JPH022871B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel benzophenone derivatives and their use as ultraviolet absorbers, more specifically, 2
This invention relates to a new benzophenone derivative having a hydroxyl group at the position or 2,2' position and a glyceryl ether group or polyglyceryl ether group at the 4-position or the 4,4' position, and its application as a water-soluble ultraviolet absorber. be. Normally, sunburn is an acute dermatitis that occurs when sunlight, especially ultraviolet rays, acts on the skin beyond its physiological tolerance range, and its manifestations are known as erythema (sunburn) and darkening (suntan). . In general, the intensity and subsequent course of manifestation vary depending on the intensity and amount of ultraviolet rays that the skin receives, but first, edema due to hyperemia of capillaries in the skin and other swelling;
Erythema (sunburn) with watery skin appears. After a few days, the inflammation subsides, the erythema disappears, and melanin pigment is deposited within the skin, turning it into a tan. Ultraviolet rays have a wavelength of 280 nm.
Short wavelength ultraviolet (UV-C) below, 280~320n
m medium wavelength ultraviolet region (UV-B), 320-400nm
Although it is classified as long-wavelength ultraviolet rays (UV-A), it is usually absorbed and scattered by the ozone layer, the atmosphere, etc.
Ultraviolet rays below m do not reach the earth's surface, so
Ultraviolet light between 290 and 400 nm (UV-B and UV-A)
Of these, 290 are biologically important.
Ultraviolet light (UV-B) with a wavelength of ~320 nm is mainly associated with acute erythematous effects (sunburn) and is called erythematous UV light, and ultraviolet light (UV-A) with a wavelength of 320-400 nm
UV rays are called suntan UV rays because they promote tanning. Therefore, as an ultraviolet absorber, it is essential to have a filtering effect for ultraviolet rays of at least 290 to 320 nm.
It is also required to absorb 400nm ultraviolet light. As is well known, benzophenone compounds have excellent ultraviolet absorption ability, such as 2,4-dihydroxybenzophenone (common name benzoresorcinol) 2,
A large number of derivatives have been synthesized, including one typified by 2',4,4'-tetrahydroxybenzophenone (trade name: Uvinal D50). Many of these attractants have common UV absorption regions of 280-290 nm (UV-B) and 330-290 nm (UV-B).
It has maximum absorption at 350nm (UV-A), and this property can be used as a light stabilizer for plastics, textiles, etc., and also in the cosmetics field to prevent skin irritation caused by sunlight and sunlight. It is added to various cosmetics for the purpose of preventing burns and photostabilizing ingredients such as pigments and fragrances. However, many of these derivatives are originally fat-soluble, and the purpose of derivatization has been to make them more fat-soluble.Water-soluble derivatives, which are an important element for use in cosmetics, , 2-
Hydroxy-4-methoxybenzophenone-5-
Except for anionic derivatives typified by sulfonate (commonly known as sulisobenzone), there were none. Furthermore, these anionic derivatives are considered to have an effect on the skin, so it is difficult to say that they are necessarily safe. An important object of the present invention is to obtain a safe ultraviolet absorber that is water-soluble and has little effect on the skin by bonding a glyceryl ether group or a polyglyceryl ether group to benzophenone. The present invention is based on the general formula (1) (In the formula, R ₁ and R ₂ represent hydrogen or a hydroxyl group, and at least one is a hydroxyl group. Also, R ₃ and R ₄ represent hydrogen or a hydroxyl group.

Represents [formula], at least one

[Formula], where n represents the number of moles added, and one of R ₃ or R ₄ is

When [Formula], n≧2, both R ₃ and R ₄ are

In the case of [Formula], n≧1, and in either case, the total number of moles added is n≦10. )
The present invention relates to a novel benzophenone derivative represented by and its use as a water-soluble ultraviolet absorber. Here, the characteristic point of the present invention is how to achieve water solubility without impairing the ultraviolet absorbing ability of the substance prior to glyceryl ether derivatization. For example, in 2,2',4,4'-tetrahydroxybenzophenone (common name Uvinal D50),
The hydroxyl group at the 2,2' position is closely related to the absorption maximum at 330-350 nm (UV-A) due to interaction with the carbonyl group, and the hydroxyl group at the 4,4' position is closely related to the absorption maximum at 280-350 nm (UV-A).
It is related to the absorption maximum at 290 nm (UV-B). By derivatizing the hydroxyl group at the 2,2′ position, 330-350 nm (UV-A)
The absorption maximum at 280-290 nm (UV
- A short wavelength shift (blue shift) to the absorption maximum in B). Therefore, the important points to achieve this purpose are:
Maintaining the 2,2'-position hydroxyl group in a free state, 4,
The aim is to make it water-soluble by derivatizing the hydroxyl group at the 4' position. In general formula (1), one of R ₃ or R ₄

