JPS62215548A - Production of 3-(4-fluoropheoxy)propionic acid - Google Patents

Abstract

PURPOSE:To obtain the titled substance useful as an intermediate for drugs at high reaction rate and in high yield, by reacting p-fluorophenol with an acrylic acid ester in the presence of a basic catalyst and then hydrolyzing the reaction product in the presence of an alkali or acid catalyst. CONSTITUTION:p-Fluorophenol is reacted with an acrylic acid ester in a molar ratio of 1:0.8-15 in the presence of 0.02-0.08mol basic catalyst (e.g. metallic Na or caustic potash based on 1mol p-fluorophenol at 50-140 deg.C to give a 3-(4- fluorophenoxy)propionic acid ester, which is hydrolyzed in water or a mixed solvent of water and an organic solvent miscible with water in the presence of an alkali catalyst (e.g. alkali hydroxide or alkali carbonate) or an acid catalyst (e.g. sulfuric acid or hydrochloric acid) to give the titled substance. EFFECT:Acrylonitrile having strong toxicity is not used.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to pharmaceutical intermediates. More specifically, 3-(4-fluorophenoxy) useful as a pharmaceutical intermediate
This invention relates to a method for producing propionic acid.

Prior art 5-(4-fluorophenoxy)propionic acid is used as an aldose reductase inhibitor in diabetes mM&WIfro
+-? Th 9 m, + −, J −−
17-, '+M + % is a useful substance as an intermediate.

5-(4-fluorophenoxy)propionic acid can be prepared according to the prior art, for example, r, Am, Chem, Bo
A, 80q a' (19sq) is known as a method of condensing p-fluorophenol and β-chloropropionic acid in the coexistence of a strong alkali.
13774 involves reacting (addition reaction) p-fluorophenol with acrylonitrile in the presence of an alkali catalyst.
A method is described in which the resulting addition product is hydrolyzed in water in the presence of an acid catalyst to obtain the desired 3-(4-fluorophenoxy)propionic acid.

Problems to be Solved by the Present Invention Among the known methods for producing 3-(4-fluorophenoxy)propionic acid described above, in the method using β-proprobionic acid, acrylic acid dehydrochlorinated from β-chloropropionic acid is Side products tend to occur and the reaction yield is extremely low at about 17%.

Furthermore, the method described in JP-A No. 60-13774 has an industrial problem in that it produces 11n, ^■ru, and 3-(4-fluorophenoxy)
Propionitrile has many disadvantages in industrial production, such as its low affinity for water and extremely slow hydrolysis reaction in water using an acid catalyst.

Means to Solve the Problem The present inventors have made earnest efforts to solve the above-mentioned drawbacks in the method for producing 3-(4-2-fluorophenoxy)propionic acid, and as a result, have arrived at the present invention. That is, the present invention is characterized in that p-fluorophenol is reacted with an acrylic ester in the presence of a basic catalyst to obtain a 3-(a-fluorophenoxy)propionic ester, which is then hydrolyzed in the presence of an alkali or acid catalyst. 5-
A method for producing (4-fluorophenoxy)propionic acid is provided.

Process 8 (addition reaction) of reacting an acrylic acid ester with t-fluorophenol of the present invention and a process (hydrolysis) of hydrolyzing the 3-(4-fluorophenoxy)propionic acid ester obtained by the addition reaction. This will be explained in detail separately.

Addition reaction: p-fluorophenol in addition reaction is usually p-70
It is easily obtained by diazolysis of loaniline. As the acrylic ester, lower alkyl esters of acrylic acid are used, specific examples of which include methyl acrylate and ethyl acrylate.

Examples include isopropyl acrylate and butyl acrylate, among which methyl acrylate and acrylic ether are preferably used.

The amount used is based on p-fluorophenol.

The amount is 0.2 to 50 times by mole, preferably 0.8 to 15 times by mole. In addition, basic catalysts include metal alkalis such as metal alkali, sodium methoxide, and sodium alkoxide such as sodium ethoxide;
Sodium phenoxide; Quaternary ammonium hydroxide; Caustic potash.

More caustic alkali than caustic soda; potassium carbonate,
Alkali carbonates such as sodium carbonate may be used.

Note that it is convenient to prepare the quaternary ammonium hydroxide in a reaction system by adding sodium hydroxide to the quaternary ammonium salt.

The amount of the basic catalyst to be used is from 0.01 times mole to 0.2 times mole, preferably 0.02 times mole, relative to p-fluorophenol.
It is used from twice the mole to 0.08 times the mole. Furthermore, the solvent was added to Tetris, benzene, toluene, and xylene.

Hydrocarbons such as naphthalene, hexane, hepetane, octane, and nonane, halogenated hydrocarbons such as chlorobenzene and chlorotoluene, and ethyl acetate.

Esters such as butyl acetate, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetophenone, and dimethylformamide.

