

2.4 g (5.79 mmol) of the compound of Example 33
And palladium carbon (about 7%) 0.5 g ethanol 40 ml
Suspended in water and stirred at room temperature under atmospheric pressure for catalytic reduction to 2
I went on time. The catalyst was filtered off and the solvent was distilled off. 1.8 g (yield 95.8%) of the oily target substance was obtained.

Example 35 4 '-(3-Bromopropoxy) -2'-hydroxy-
3'-propyl acetophenone

4'-dimethylaminocarbonylthio-
2'-Hydroxy-3'-propylacetophenone 20g
(0.071 mol) potassium hydroxide solution (KOH 20 g (0.357
(Mol) dissolved in 170 ml of water-ethanol mixed solution (9: 1))
And was stirred and refluxed under a nitrogen stream for 3.5 hours. After cooling
The mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
The solvent was distilled off, and 2-hydroxy-4-as a brown oily substance.
Obtained mercapto-3-propylacetophenone. Next, 2-hydroxy-4-mercapto-3-propyl was prepared by suspending 71.6 g (0.355 mol) of 1,3-dibromopropane and 9.8 g (0.071 mol) of potassium carbonate in 113 ml of acetone and dissolving the mixture in 50 ml of acetone under a nitrogen stream. Acetophenone was added, and the mixture was stirred and refluxed for 2 hours. After cooling, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane → benzene / hexane mixed solution (1: 1)) and then recrystallized from toluene-hexane to obtain 15 g of the desired product (yield 63.7%). mp46-47
℃

Example 36 4- [6-acetyl-3- [3-[(4-acetyl-3
-Hydroxy-2-propylphenyl) thio] propoxy] -2- (3-hydroxypropyl) phenoxy] ethyl butyrate

1.84 g (5.55 mmol) of the compound of Example 35, 1.80 g (5.55 mmol) of the compound of Example 34 and 1.50 g (10.8 mmol) of potassium carbonate were suspended and stirred under reflux for 6 hours. After cooling, the insoluble material was removed by filtration and concentrated. The concentrate was dissolved in ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (chloroform / ether mixture (19: 1)), and 2.7 g (yield 8
4.7%) obtained.

Example 37 4- [6-acetyl-3- [3-[(4-acetyl-3
-Hydroxy-2-propylphenyl) thio] propoxy] -2- (3-hydroxypropyl) phenoxy] butyric acid

2.7 g (4.70 mmol) of the compound of Example 36
Was dissolved in 5 ml of ethanol and sodium hydroxide solution (N
0.5 g (12.5 mmol) of aOH and 6 ml of water were added all at once and heated at 60 ° C. for 10 minutes. It was poured into ice water, washed with ether and separated. Ethyl acetate was added to the aqueous layer, and the mixture was acidified by adding 4 ml of hydrochloric acid under stirring with ice cooling. After liquid separation, the organic layer was washed twice with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and acetonitrile was added to the residue for crystallization to obtain 2.0 g (yield 77.9%) of crude crystals of the desired product.

The crude crystals were subjected to silica gel column chromatography (chloroform-ethanol mixed solution (49: 1)).
The fractions containing the desired product were combined. The solvent was distilled off, and acetonitrile was added to the residue for crystallization. The obtained crude crystals of the desired product were again subjected to silica gel column chromatography (chloroform / ethanol mixed solution (ethanol content changed to 0.5 to 1.5%)), and fractionated parts containing the desired product were combined. The solvent was distilled off, and acetonitrile was added to the residue for crystallization to obtain 0.49 g of the desired product. mp 101 ~
103 ° C

Elemental analysis value C H C ₂₉ H ₃₈ O ₈ S Calculated value (%) 63.72 7.01 Measured value (%) 63.55 7.06