When substituting with [Formula], n ≧ 2 makes it water-soluble, and both R ₃ and R ₄ are

When substituting with [Formula], it becomes water-soluble when n ≧ 1, but when n = 1, two stereoisomers (racemic and meso) exist, and one (low melting point) is water-soluble. Become. However, as the number of added moles n increases, the molar extinction coefficient (ε) does not change much, but the absorbance A per unit weight decreases. Therefore, considering practical aspects, n≦10 is preferable.
If ≦4, it is optimal. The benzophenone derivative of the present invention is R ₃ or
monosubstituted R ₄ and disubstituted R ₃ and R ₄ ;
In either case, it is a pale yellow to yellow-orange semi-solid to liquid substance, with 280 to 290 nm (UV-B) and 320 nm
It exhibits light absorption characteristics with maximum absorption at ~330 nm (UV-A). This property not only has a perfect filtering effect on ultraviolet rays in the erythema region, but also shows a considerable filtering effect on ultraviolet rays in the melanizing region, making it extremely useful for sunscreen applications. These benzophenone derivatives are compounded in the form of cosmetics, milky lotions, creams, foundations, white powders, ointments, etc., and can be particularly advantageously used in hydrogen products, and are used to stabilize pigments and fragrances, sunscreens, etc. . In addition, the blending concentration at this time is generally about 0.01 to 10% based on the base, but the optimal concentration can be determined depending on the type of base, whether or not it is used in combination with other UV absorbers/cutting agents, and the purpose of use. It is practical to choose. The benzophenone derivative according to the present invention has R ₁ , R ₂ ,
A method that utilizes the addition reaction of raw benzophenone having a hydroxyl group or each of R ₃ and R ₄ with glycidol, or synthesis of benzophenone glycidyl ether using raw benzophenone and epichlorohydrin, and further hydrolysis or addition reaction with glycerin, etc. The most common method is to use this, but other methods are also possible. It is best to use an appropriate method depending on the required number of moles to be added. Examples of synthesis of the compounds of the present invention are shown below. Synthesis Example 1 (Synthesis of 2-hydroxybenzophenone-4-polyglyceryl ether by addition reaction of glycidol) In a 500 ml three-necked flask equipped with a stirring bar and a cooling tube, 21.4 g of 2,4-dihydroxybenzophenone was added to 100 ml of toluene. (1.1 mol) of sodium methoxide (Na0.3 g/MeOH10 ml) was added as a catalyst.
The mixture was heated and stirred on an oil bath at 120-125°C. A mixture of 22.2 g (0.3 mol) of glycidol dissolved in 50 ml of toluene was slowly added dropwise to this via a dropping funnel. The reaction solution, which was initially in a dispersed state due to heating and stirring at 120 to 125°C, gradually dissolved as the reaction progressed. After 12 hours, after confirming the decrease of the raw material benzophenone by TLC, the reaction solution was cooled and separated into a toluene layer and an oil layer. After removing the toluene layer by decantation, 200 ml of chloroform and 200 ml of water were added to perform extraction. The chloroform layer contains toluene, trace amounts of raw materials, mono-adducts, and branched di-adducts, and the aqueous layer contains more than true-chain di-adducts and tri-adducts. Remove the water layer,