Aprotic polar solvents such as dimethyl acetamide and dimethyl sulfoxide can be used. Note that when quaternary ammonium hydroxide is used as a catalyst, water or a mixture of water and the organic solvent can be used as the solvent. There is no particular limit to the amount of solvent used, but if too much is used, the reaction rate will decrease.
5 ν+ 11) Mei 14 →Make Z total /
4ji Fake capital Sakut 1 Rumor ψ It may be done.

The actual operation in the addition reaction is to prepare p-fluorophenol, acrylic ester, a basic catalyst, and a solvent as necessary, and to prepare the mixture at 40°C to 180°C, preferably from 50°C to 14°C.
Stirring may be performed at 0°C.

In order to suppress a rapid reaction, a method in which P-fluorophenol is mixed with a basic catalyst at a predetermined temperature and an acrylic acid ester diluted with a solvent is dropped into the mixture;
Conversely, a basic catalyst and an acrylic ester are mixed at a predetermined temperature, and p dissolved in the mixture or dissolved in a solvent is added.
- A method such as dropping fluorophenol dropwise is adopted as appropriate.

Check the reaction time using a gas chromatograph, etc.
It is convenient to determine this, but it is usually sufficient to carry out the reaction for 2 to 20 hours.

In addition, p-fluorophenol and acrylic ester I
Since an equilibrium state is formed with d3-(4-fluorophenoxy)propionic acid ester, it is convenient to use a large amount of acrylic ester within the range described above and recover the acrylic ester after the reaction is completed. be.

When the addition reaction is completed in the manner described above, the remaining p
- Fluorophenol is extracted and removed with aqueous alkaline solution, and then excess acrylic ester and solvent are removed by distillation or the like to obtain 5-(4-fluorophenoxy)furopionic acid ester.

Hydrolysis: The 3-(4-fluorophenoxy)propionic acid ester obtained as described above is hydrolyzed in water or a mixed solvent of water and an organic solvent miscible with water in the presence of an alkali or acid catalyst. do.

Examples of the alkali catalyst include alkali hydroxides such as caustic potash and caustic soda, or charcoal powder.

An alkali carbonate salt such as potassium carbonate is used, and the amount used is preferably 3 moles per mole of 3-(4-fluorophenoxy)propionic acid ester. Hydrolysis is carried out in an aqueous medium or a mixed solvent of methanol, ethanol, etc. and water under such conditions that the treatment is usually carried out at a temperature of 0 to 50°C for 50 minutes to 5 hours.

Note that a phase transfer catalyst as described later may be added to the hydrolysis reaction solution as necessary. After hydrolysis, the reaction solution is neutralized and the target product is taken out as crystals.

Also, examples of acid catalysts include hydrochloric acid, sulfuric acid, and hydrobromic acid.

Mineral acids such as phosphoric acid are used, and among these, sulfuric acid and hydrochloric acid are preferably used. The amount used is 0.3 to 20 times, preferably 1 to 10 times, by mole relative to 3-(4-fluorophenoxy)propionic acid ester. The ore concentration in the reaction solution for hydrolysis is 5 to 60% by weight, preferably 8 to 4% by weight.
It is 0% by weight.

In the hydrolysis, it is also possible to use a phase transfer catalyst such as tetraalkylammonium hydroxide or benzyltrimethylammonium hydroxide in addition to an acid catalyst.

The reaction is usually carried out in water at a reflux temperature of 80 to 110°C, but it can also be carried out in a mixed solvent of water and alcohols such as methanol or ethanol, which are miscible with water, or at even higher temperatures using an autoclave. The time required for the hydrolysis reaction varies depending on the reaction conditions and is conveniently determined by monitoring the reaction situation with a gas chromatograph or liquid chromatograph. When the reaction is carried out under reflux using 15 times the amount of fluorophenoxy) fropionic acid, the reaction is completed in about 8 hours.After the hydrolysis reaction is completed, it is cooled and the precipitated crystals are separated in a furnace or after cooling.

Extract with an organic solvent that is immiscible with water, such as benzene, toluene, chlorobenzene, ethyl acetate, dichloromethane, perchloromethane, etc.

The obtained 3-(4-fluorophenoxy)propionic acid has sufficient purity for synthesizing "Turvinyl", but if desired, it can be purified by recrystallization or the like.

The method of the present invention does not use acrylonitrile, which is highly toxic and difficult to handle.

5. The hydrolysis rate of 3-(4-fluorophenoxy)propionic acid ester is extremely fast compared to that of 3-(4-fluorophenoquine)propionic acid ester;
-(4-Fluorophenoxy)propionic acid ester is characterized by an extremely high hydrolysis yield, and is a manufacturing method of extremely great industrial value.

Example The present invention will be explained in more detail by way of examples.

Example 1 P-fluorophenol 551 was charged into a four-hole flask and the temperature was raised to 90°C. At this temperature, 0.099% of sodium methoxide was added with stirring.

