JPS5822116B2 - Method for producing urocanic acid ethyl ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing urocanic acid ethyl ester.

Urocanic acid has been recognized to be useful as a UV absorber derived from living organisms, and is already used in eye drops and cosmetics, but urocanic acid itself is poorly soluble or insoluble in common organic solvents. For this reason, its uses are limited.

Therefore, in recent years, urocanic acid esters, which have good solubility, have begun to be used instead of urocanic acid. Among them, its ethyl ester, urocanic acid ethyl ester, is less toxic and less irritating to the skin, so it is used as a UV absorber in cosmetics. It is widely used as an anti-degradation agent for polymers and an anti-fading agent for dyes.

Although urocanic acid ethyl ester is thus a useful compound, its production is generally difficult, and there are few reports regarding its production method.

Conventionally, esters of urocanic acid have generally been produced by the reaction of an alkali metal salt of urocanic acid with an alkyl halide (for example, Japanese Patent Publication No. 50-28500), or the reaction of urocanic acid with an alcohol in the presence of an acid catalyst. (For example, Japanese Patent Publication No. 51-20515), but the yield is low because both reactions tend to involve side reactions.
The coloring of the product is also significant.

Moreover, the raw material urocanic acid itself is extremely expensive, and this method is not industrially advantageous.

By the way, 4(5)-imidazole aldehyde is a raw material for the production of urocanic acid, but if it becomes possible to directly produce ethyl urocanate without going through urocanic acid, it will be possible to produce it industrially. We believe that this is extremely beneficial, and as a result of intensive research, we found that by reacting 4(5) imidazole aldehyde and triethylphosphonoacetate in the presence of the above-mentioned specific compound such as sodium hydride, it is possible to easily and It was discovered that urocanic acid ethyl ester could be obtained in good yield, and the present invention was completed.

That is, an object of the present invention is to provide an industrially easy method for producing urocanic acid ethyl ester with good yield.

The present invention combines 4(5) imidazole aldehyde and triethylphosphonoacetate with sodium hydride, potassium hydride, lithium hydride, potassium amide, lithium amide, sodium amide, potassium tert-butoxide,
This is a method for producing urocanic acid ethyl ester, characterized in that the reaction is carried out in the presence of at least one compound selected from the group consisting of sodium tert-butoxide and lithium tert-butoxide.

The amount of triethylphosphonoacetate used in the present invention is 1 mole of 4(5)-imidazole aldehyde.
．． 0 to 2.0 mol is suitable, and 1.2 to 1.8 mol is more preferred.

If it is less than 1.0 mol, sufficient yield cannot be obtained, and
If the amount is more than 2.0 mol, side reactions will become significant and the yield will drop significantly.

On the other hand, the amount of sodium hydride, potassium hydride, lithium hydride, potassium amide, lithium amide, sodium amide, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide alone or in combination is 4(5)- 1.0 to 1.2 of the sum of the moles of each of imidazole aldehyde and triethylphosphonoacetate
The range of twice the molar amount is good, more preferably 1.05 to 1.
It is 15 times the molar amount.

That is, if it is less than 1.0 times the mole, the yield will be low;
If the amount exceeds twice the molar amount, the product becomes extremely colored and difficult to purify, and at the same time, the yield also decreases.

Incidentally, if it is not used, urocanic acid ethyl ester will not be produced.

In the method of the present invention, the reaction proceeds even in the absence of a solvent (diluent), but the yield of the target compound tends to be relatively low.
In order to obtain a higher yield, it is preferable to use an aprotic solvent that is non-reactive, has a high boiling point, and is highly polar.

For example, dimethyl sulfoxide, N, N-dimethylformamide, pyridine, α-rubicoline β-picoline,
Particularly preferred examples include γ-picoline, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, dioxane, etc., but the present invention is not limited to these.

Of course, the exemplified solvents may be used alone or in appropriate combinations.

In addition, the reaction temperature is preferably 20 to 160°C and 70 to 140°C.
A range of C is preferred.

When the temperature is lower than 20°C, the reaction rate is slow, and when it is higher than 160°C, a decrease in yield and coloration of the product are observed.