Water was removed by drying under reduced pressure to obtain a viscous liquid. Since this contained more than linear di-adducts and tri-adducts, various adducts were fractionated using a silica gel column using chloroform-methanol as an eluent. The linear di-adduct is semi-solid, and the tri-adduct and above are all pale yellow liquids. Total yield of the water-soluble di-adduct was 24 g (yield 54%). Yield of water-soluble diadduct: 15 g (yield: 35%). Optical properties and elemental analysis of Γ2-hydroxybenzophenone-4-diglyceryl ether Ultraviolet absorption λmax (water) 292 nm, 325 nm (see Figure 1) Infrared absorption (see Figure 2) 3370 cm ^-1 O-H Stretching vibration 2940cm ^-1 and 2880cm ^-1 C-H stretching vibration 1625cm ^-1 C=O stretching vibration 1260cm ^-1 = C-O-C antisymmetrical stretching vibration 1115cm ^-1 and 1030cm ^-1 C-O stretching vibration 700cm ^-1 Benzene nucleus out-of-plane bending vibrational elemental analysis C H Experimental value 61.89 6.43 Theoretical value 62.98 6.08 Synthesis example 2 (Synthesis of 2,2'-dihydroxybenzophenone-4-diglyceryl ether via glycidyl ether) Stirrer, Cooler, thermometer, dropping funnel and _N2
2,2',4-trihydroxybenzophenone 23 in a 500ml 3-necked flask equipped with a gas inlet tube.
g (0.1mol) epichlorohydrin 9.5g (0.1mol)
I put it in. The inside of the flask was replaced with nitrogen through N ₂ gas and heated to 60-65° C. on a water bath while stirring. 5.7g of sodium methylate from the dropping funnel
A solution of (0.1 mol) dissolved in 100 ml of methanol was dropped over a period of 2 to 3 hours. (Crystals of common salt began to precipitate about 10 minutes after the dropwise addition was started.) After the dropwise addition was completed, the reaction was continued at the same temperature for an additional hour. After cooling, the contents were suction filtered, thoroughly washed with water, and then dried. Further recrystallization from 50 ml of benzene gave 18 g of 2,2'-dihydroxybenzophenone-4-glycidyl ether as pale yellow needle crystals with a mp of 103°C. 300ml of moisture-proofed 14.3g (0.05mol) of the crystals obtained
46g (0.5mol) of glycerin in an Erlenmeyer flask
was added and dissolved. sodium hydride
0.1g was added and stirred at 100℃ for 4 hours. The resulting mixture was converted into chloroform/methanol without treatment.
Perform silica gel chromatography at 5/1 (v/v),
The solvent of the eluate was distilled off to give pale yellow semi-solid 2,
13.0 g of 2'-dihydroxybenzophenone-4-diglyceryl ether was obtained. Optical properties and elemental analysis of Γ2,2'-dihydroxybenzophenone-4-diglyceryl ether Ultraviolet absorption λmax (water) 290nm 330nm (see Figure 3) Infrared absorption (see Figure 4) 3370cm ^-1 O- H stretching vibration 2950cm ^-1 and 2900cm ^-1 C-H stretching vibration 1620cm ^-1 C=O stretching vibration 1255cm ^-1 = C-O-C antisymmetrical stretching vibration 1120cm ^-1 and 1040cm ^-1 C-O stretching vibration 780cm ^{- 1} Benzene nucleus out-of-plane bending vibration elemental analysis C H Experimental value 60.01 5.99 Theoretical value 60.32 5.82 Synthesis example 3 (Synthesis of 2-hydroxybenzophenone-4,4'-bisglyceryl ether via glycidyl ether) Stirrer, Cooler, thermometer, dropping funnel and _N2
2,4,4'-trihydroxybenzophenone 23 in a 500ml 3-necked flask equipped with a gas inlet tube.
g (0.1mol) epichlorohydrin 18.5g
(0.2mol) was added. Pass _N2 gas through the flask and replace with nitrogen while stirring on a water bath for 60 to 65 minutes.
heated to ℃. A solution of 11.4 g (0.2 mol) of sodium methylate dissolved in 100 ml of methanol was added dropwise from the dropping funnel over 2 to 3 hours. (10 minutes after starting dripping)
After about a minute, salt crystals began to precipitate. ) After the completion of the dropwise addition, the reaction was continued at the same temperature for an additional hour. After cooling,
The contents were suction filtered, thoroughly washed with water, and then dried. Further recrystallization from 50 ml of benzene gave 19 g of 2-hydroxybenzophenone-4,4'-bisglycidyl ether as pale yellow needle crystals. Obtained crystals 17.1g (0.05mol), sodium acetate 41
gPour 100ml of water into a 500ml Erlenmeyer flask equipped with a condenser and reflux gently for 3 hours. The resulting mixture is neutralized with hydrochloric acid, water is distilled off, it is dissolved in isopropyl alcohol, and the precipitated common salt is filtered off. The solvent was completely distilled off under reduced pressure, silica gel column chromatography was performed using chloroform/methanol (5/1 v/v) as the eluent solvent, and the eluate was distilled off to give 2-hydroxybenzophenone-4, 4′−