Methyl acrylate 612 was added dropwise for 5 hours.

After the dropwise addition was completed, the mixture was further stirred at 90 to 95°C for 5 hours.

(Addition reaction) The reaction mixture was then cooled and 100 g of toluene was added.

Here is 100L of 20g of caustic noda aqueous solution? was added to remove unreacted p-fluorophenol. Toluene was distilled off from the organic layer under reduced pressure to obtain 3-(4-fluorophenoxy)propio/methyl acid. (6o, 3f) This product showed a boiling point of 257°C.

3-(4-fluorophenoxy)propio/methyl acid 6
0.5f was added to 25% sulfuric acid aqueous solution 6001 and refluxed for 8 hours. (Hydrolysis) The precipitated crystals were separated by F and dried to obtain 51.22 ml of 5-(4-fluorophenoxy)propionic acid. (Melting point 84-6℃
Yield 91.4% based on 3-(4-fluorophenoxy)propionic acid methyl ester) (GC purity 98.0
H) Furthermore, p-fluorophenol of 1&92 was recovered by neutralizing the alkaline extract of unreacted p-fluorophenol in the addition reaction and extracting with toluene. (p
- Conversion rate of fluorophenol: 64.3%) Example 2 20 p of p-fluorophenol was added to a flask.

Ethyl acrylate 120p, sodium ethyl)0.
Pour in 57r and raise the temperature to 80℃ and keep at this temperature.

The mixture was stirred for 20 hours (addition reaction). Next, residual ethyl acrylate was distilled off using a 4-tally evaporator, and then p-fluorophenol was extracted and removed with alkali in the same manner as in Example 1, yielding 30.71% of ethyl 3-(4-fluorophenoxy)propionate. was obtained (boiling point 266°C). To this was added 35 of a 20% aqueous hydrochloric acid solution, and the mixture was heated under reflux for 10 hours (hydrolysis). The mixture was then cooled, and 702 ml of methylene chloride was added to extract the target product, 3-(4-fluorophenoxy)propionic acid. When methylene chloride was distilled off from the extract under reduced pressure, 24.99 of 3-(4-fluorophenoxy)cropionic acid was obtained. The yield from p-fluorophenol was 75.8%.

(Melting point: 83-85°C, GC purity: 98°C) Example 5 Trit was used as a basic catalyst in the addition reaction of Example 2.
p on B (benzyltrimethylammonium hydroxide) in the same manner as in Example 2 except that 3d was used.
- A reaction between fluorophenol and ethyl acrylate was carried out. After the reaction was completed, the remaining ethyl acrylate was distilled off using a rotary evaporator, and p was added in the same manner as in Example 1.
-Fluoropheno" t Removal L 3 Ethyl (4-fluoro)phenoxypropionate was obtained. To this, 25
-H25o4 aqueous solution 4002 was added and refluxed for 12 hours.

Then, the same treatment as in Example 2 was carried out to obtain 3 with a yield of 73.5%.
-(4-fluorophenoxy)propionic acid was obtained.

The melting point was 82-84°C. (GC purity 97%) Example 4 As a basic catalyst, force I71. of purity 46%. Except that Q1 was ground and used, p-fluorophenol and methyl acrylate were reacted in the same manner as in Example 1 to obtain an adduct, methyl 3-(4-fluorophenoxy)propionate. To this was added 600 d of a 25% H2SO4 aqueous solution and the mixture was hydrolyzed to give 5-(4-fluorophenoxy)propionic acid with a total yield of 60.2%. The melting point is 8
The temperature was 2-B4°C.

Example 5 11.5v of methyl 3-(4-fluorophenoxy)propionate obtained by the same reaction as in Example 1 and 322% of the 15% sodium chloride water bath solution were placed in a +GOge Erlenmeyer flask and heated to room temperature (25°C). ) and stirred strongly using a magnetic stirrer. 1 hour later.

The pH of the solution was adjusted to 1 to 2 by adding concentrated salt. The precipitated white crystals were separated in a furnace and dried to obtain 7.56f of 5-(4-fluorophenoxy)propion'#Jtt-. The yield of the hydrolysis reaction was 70.7%. Seen here 95-
The melting point of (4-2 fluorophenoxy)propionic acid is 8
The temperature was 1-84°C.

Effects of the invention High purity 3-(4-fluorophenoxy)propionic acid can be produced in a short reaction time without using acrylonitrile, which is difficult to handle industrially due to its strong toxicity. became.

Claims (1)

[Claims] 1. Characterized by reacting p-fluorophenol with an acrylic ester in the presence of a basic catalyst to obtain a 3-(4-fluorophenoxy)propionic ester, which is then hydrolyzed in the presence of an alkali or acid catalyst. 5-(
A method for producing 4-fluorophenoxy)propionic acid.