TWI381829B - Polymerizable water-soluble or alcohol-soluble uv-light absorbent - Google Patents

Description

Polymerizable water-soluble or alcohol-soluble ultraviolet light absorber

The present invention relates to a novel polymerizable water-soluble or alcohol-soluble ultraviolet light absorber, and the present invention also discloses a method for producing the novel chemical and its use in optical medical materials.

Most of the ultraviolet light in sunlight is irradiated to the surface of the earth with radiant energy having a wavelength between 290 nm and 400 nm. Ultraviolet light with a short wavelength below 175 nm is absorbed by oxygen at about 100 km latitude, while ultraviolet rays with radiation between 175 nm and 290 nm are absorbed by the ozone layer at about 15 km above sea level. It is well known that exposure to ultraviolet radiation not only damages the skin, but also causes corneal damage and visual symptoms, and is one of the main causes of cataract formation. Therefore, how to provide adequate visual protection against UV radiation, reduce the chance of cataract incidence, and protect people who are particularly vulnerable to UV rays, such as patients undergoing eye surgery or patients sensitive to light, is a matter of concern. .

In general, the addition of UV absorbers to contact lenses or general glasses can reduce the harmful effects of UV radiation by absorbing UV light between 290 nm and 400 nm, which not only protects the vision system but also reduces cataracts. Incidence rate opportunities. So far, many different types of UV absorbers have been developed and effectively used in contact lens or general eyeglasses. However, it is generally preferred to prevent the UV absorber from being lost by the lens in different environments. The grafting or copolymerization of the lens material with the polymerizable ultraviolet absorber is carried out. For example, U.S. Patent No. 4,304,895 discloses a reactive ultraviolet light absorber for use in contact lenses, as follows:

Although the above-mentioned reactive benzophenone-based ultraviolet absorber can participate in polymerization, this type of ultraviolet absorber is inferior in stability. When applied to a lens, the anti-ultraviolet property of the type of absorbent is often slowly attenuated due to the period of use and storage of the lens. At the same time, the above ultraviolet absorber is hydrophobic and insoluble in the hydrophilic acrylic comonomer and copolymer. Even though these compounds are slightly soluble in hydrophilic comonomers and copolymers, when the copolymers hydrate, they tend to agglomerate from the microphase separation. This agglomeration causes the material to become foggy, destroying the transparency of the material.

In addition, the reactive ultraviolet light absorber disclosed in U.S. Patent No. 4,528,311 is as follows:

The above-mentioned benzotriazole type ultraviolet absorber is polymerizable and has good stability, but the compound still tends to be hydrophobic, and the hydrophobic property causes microphase separation and haze formation.

The ultraviolet light absorber disclosed in U.S. Patent No. 6,036,891, the new compound 2-(2'-hydroxy-5'-hydroxyethoxyethylphenyl)-2H-benzotriazole (2-(2) '-hydroxy-5'-hydroxyethoxyethylphenyl)-2H-benzotriazole is reacted with methacryloyl chloride to produce a mono-ester compound as follows:

However, the above patent specification does not mention how to obtain the new compound 2-(2'-hydroxy-5'-hydroxyethoxyethylphenyl)-2H-benzotriazole, nor does it provide a synthetic method for the key raw materials. It should be a big flaw of the invention patent. At the same time, the obtained reactive ultraviolet light absorber has higher hydrophilicity than the absorbent developed by the prior art, but its water solubility is still low. The ultraviolet light absorber provided in Japanese Patent JP3655061 is as follows:

There is also the problem that water solubility is still low.

Hydrophilicity and water solubility or alcohol solubility are different properties. Since the contact lens material must be hydrophilic, the lens can follow the eyeball to achieve the function of correcting vision, and the hydrophilicity can increase the comfort. Due to the importance of the hydrophilicity of contact lenses or artificial crystals, the raw materials for the manufacture of lenses must be hydrophilic. After synthesis, a small amount of non-polymerized ingredients must be washed away to ensure no toxicity. In general, in the manufacturing process, a large amount of solvent must be used to wash away the remaining unreacted monomers, which is time consuming and laborious, and increases the cost. If a water-soluble or alcohol-soluble component is used for the reaction, not only will the material be produced after the polymerization, but there will be no volatile organic compounds (VOC) emissions and environmental problems when the remaining unreacted monomers are washed away. It can also reduce production costs.

The novel formula (I) polymerizable ultraviolet light absorber of our invention belongs to the class of di-ester compounds, and has excellent water solubility or alcohol solubility, and monomer with good hydrophilicity or water solubility. By carrying out the reaction, it is possible to stably produce a copolymerized product which is excellent in transparency and good in transparency.