The reaction of the present invention is carried out using a reflux condenser, a drying tube, a heating device, a stirrer, a thermometer, etc., in which the required amounts of 4(5)-imidazole aldehyde, triethylphosphonoacetate, and the above-mentioned aprotic solvent are usually mixed. After placing in a reaction vessel, add sodium hydride, potassium hydride, lithium hydride, potassium amide, lithium amide, sodium amide, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide while cooling and stirring in a nitrogen stream. It is obtained by adding either singly or in combination in small amounts to the above mixture, and after the addition, the contents are kept at 20 to 160°C and reacted for usually 4 to 48 hours.

The urocanic acid ethyl ester produced by the reaction is
It is usually isolated from the reaction mixture by the following method.

After the reaction, the reaction mixture is cooled, and methanol is added to the reaction mixture while cooling to perform excess hydrogenation.

When hydrogen has stopped generating, add concentrated hydrochloric acid to the contents to make them weakly acidic, add chloroform and shake, and separate and remove the chloroform layer.

After repeating the extraction with chloroform several times, add saturated carbon dioxide to the aqueous layer.l) Add rum solution until no carbon dioxide gas is generated, then add a large amount of ethanol, and remove the precipitate one by one.

The P solution is once desolventized and evaporated to dryness under reduced pressure, and ethanol is added again to extract the ethanol-soluble matter from the residue.

A small amount of activated carbon is added to the obtained ethanol solution to decolorize it, and the solution is filtered, and the r solution is concentrated under reduced pressure to precipitate urocanic acid ethyl ester as white needle-like or scale-like crystals.

As described above, the reaction and post-treatment operations are simple, and the purity of the obtained urocanic acid ethyl ester is extremely high, and the yield is also good at about 50 to 75%.

In summary, the present invention converts urocanic acid ethyl ester, which has conventionally been produced using urocanic acid itself as a raw material, into the previously unknown 4(5)-imidazole aldehyde and triethylphosphonoacetate without going through urocanic acid. Due to a kind of Uitzteitsch reaction with
A novel method for directly producing urocanic acid ethyl ester simply and easily with high yield from 4(5)-imidazole aldehyde (which can be industrially produced at relatively low cost), which is a precursor of urocanic acid. The industrial significance is extremely significant.

Examples will be described below.

In addition, % shown in the examples means mol % based on 4(5)-imidazole aldehyde in terms of yield, and in other cases simply means % by weight.

Example 1 96 g (1,0 mol) of 4(5)-imidazole aldehyde, 314 g (1,4 mol) of triethylphosphonoacetate, and 10,100 O of dehydrated dimethyl sulfoxide were placed in a 3000 ml bottle equipped with a reflux condenser, a drying tube, and a stirrer. 61.2 g (255 moles) of sodium hydride are added gradually with cooling and stirring at room temperature and bubbling dry nitrogen gas until the contents are uniformly dissolved in a bottom flask.

After the addition, the temperature is raised to 100°C and the reaction is carried out at that temperature for 5 hours.

After the reaction, add 100 TLl of methanol when cold, and after the generation of hydrogen gas has subsided, add 380 g of 35% hydrochloric acid.
Add.

Add 500 ml of chloroform, shake thoroughly, and separate and remove the chloroform layer.

The same operation was repeated twice using 200 ml of chloroform each time, and the aqueous layer was collected.

A saturated aqueous solution of thorium carbonate is added to the aqueous layer until the generation of carbon dioxide gas is no longer observed, then 10,100 O ethanol is added, and the precipitate is removed by filtration.

After the filtrate is heated under reduced pressure to evaporate to dryness, the ethanol-soluble matter in the residue is extracted three times with 100 ml of ethanol each time while hot.

The obtained ethanol solution was decolorized using 10 g of activated carbon.
Filter and concentrate the filtrate under reduced pressure.

The precipitated crystals were collected by filtration, washed quickly with cold water, and then
Dry under reduced pressure at ℃ for 2 hours to obtain white ethyl urocanate 11.
3g was obtained.