Example 38 3- [3-Acetyl-2,6-bis (benzyloxy)
Phenyl] -2-propanone

16 g (32.0 mmol) of the compound of Example 3 was dissolved in 250 ml of acetone, and a solution prepared from 3.2 g (32.0 mmol) of chromic anhydride, 9.2 ml of water and 2.7 ml of concentrated sulfuric acid was added dropwise with stirring at 0 ° C. or lower. did. After continuing the reaction at the same temperature for 1 hour, a small amount of isopropanol was added, and the mixture was stirred for 10 minutes and poured into 1.3 liters of ice water. The mixture was extracted 3 times with ether, washed with a sodium sulfite solution and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (benzene → benzene / chloroform mixed solution → chloroform / ethyl acetate mixed solution) to obtain 9.3 g (58.4
%)Obtained. This oily substance could be crystallized with a mixed solution of benzene and hexane. mp57 ~ 58 ℃

Example 39 3- (3-Acetyl-2,6-dihydrophenyl) -2
-Propanon

9 g (23.2 mmol) of the compound of Example 38 was dissolved in 50 ml of ethanol, and palladium activated carbon (about 7%) was added.
2 g was added, and hydrogen catalytic reduction was performed at room temperature for 4 hours. After removing the catalyst by filtration, the filtrate was concentrated, ether was added to the residue, and the precipitated crystals were filtered. Target product 2.9g (mp 168-169
C) was obtained. The filtrate was concentrated to obtain 1.3 g of the desired product in the same manner. Total amount 4.2g (87.1%)

Example 40 O- [4-acetyl-3-hydroxy-2- (2-oxopropyl) phenyl] N, N-dimethylcarbothioate

4.2 g (20.2 mmol) of the compound of Example 39
And 2.6 g (21.0 mmol) of N, N-dimethylthiocarbamoyl chloride (hereinafter referred to as chloride) in 50 ml of acetone.
2.8 g (21.0 mmol) of potassium carbonate was added, and the mixture was refluxed for 2 hours. 0.5 g (4.05 mmol) of chloride and 0.5 g (3.62 mmol) of potassium carbonate were added, and after refluxing for 2 hours, the same amounts of chloride and potassium carbonate were further added and refluxing for 1 hour. When hot, the insoluble material was removed by filtration, the filtrate was concentrated, and the residue was dissolved in chloroform.
It was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (chloroform) and crystallized with a mixed solution of benzene and hexane to obtain 4.3 g (72.2%) of the desired product. mp 152 ~
154 ° C

Example 41 S- [4-acetyl-3-hydroxy-2- (2-oxopropyl) phenyl] N, N-dimethylcarbamothioate

4.3 g (14.6 mmol) of the compound of example 40
Was stirred under a nitrogen stream at 195 to 200 ° C (oil bath temperature) for 45 minutes. After cooling, it was purified by silica gel column chromatography (chloroform) and crystallized using ether. The crystals were collected by filtration to obtain 3.4 g (79.1%) of the desired product. m.
p. 100 to 101 ° C

Example 42 5-Acetyl-2,4-dihydroxy-2-methyl-1
-Cheerdan

3.4 g (11.5 mmol) of the compound of Example 41
Is dissolved in 2.9 ml of ethanol and 3.2 g of potassium hydroxide
A solution of (57.0 mmol) in 27 ml of water was added, and the mixture was refluxed for 2 hours. After cooling, it was poured into ice water and washed with ethyl acetate. To the aqueous layer was added concentrated hydrochloric acid 5.4 ml, extracted with ethyl acetate,
It was washed with water and saturated saline in this order. After drying over anhydrous sodium sulfate, the solvent was evaporated, and the residue was recrystallized from ethyl acetate. The crystals were collected by filtration to obtain 2.1 g of the desired product. The filtrate was concentrated and 0.2 g of the desired product was obtained in the same manner. Total amount 2.3g (89.1
%) Mp 158-160 ℃

Example 43 (-)-4- [3-[[3- [4-acetyl-3-hydroxy-2- (2-oxopropyl) phenyl] thio]
Propoxy] -6- (1-hydroxyethyl) -2-propylphenoxy] butyric acid