The present invention provides a novel polymerizable water-soluble or alcohol-soluble ultraviolet light absorber which is represented by the following formula (I): Wherein R ₁ is hydrogen or C ₁ -C ₅ alkyl, R ₂ is hydrogen, chlorine, bromine or iodine, R ₃ is hydrogen or methyl, and m is from 3 to 12.

The present invention also provides a copolymer which is formed by polymerizing a compound represented by the formula (I) with a hydrophilic or water-soluble monomer. The copolymer thus obtained, which is optical and transparent, can be used for the manufacture of optical medical materials such as contact lenses or artificial crystals and the like.

The novel polymerizable water-soluble ultraviolet light absorber provided by the present invention is represented by the following formula (I): Wherein R ₁ is hydrogen or C ₁ -C ₅ alkyl, R ₂ is hydrogen, chlorine, bromine or iodine, R ₃ is hydrogen or methyl, and m is from 3 to 12.

The preparation method of the above compound of the formula (I) is explained below. Via a compound of formula (II) below, Reacting with polyethylene glycol (PEG) of formula (III), Obtaining a compound of formula (IV), Further reacting a compound of formula (IV) with an acrylic compound of formula (V), A compound of formula (I) is obtained. Wherein R ₁ , R ₂ , m, and R _{3 are} as defined above, and x is 3 to 12.

Or, the method for preparing the compound of the above formula (I) is also via a compound of the following formula (II) Reacting with a compound of the following formula (VI), The compound of formula (I) is obtained. Wherein R ₁ , R ₂ , and R _{3 are} as defined above, and n is 3 to 12.

The water-soluble compound of the above formula (I) of the present invention also has excellent alcohol-soluble, and is suitable for use in the manufacture of a contact lens or an artificial crystal having good hydrophilicity.

Preferred compounds of the formula (I) in the present invention are exemplified as follows: Compound (I)-a: R ₁ = H, R ₂ = H, R ₃ = H, m = 6-8; Compound (I)-b: R ₁ = H, R ₂ = H, R ₃ = CH ₃ m=9-11; compound (I)-c: R ₁ =H, R ₂ =H, R ₃ =CH ₃ , m=5-7; compound (I)-d: R ₁ =C (CH _{3 3} , R ₂ =H, R ₃ =CH ₃ , m=5-7; compound (I)-e: R ₁ =C(CH ₃ ) ₃ , R ₂ =H, R ₃ =CH ₃ ,m= 3-5.

The present invention also provides a copolymer formed by polymerizing a compound of the formula (I) with a hydrophilic or water-soluble monomer. The hydrophilic polymer having good hydrophilicity and optical properties thus obtained can be used for the manufacture of contact lenses or artificial crystals, and can simplify the extraction step of unreacted monomers in the future. Suitable hydrophilic materials comprise so-called hydrogels or silicone hydrogels.

The polymerization of the compound of the formula (I) of the present invention with a hydrophilic or water-soluble monomer can be carried out by any known method. The processes and conditions are generally known to those skilled in the art. Generally, other additives may be added to the reaction to be carried out according to requirements. Suitable additives include, but are not limited to, crosslinking agents, surfactants, diluents, Stabilizers, photoinitiators, dyes, etc.

For the sake of further explanation, the following examples will be more specifically described.

The invention is further described with reference to the following examples, which are not intended to limit the scope of the invention, and the modifications and variations that can be easily made by those skilled in the art are included in the scope. Unless otherwise stated, the percentages used in the examples are by weight and the temperature is in degrees Celsius.

Example

The structure of the compounds mentioned in the examples is as follows: Compound (I)-a: R ₁ = H, R ₂ = H, R ₃ = H, m = 6-8; Compound (I)-b: R ₁ = H, R ₂ = H, R ₃ = CH ₃ m=9-11; compound (I)-c: R ₁ =H, R ₂ =H, R ₃ =CH ₃ , m=5-7; compound (I)-d: R ₁ =C (CH _{3 3} , R ₂ =H, R ₃ =CH ₃ , m=5-7; compound (I)-e: R ₁ =C(CH ₃ ) ₃ , R ₂ =H, R ₃ =CH ₃ ,m= 3-5.

Formula (II)-1: R ₁ =H, R ₂ =H; Formula (II)-2: R ₁ =C(CH ₃ ) ₃ , R ₂ =H; PEG375AA: , n=6-8, purchased from Aldrich; PEG360MA: , n=5-7, purchased from Aldrich; PEG526MA: , n=9-11, purchased from Aldrich; PEG200: , x = 3-5, purchased from Fluka.