Yield 71%. The product obtained here was confirmed to be urocanic acid ethyl ester from the physical property values and spectroscopic data shown below.

Melting point = 89-91℃, ultraviolet absorption maximum (methanol solution): 28 & 5 nm, infrared absorption spectrum (KB r
): 1705cIIL (c-0) nuclear magnetic resonance spectrum (CD (1?3): δ129 (t, 3H methyl) δ4.22 (q2H methylene) δ6.41 (d
, IH, olefin) δ 7.32 (s IH imidazole ring) δ 7.60 (d, IH, olefin) δ 7.74 (s IH imidazole ring) Example 2 In a reactor similar to Example 1, 4 (5) - 96 g (1.0 mol) of imidazole aldehyde, 291.5 g (1.3 mol) of triethylphosphonoacetate, and 800 g of N1N-dimethylformamide were added, and then, while cooling, 96 g of l-IJiumamide was added under a nitrogen atmosphere. 5g (2,4
5 mol) and reacted at 120°C for 5 hours.

After the reaction was completed, post-treatment was carried out in the same manner as in Example 1.

124.6 g of urocanic acid ethyl ester was obtained.

Yield 75%. The product obtained here was also analyzed in the same manner as in Example 1, and was confirmed to be urocanic acid ethyl ester.

Example 3 In a reactor similar to Example 1, 96 g (1.0 mol) of 4(5)-imidazole aldehyde, 336 g (1.5 mol) of triethylphosphonoacetate, and 2000 m of pyridine were added.
After adding 1, 303 g (2.7 mol) of potassium tert-butoxide was added under a nitrogen atmosphere while cooling, and the mixture was heated to reflux temperature (
The reaction is carried out at a temperature of about 118° C. for 10 hours.

After the reaction, most of the pyridine was distilled off under reduced pressure, and the same post-treatment as in Example 1 was carried out to obtain 116.0 g of urocanic acid ethyl ester.

Yield 70%.

The material obtained here was also analyzed in the same manner as in Example 1.

It was confirmed that it was urocanic acid ethyl ester.

Example 4 Example 1 except that the molar ratio of 4(5)-imidazole aldehyde and triethylphosphonoacetate was varied.
The reaction was carried out in the same manner as above, and the yield of urocanic acid ethyl ester was investigated.

The results are shown in Table 1.

Here, the amount of sodium hydride used was 1.05 times the sum of the moles of 4(5)-imidazole aldehyde and triethylphosphonoacetate.

Furthermore, in Table 1 A, triethylphosphonoacetate B means 4(5)-imidazole aldehyde.

Table 1 A/B (molar ratio) Yield (%) 0.8 42 1.0 53 1.2 68 1.5 74 1.8 61 2.0 50 2.2 27 As is clear from Table 1 On the other hand, if the molar ratio is smaller than 1.0, a satisfactory yield cannot be obtained, and if the molar ratio is larger than 20, the yield tends to decrease significantly.

Therefore, the range of 1.0 to 2.0 is further reduced to 1.2 to 1.8.
The range is more preferable.

Example 5 Solu-IJ relative to the total number of moles of each of 4(5)-imidazole aldehyde and triethylphosphonoacetate
Example 2 except that the ratio of moles of umamide was changed.
The reaction was carried out in the same manner as above, and the yield of urocanic acid ethyl ester was determined.

The results are shown in Table 2.

In Table 2, A means triethylphosphonoacetate and B means 4(5)-imidazole aldehyde.

Table 2 Sodium amide/(A+B) Yield (%) (molar ratio) 0.90 49 1.00 64 1.05 75 1.10 73 1.15 68 1.20 59 1.30 46 As above , when the amount of the test compound (reaction accelerator) such as sodium amide is less than 1.00 times the total number of moles of 4(5)-imidazole aldehyde and triethylphosphonoacetate, the yield is low again 1
．． When the amount was more than 20 times the molar amount, the yield decreased and at the same time coloring became noticeable.

Therefore, the molar ratio is preferably in the range of 1.00 to 1.20.
A range of 1.05 to 1.15 is most preferred.