13.2 g of bisglyceryl ether was obtained as a pale yellow oil. Optical properties and elemental analysis of Γ2-hydroxybenzophenone-4,4'-bisglyceryl ether Ultraviolet absorption λmax (water) 288 nm 326 nm (see Figure 5) Infrared absorption (see Figure 6) 3380 cm ^-1 O- H stretching vibration 2950cm ^-1 and 2880cm ^-1 C-H stretching vibration 1640cm ^-1 C=O stretching vibration 1255cm ^-1 = C-O-C antisymmetrical stretching vibration 1120cm ^-1 and 1040cm ^-1 C-O stretching vibration 700cm ^{- 1} Benzene nucleus out-of-plane bending vibrational elemental analysis C H Experimental value 59.45 6.26 Theoretical value 60.32 5.82 Synthesis example 4 (Synthesis of 2,2'-dihydroxybenzophenone-4,4'-bispolyglyceryl ether by addition reaction of glycidol) In a 500 ml three-necked flask equipped with a stirring bar and condenser, add 24.6 g (0.1 mol) of 2,2',4,4'-tetrahydroxybenzophenone to 100 ml of toluene.
Pour in the mixed solution in which is dispersed, add 1 ml of sodium methoxide (0.3 g of Na/10 ml of MeOH),
The mixture was heated and stirred on an oil bath at 120-125°C. A mixture of 29.6 g (0.4 mol) of glycidol dissolved in 50 ml of toluene was slowly added dropwise to this via a dropping funnel.
By heating and stirring at 120 to 125° C., the reaction solution, which was initially in a dispersed state, dissolved as the reaction progressed. 12hr
After confirming the reduction of the raw material benzophenone by TLC, the reaction solution is cooled and separated into a toluene layer and an oil layer. After removing the toluene layer by decantation, the oil layer was dried under reduced pressure. This oily substance contains trace amounts of raw materials, monoadducts,
Since it contains various adducts such as di-adducts, a silica gel column was developed using chloroform-methanol as an eluent to fractionate the various adducts. Of these, 2,2'-dihydroxybenzophenone-4,4'-bisglyceryl ether or higher is water-soluble. However, since 2-2'-dihydroxybenzophenone-4,4'-bisglyceryl ether is symmetrical, there are two types of diastereomers: lacelle and meso, and one has mp.143-145. ℃
crystals, the other is in a semi-solid state, and the latter is water-soluble. All of the tri-adducts and above were yellow to yellow-orange sticky liquids or liquids. Total yield of water-soluble di-adducts and above was 27 g (yield 50%). Water-soluble di-adduct (2,2'-dihydroxybenzophenone-
Yield 13g of 4,4'-bisglyceryl ether)
(yield 24%). Γ2,2'-dihydroxybenzophenone-4,
Optical properties and elemental analysis of 4'-bisglyceryl ether Ultraviolet absorption λmax (water) 286 nm, 332 nm (see Figure 7) Infrared absorption (see Figure 8) 3350 cm ^-1 O-H stretching vibration 2930 cm ^-1 and 2870cm ^-1 C-H stretching vibration 1610cm ^-1 C=O stretching vibration 1245cm ^-1 = C-O-C antisymmetric stretching vibration 1120cm ^-1 and 1030cm ^-1 C-O stretching vibration 770cm ^-1 Benzene nucleus out-of-plane bending Vibration elemental analysis C H Experimental value 55.23 6.25 Theoretical value 57.87 5.58 Next, in order to confirm the safety of the new compound of the present invention, an animal test (Angora rabbit 5
Table 1 shows the results of human patch tests (total of 50 men and women). The test method is as follows. [A] Animal test a. Primary skin irritation test: A sample (5% aqueous solution) was administered transdermally to the back of a hair-removed Angora rabbit once a day for 4 consecutive days, and visually observed 1 hour later. b Eye mucosal irritation test: 0.05ml of sample (5% aqueous solution) was instilled into the right eye of an Angora rabbit, and 1, 4,
After 24 hours, changes such as edema and hyperemia were observed over time. [B] Human body patch test Drop 0.05ml of a 5% sample aqueous solution onto a lint cloth.
This was pasted on the back of the person using a patch test adhesive, removed after 24 hours, and replaced with a new one.48
After a period of time, the reaction state of the skin was observed.