Embodiment 1

Preparation of Compound (I)-a 20 g of the compound of the formula (II)-1, 26.8 g of PEG375AA, 2.7 g of p-Toluenesulfonic acid and 100 g of toluene were placed in a 1 liter four-neck reaction flask; The reaction flask is equipped with a thermometer and a distillation water removal device, respectively. The reaction flask was stirred and heated to 112 ° C on a stirring heater. After collecting about 1 ml of water in a distillation water removal device, the reaction was observed by TLC. After cooling to 90 ° C, 100 ml of 1 N carbonic acid was slowly added while maintaining the temperature. The sodium hydrogen hydride (NaHCO ₃ ) aqueous solution was stirred for 15 minutes. The mixed solution was poured into an extraction flask and allowed to stand for separation. The lower aqueous solution was poured into a waste liquid tank, and then 100 ml of a 1 N NaHCO ₃ aqueous solution was added and poured into an extraction flask, and then allowed to stand. The layers were separated, the lower aqueous solution was discarded, and the organic layer was concentrated to give 45 g of crude product (I)-a.

Purification of Compound (I)-a Approximately 300 g (15 times the amount of the sample) of the column packing (label: Waters; specification: preparative C18 125 After uniformly mixing with 450 ml of methanol, slowly pour into the column (label: Pyrex; size: 25G3) for filling. After the packed material in the column is compacted, the same amount of deionized water will be used. After replacing the methanol, continue to replace it with 2 liters of dyke (methanol: water = 1:1), and then weigh about 20 grams of crude product (I)-a and slowly pour it into the column, first about 2 liters. Drainage liquid (methanol: water = 1:1) was extracted and collected in an amount of 200 ml per bottle, and then changed to methanol (water: 7:3), and the levee liquid was continuously charged and collected and sampled for analysis by HPLC. After collecting 4 liters, the target product with higher purity began to appear, and the reverse TLC sheet (Merck RP-18 F ₂₅₄ S) was used to judge the end point of the bank. After the HPLC test result was completed, the sample conforming to the product specification was concentrated, that is, A target product in the form of a brown oil was obtained.

Compound (I)-a spectrum ¹ H NMR (CDCl ₃ ): δ: 11.18 (s, 1H), 8.26 (s, 1H), 7.90 (q, 2H), 7.50 (q, 2H), 7.20 (d, 1H) ), 7.12 (d, 1H), 6.41 (m, 1H), 6.15 (m, 1H), 5.82 (m, 1H), 4.25 (m, 4H), 3.63 (m, 24H), 2.99 (t, 2H) , 2.68 (t, 2H).

Embodiment 2~4

The synthesis and purification steps of Example 1 were repeated, and the preparation of Compound (I)-b, Compound (I)-c and Compound (I)-d was carried out, and the relevant reaction was carried out using the starting materials of Table 1.

The ¹ H NMR spectrum of the obtained finished compound (I)-b, compound (I)-c, and compound (I)-d was as follows.

Compound (I)-b spectrum ¹ H NMR (CDCl ₃ ): δ: 11.19 (s, 1H), 8.26 (s, 1H), 7.93 (q, 2H), 7.52 (q, 2H), 7.21 (d, 1H) ), 7.12 (d, 1H), 6.12 (s, 1H), 5.56 (s, 1H), 4.26 (m, 4H), 3.63 (m, 36H), 3.00 (t, 2H), 2.69 (t, 2H) , 1.94 (s, 3H).

Compound (I)-c spectrum ¹ H NMR (CDCl ₃ ): δ: 11.17 (s, 1H), 8.24 (s, 1H), 7.91 (q, 2H), 7.47 (q, 2H), 7.20 (d, 1H) ), 7.11 (d, 1H), 6.12 (s, 1H), 5.56 (s, 1H), 4.26 (m, 4H), 3.63 (m, 20H), 3.00 (t, 2H), 2.69 (t, 2H) , 1.89 (s, 3H).

Compound (I)-d spectrum ¹ H NMR (CDCl ₃ ): δ: 11.81 (s, 1H), 8.14 (s, 1H), 7.92 (q, 2H), 7.47 (q, 2H), 7.20 (s, 1H) ), 6.12 (s, 1H), 5.57 (s, 1H), 4.28 (m, 4H), 3.64 (m, 20H), 3.00 (t, 2H), 2.73 (t, 2H), 1.94 (s, 3H) , 1.50 (s, 9H).

Embodiment 5

Preparation of Compound (I)-e 100 g of the compound of the formula (II)-2, 590 g of PEG 200, 5.6 g of p-toluenesulfonic acid (PTSA) and 500 ml of toluene were placed in a 1 liter four-neck reaction flask; It is equipped with a thermometer and a distilled water removal device. The reaction flask was stirred and heated to 112 ° C on a stirring heater. After collecting about 5 ml of water in a distillation water removal device, the reaction was observed by TLC. After cooling to 90 ° C, slowly add 468 ml of the aqueous solution while maintaining the temperature. After 15 minutes, the mixed solution was poured into an extraction flask and allowed to stand for separation. The lower aqueous solution was poured into a waste liquid tank, and then 400 ml of an aqueous solution was added and poured into an extraction flask, and the mixture was allowed to stand for separation, and the lower aqueous solution was discarded, and the organic layer was collected. Concentrate to give 162 g of product.