Example 6 A reaction was carried out according to Example 3 using the above solvent other than pyridine, and the yield of urocanic acid ethyl ester was investigated.

The results are shown in Table 3. However, in this case, the reaction is 140
It was carried out at ℃.

Table 3 Solvent Yield (%) Nil 50 Dimethyl sulfoxide 72 γ-picoline 68 Diethylene glycol diethyl 71 Ether dioxane 7 ON, N-dimethylformamide 73 Diethylene glycol dimethyl 71 Ether α-picoline 70 β-picoline 71 Phenyl cellosolve
0 xylene
0.5 triamylamine
3 Aniline 0 As is clear from the results in Table 3, in this reaction,
Although the various types of solvents mentioned above are effective, solvents that easily release protons, hydrocarbons, and aliphatic amines inhibit this reaction, making it almost impossible to obtain urocanic acid ethyl ester.

Example 7 The reaction was carried out in the same manner as in Example 2, except that the reaction temperature and time were changed, and the results of examining the influence of the reaction temperature were shown in the fourth section.
Shown in the table.

Table 4 Reaction temperature ('C) Time Yield (%) 0
150D 1710
5D 2910 10
D 4220 48D
6350 24H70 707H68 1005H71 1405H76 160 (under pressure) 5H60 180 (under pressure) 5H48 (Note) D double H: As shown above, the reaction rate is slow below 20°C, so it takes a long time to complete the reaction. Moreover, when the temperature was higher than 160°C, a decrease in yield was observed, and the coloring of the product was also severe.

Therefore, the reaction temperature is preferably 7 to 160°C.
The temperature is 0 to 140°C.

Example 8 The same procedure as in Example 1 was carried out except that 2.55 moles of each of potassium hydride and lithium hydride (same mole as sodium hydride) were used instead of sodium hydride.

As a result, the yield of urocanic acid ethyl ester was 70% for potassium hydride and 70% for lithium hydride.
It was 2%.

Example 9 2.45 mol each of potassium amide and lithium amide (same mol as sodium amide) in place of sodium amide
The same procedure as in Example 2 was carried out except for the use.

As a result, the yield of urocanic acid ethyl ester was 73.5% in the case of potassium amide and 72% in the case of lithium amide.

Example 10 The same procedure as in Example 3 was carried out except that 2.7 moles of sodium tert-butoxide and lithium tert-butoxide (same mole as potassium butoxide) were used in place of potassium tert-butoxide.

As a result, the yield of urocanic acid ethyl ester was 69% for sodium tert-butoxide and 67% for lithium tert-butoxide.

Claims (1)

[Claims] 1 4(5)-imidazole aldehyde and triethylphosphonoacetate are combined into sodium hydride, potassium hydride, lithium hydride, potassium amide, lithium amide, sodium amide, sodium tert-butoxide, lithium tert-butoxide, A method for producing urocanic acid ethyl ester, which comprises reacting in the presence of at least one compound selected from the group consisting of tert-butoxide and potassium tert-butoxide. 2. The production method according to claim 1, wherein the reaction is carried out in an aprotic solvent. 3 The aprotic solution is dimethyl sulfoxide, N,
N-dimethylformamide, pyridine, α-picoline,
The manufacturing method according to claim 1, wherein β-picoline, γ-picoline, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, dioxane, or a combination thereof. 4. The manufacturing method according to claim 1, wherein triethylphosphonoacetate is used in a ratio of 1.0 to 2.0 mol per 1 mol of 4(5)-imidazole aldehyde. 5 At least one compound selected from the group consisting of sodium hydride, sodium amide, potassium hydride, lithium hydride, potassium amide, lithium amide, potassium tert-butoxide, sodium tert-butoxide, and lithium tert-butoxide, The manufacturing method according to claim 1, wherein the amount is 1.0 to 1.2 times the sum of the number of moles of (5)-imidazole aldehyde and the number of moles of □trimethylphosphonoacetate. 6. The manufacturing method according to claim 1, wherein the reaction is carried out within the range of 20 to 160°C. 7. The manufacturing method according to claim 1, wherein the reaction is carried out within the range of 70 to 140°C.