1.17 g of the compound of Example 25 (corresponding to 1.7 g (3.21 mmol) of diastereomeric salt) was dissolved in 11 ml of dimethylformamide, and 1.1 g of the compound of Example 42 (4.
90 mmol) and potassium carbonate 1.5 g (10.9 mmol)
Was added and the mixture was stirred at 40 to 45 ° C for 5 hours under a nitrogen stream. The reaction mixture was poured into ice water, 2 ml of concentrated hydrochloric acid was added, and the mixture was extracted twice with ethyl acetate. The mixture was washed with water (4 times) and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform / ethanol mixture (200: 3)) to obtain 1.3 g (74.2%) of the desired product as a brown oil. Furthermore, silica gel column chromatography (chloroform / ethyl acetate /
Purified with acetic acid mixture (18: 4: 1)), 0.6g (23.2%)
The desired product of was obtained as a light brown oil. Optical rotation: [α]
_D ²¹ -10.8 ° (0.10g, ethanol, 10ml, 100mm)

IR (NaCl liquid film method): 1713 cm ^-1 (ν
_co carboxylic acid), 1628 cm ^-1 (ν _co ketone) MS (m / z): 528 (M ⁺ 100%), 510 (M ⁺ -H)
₂ O), 265, 223

NMR (CDCl ₃ , δ value): 0.97 (3
H, t), 1.49 (3H, d), 1.56 ((2H, m),
Around 2.2 (2H × 2, m), 2.22 (3H, s), 2.59
(3H, s), about 2.6 (2H × 2, m), 3.19 (2H,
t), about 3.9 (2H, m), 3.92 (2H, s), 4.04
(2H, t), 5.13 (1H, q), 6.64 (1H, d),
6.85 (1H, d), 7.23 (1H, d), 7.60 (1H,
d), 12.80 (1H, s)

Example 44 4- [6-acetyl-3-[[3- [4-acetyl-3
-Hydroxy-2- (2-oxopropyl) phenyl]
Thio] propoxy] -2-propylphenoxy] ethyl butyrate

1.1 g (4.90 mmol) of the compound of example 42
Was dissolved in 12 ml of dimethylformamide, and 2.6 g (6.76 mmol) of the compound of Example 22 and 1.35 g of potassium carbonate were dissolved.
(9.77 mmol) was added, and the mixture was stirred under a nitrogen stream at 44 to 50 ° C for 1.5 hr. The reaction mixture was poured into 150 ml of ice water and extracted 3 times with ethyl acetate. The mixture was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform / ether mixture (19: 1)) to obtain 2.6 g (92.6%) of the desired product as an oil.

Example 45 4- [6-acetyl-3-[[3- [4-acetyl-3
-Hydroxy-2- (2-oxopropyl) phenyl]
Thio] propoxy] -2-propylphenoxy] butyric acid

2.5 g of the compound of Example 44 (4.37 mmol)
Was dissolved in 10 ml of ethanol, and a solution prepared by dissolving 0.55 g (13.8 mmol) of sodium hydroxide in 10 ml of water was added under ice-cooling. The cooling was stopped and the mixture was left at room temperature for 1 hour. The mixture was poured into ice water, washed with ether, and the cooled aqueous layer was acidified with hydrochloric acid and then extracted with ethyl acetate (twice). The mixture was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated.
The residue was recrystallized twice from acetonitrile and then subjected to silica gel column chromatography (chloroform / ethanol (20: 1) mixture) to concentrate the fraction containing the target substance.
The residue was recrystallized from acetonitrile. The target crystal
1.9 g (79.9%) was obtained. mp 107-108 ℃

IR (KBr tablet method): 1721 cm ^-1 (ν _co
Carboxylic acid), 1705 and 1628cm ^-1 (ν _co ketone) MS (m / z): 544 (M +), 526, 458, 265 (100%)

NMR (CDCl ₃ , δ value): 0.98 (3
H, t), 1.56 (2H, m), around 2.2 (2H x 2,
m), 2.23 (3H, s), 2.58 (3H, s), 2.59 (3
H, s), about 2.6 (2H × 2, m), 3.20 (2H,
t), 3.82 (2H, t), 3.93 (2H, s), 4.10 (2
H, t), 6.64 (1H, d), 6.84 (1H, d), 7.53
(1H, d), 7.60 (1H, d), 12.81 (1H, s)