[Table] +: Reaction -: No reaction As described above, the ultraviolet absorber of the present invention has almost no safety problems and is expected to have an effective sunscreen effect. The table shows a comparison of solubility between the new benzophenone derivative, which is thought to have a low possibility of water solubility, and the known raw material benzophenone in the present invention.

【table】

[Table] As shown in the table, the water solubility of the new compounds of the present invention is greatly improved, and it is expected that they will have an effective sunscreen effect in lotions and the like. The formulation of the ultraviolet absorber of the present invention is shown below. The blending ratio is in parts by weight. Example 1 Sunscreen lotion Ethanol 5.0 Propylene glycol 5.0 Polyoxyethylene (50) Hydrogenated castor oil 0.5 Citric acid 0.02 Sodium citrate 0.1 Methylparaben 0.05 Fragrance Appropriate amount Water 84.0 2-Hydroxybenzophenone-4-diglyceryl Ether 5.0 Example 2 Sunscreen cream Stearic acid 8.0 Whale wax 4.0 Setanol 4.0 Lanolin 2.0 Isopropyl myristate 6.0 Squalane 7.0 Polyoxyethylene sorbitan monostearate
5.0 Sorbitan monostearate 1.0 Propylene glycol 5.0 Butylparaben 0.2 Butylated hydroxytoluene 0.05 Fragrance Appropriate amount of water 54.5 2,2'-dihydroxybenzophenone-4,4'-
Bisglyceryl ether 3.0

[Brief explanation of drawings]

FIG. 1 shows the ultraviolet absorption spectrum (water) of 2-hydroxybenzophenone-4-diglyceryl ether produced by the method of Synthesis Example 1. Figure 2 shows the infrared absorption spectrum of the compound shown in Figure 1. Figure 3 shows the ultraviolet absorption spectrum (water) of 2,2'-dihydroxybenzophenone-4-diglyceryl ether produced by the method of Synthesis Example 2. Figure 4 shows the infrared absorption spectrum of the compound shown in Figure 3. Figure 5 shows the ultraviolet absorption spectrum (water) of 2-hydroxy-4,4'-bisglyceryl ether produced by the method of Synthesis Example 3.
Figure 6 shows the infrared absorption spectrum of the compound shown in Figure 5. Figure 7 shows 2, which was made by the method of Synthesis Example 4.
Ultraviolet absorption spectrum of 2'-dihydroxy-4,4'-bisglyceryl ether (water). FIG. 8 is an infrared absorption spectrum of the compound shown in FIG.

Claims (1)

[Claims] 1. Novel benzophenone derivative represented by general formula (1) (In the formula, R ₁ and R ₂ represent hydrogen or a hydroxyl group, and at least one of water is a hydroxyl group. Also, R ₃ and R ₄ represent hydrogen or [formula], and at least one is [formula], Here n represents the number of moles added, R ₃ or
When one of R ₄ is [Formula], n≧2, and when both R ₃ and R ₄ are [Formula], n≧1, and in either case, the total number of moles added is n≦10. ) 2 Ultraviolet absorber represented by general formula (1) (In the formula, R ₁ and R ₂ represent hydrogen or a hydroxyl group, and at least one is a hydroxyl group. Also, R ₃ and R ₄ represent hydrogen or [formula], and at least one is [formula], where n represents the number of moles added, R ₃ or
When one of R ₄ is [Formula], n≧2, and when both R ₃ and R ₄ are [Formula], n≧1, and in either case, the total number of moles added is n≦10. )