Example 46 4- [6-acetyl-3- [3-[(4-acetyl-3
-Hydroxy-2-propylphenyl) thio] propoxy] -2-propylphenoxy] methyl butyrate

4- [6-acetyl-3- [3- (4-acetyl-3-hydroxy-2-propylphenylthio)]
34 g of propoxy] -2-propylphenoxy] butyric acid was dissolved in 120 ml of methanol, 1 ml of concentrated sulfuric acid was added, and the mixture was heated under reflux for 1 hour. The solvent was distilled off, the residue was dissolved in 300 ml of ether and washed with water, and then twice with 50 ml of 5% sodium hydroxide solution. After further washing with saturated saline, it was dried with anhydrous Glauber's salt. The solvent was distilled off, and the residual oily substance was converted to isopropyl ether.
It was dissolved in 100 ml and cooled. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 29.5 g of the desired product with mp54-6 ° C.

Example 47 4- [3- [3-[(4-acetyl-3-hydroxy-
2-Propylphenyl) thio] propoxy] -6- (2
-Chloro-1-oxoethyl) -2-propylphenoxy] methyl butyrate

16.3 g (30 mmol) of the compound of example 46 and benzyltrimethylammonium iododichloride (BTMA-ICl ₂ ) [synthesis, 545 (1988)] 2
0.8 g (60 mmol) was dissolved in 75 ml of tetrahydrofuran and left at room temperature for 24 hours. Add 300 ml of ether and add 5
It was washed with 300 ml of a% sodium hydrogen sulfite solution. The extract was washed twice with saturated saline and dried over anhydrous Glauber's salt. The oily substance obtained by distilling off the solvent was subjected to silica gel column chromatography (methylene chloride). 13.8 g of the desired product was obtained as a pale yellow oil.

Example 48 4- [3- [3-[(4-acetyl-3-hydroxy-
2-Propylphenyl) thio] propoxy] -6- (2
-Acetoxy-1-oxoethyl) -2-propylphenoxy] methyl butyrate

13.8 g (23.8 mmol) of the compound of Example 47
And potassium acetate 9.2 g (93.7 mmol) in glacial acetic acid 21 ml.
In addition, the mixture was heated under reflux for 4 hours and 10 minutes with stirring. After cooling, the reaction mixture was dissolved in 200 ml of chloroform and washed with water, saturated sodium hydrogen carbonate solution, and then saturated saline. The reddish brown oily substance obtained by drying over anhydrous sodium sulfate and distilling off the solvent was purified by column chromatography (chloroform / methanol mixture (100: 1)) to obtain 8.7 g of the desired product.

Example 49 4- [3- [3-[(4-acetyl-3-hydroxy-
2-Propylphenyl) thio] propoxy] -6- (2
-Hydroxy-1-oxoethyl) -2-propylphenoxy] butyric acid

8.7 g of the compound of Example 48 was added to 48 ml of ethanol.
Dissolved in. 58 ml of a 2% sodium hydroxide solution was added dropwise over about 35 minutes while heating and refluxing under a nitrogen stream. After completion of the dropping, the mixture was heated under reflux for 25 minutes. It was cooled, diluted with ice water, and acidified by adding 3 ml of concentrated hydrochloric acid. It was extracted with 200 ml of chloroform, washed with saturated saline, and dried with anhydrous sodium sulfate. The oily substance obtained by distilling off the solvent is subjected to silica gel column chromatography (chloroform / methanol mixture (100: 2)).
Purified in. Fractions containing the desired product were combined, the solvent was distilled off, and the residue was crystallized using 30 ml of acetonitrile. Further, recrystallization from acetonitrile twice gave about 1.5 g of the desired product. Preparative chromatography of this crystal (system: LC-3000, column: Inertsil Prep OD
S, column temperature: 30 ° C, moving bed: tetrahydrofuran
A water mixture (65:35 v / v), flow rate: 10 ml / min) was performed, the target product fractions were combined, and the solvent was concentrated under reduced pressure at room temperature. The insoluble oily matter was extracted with chloroform and dried over anhydrous sodium sulfate. The oily substance obtained by distilling off the solvent was recrystallized from 15 ml of acetonitrile. The obtained crystals were dried over phosphorus pentoxide under reduced pressure in a vacuum pump to obtain 1.18 g of the desired product as pale yellowish white crystals with an mp of 105-107 ° C.

Elemental analysis value C H C ₂₉ H ₃₈ O ₈ S Calculated value (%) 63.72 7.01 Measured value (%) 63.71 7.12

Example 50 4- [3- [3- (4-acetyl-3-hydroxy-2
-Propylphenylsulfinyl) propoxy] -6-
(1-Hydroxyethyl) -2-propylphenoxy]
Methyl butyrate

4- [3- [3- (4-acetyl-3-hydroxy-2-propylphenylthio) propoxy]-
1.43 g of methyl 6- (1-hydroxyethyl) -2-propylphenoxy] butyrate is dissolved in 20 ml of methylene chloride, and m-chloroperbenzoic acid (equal moles) is added little by little with stirring in an ice-water bath. After stirring at room temperature for 1 hour, the organic layer was washed successively with cold dilute aqueous potassium carbonate solution (twice), water and brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (ethyl acetate) to obtain 1.00 g of the desired product (yield 68.0%) as a pale yellow oil.

Example 51 4- [3- [3- (4-acetyl-3-hydroxy-2
-Propylphenylsulfinyl) propoxy] -6-
(1-Hydroxyethyl) -2-propylphenoxy]
Butyric acid

0.97 g of the compound of Example 50 was added to 10 ml of ethanol.
Dissolve in water and stir in an ice-water bath, then add 0.17 g of sodium hydroxide in water 5
The ml solution was added dropwise. After stirring at room temperature for 1.5 hours, ice water and concentrated hydrochloric acid were added to the reaction solution to make it acidic, and the mixture was extracted with ethyl acetate. The organic layer is washed successively with water and brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure,
The residue was purified by column chromatography (methylene chloride: ethanol = 9: 1) and further by reverse layer medium pressure chromatography (20 mm I.D. × 300 mm, C-18, acetonitrile: water = 4: 1). 0.36 g of target product (yield 38.1
%) As a pale yellow oil.

NMR (CDCl ₃ , δ value): 0.86 to 0.96
(6H, m), 1.46 (3H, d, J = 6Hz), ~ 1.5
(2H, m), 1.52 to 1.58 (1H, m), 1.60 to 1.70
(1H, m), 2.13 (2H, m), ~ 2.1 (1H, m)
m), 2.3-2.4 (1H, m), 2.4-2.5 (1H,
m), ~ 2.5 (2H, m), 2.60 (2H, t, J = 7H
z), 2.68 (3H, s), 2.74 to 2.82 (1H, m), 2.8
7 ~ 2.93 (1H, m), 3.06 ~ 3.14 (1H, m), 3.79
~ 3.89 (2H, m), 3.98 ~ 4.05 (1H, m), 4.05 ~
4.14 (1H, m), 5.11 (1H, q, J = 6Hz), 6.61
(1H, d, J = 9Hz), 7.21 (1H, d, J = 9H)
z), 7.51 (1H, d, J = 9Hz), 7.84 (1H, d,
J = 9Hz), 12.75 (1H, s)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07C 323/62 7419-4H

Claims (1)

[Claims] 1. The general formula (1) [In the formula, A and B are each independently a carbonyl group or a hydroxymethylene group, E is a hydrogen atom, a hydroxyl group or an acetoxy group, G and L are each independently an ethyl group,
An acetyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a hydroxycarbonylmethyl group or a lower alkoxycarbonylmethyl group, m represents 0, 1 or 2, and R ¹ represents a hydrogen atom or a lower alkyl group, When A is a carbonyl group, E is a hydrogen atom, and G and L are ethyl groups, m represents 1 or 2 and B represents a hydroxymethylene group] or a phenoxyalkylcarboxylic acid derivative or an alkali salt thereof.