28.8 g of the above product, 8.8 g of Methacrylic acid, 0.98 g of p-toluenesulfonic acid (PTSA) and 200 ml of toluene were placed in a 1 liter four-neck reaction flask; the reaction flask was equipped with a thermometer and distilled Water device. The reaction flask was stirred and heated to 112 ° C on a stirring heater. After collecting about 0.8 ml of water in a distillation water removal device, the reaction was observed by TLC. After the reaction was completed, the temperature was lowered to 90 ° C, and the temperature was kept slow. Add 200 ml of 1N aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) and stir for 15 minutes. Pour the mixed solution into the extraction flask and let it stand. Pour the lower layer of the aqueous solution into the waste container, and then add 200 ml of 1N aqueous solution of sodium hydrogencarbonate. After the extracting flasks were mixed, the layers were allowed to stand, the lower aqueous solution was discarded, and the organic layer was collected to give 18 g of crude product (I)-e.

Purification of Compound (I)-e Approximately 225 g (15 times the amount of sample) of the column packing (label: Waters; specification: preparative C18 125 After mixing with 225 ml of methanol, mix it slowly and slowly pour it into the column (label: Pyrex; size: 25G3) for filling. After the packed material in the column is compacted, the same amount of deionized water will be used. The methanol was replaced, and after replacing with 1 liter of methanol:water=9:1, the crude product (I)-e was weighed into about 17 grams and slowly poured into the column, first with about 1 liter of methanol. : Water = 9:1 rushing liquid is extracted and collected in an amount of 200 ml per bottle. After changing to 100 ml per bottle, it is continuously collected and sampled for analysis by HPLC. After about 2 liters, the purity is compared. High target product appeared, and the reverse TLC sheet (Merck RP-18 F ₂₅₄ S) was used to judge the end point of the bank. After the HPLC test result was completed, the sample conforming to the product specification was concentrated to obtain a target product with a brown oil. .

Compound (I)-e ¹ H NMR spectrum ¹ H NMR (CDCl ₃ ): δ: 11.81 (s, 1H), 8.14 (s, 1H), 7.92 (q, 2H), 7.47 (q, 2H), 7.20 ( s, 1H), 6.11 (s, 1H), 5.56 (s, 1H), 4.26 (m, 4H), 3.63 (m, 12H), 3.00 (t, 2H), 2.74 (t, 2H), 1.93 (s , 3H), 1.50 (s, 9H).

Embodiment 6

Commercially available Benzotriazole A [phenylpropionic acid, 3-(2H-benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxy-, 2- was used in the solubility test . [(2-Methyl-1-carbonyl-2-propenyl)oxy]ethyl ester; Benzenepropanoic acid, 3-(2H-benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4- Hydroxy-,2-[(2-methyl-1-oxo-2-propenyl)oxy]ethyl ester] with compound (I)-a, compound (I)-b, compound (I)-c, compound (I) -d and compound (I)-e, solubility test was carried out in an alcoholic water system of 40% isopropanol (IPA) / 60% water. testing method

The solubility of the solution in 40% isopropanol (IPA) aqueous solution was determined as follows: Waters 717autersampler, Waters 996 PDA (photodiode array detecter), Waters 600 pump, set injection volume 20 μL, analytical column: Phennamex Luna C18, flow rate 1 mL/min, mobile phase is cyanomethane. In the preparation of the calibration curve, the sample was prepared as a 1023 mg/L 40% IPA aqueous solution, and diluted to 512.5 mg/L and 102.5 mg/L by serial dilution. After HPLC analysis, the area was analyzed by concentration. Measuring line, the solubility of the sample in 40% IPA aqueous solution, firstly prepare the sample as a saturated solution at 40% IPA at room temperature, and then dilute the sample, so that the absorption peak area of the analysis result can be within the detection range. , push back the true concentration with the calibration line. The result is shown in Figure 1.

As can be seen from Fig. 1, the solubility test was carried out in a 40% IPA/60% aqueous alcohol water system, and the results showed that the compound (I)-a, the compound (I)-b, the compound (I)-c, and the compound (I) of the present invention. The solubility test of -d and compound (I)-e is superior to the currently commercially available product Benzotriazole A.

Example 7

Application Experiments The percentages of raw materials and composition used in the experiment are shown in Table 2: HEMA: 2-hydroxyethyl methacrylate EGDMA: ethylene glycol dimethacrylate I907: Irgacure 907 purchased from Ciba TPO: Darocur TPO purchased from Ciba RUVA: Compound (I)-e

A hydrogel film was synthesized in the ratio of the respective components of the polymerizable mixture in Table 2. The film thickness was between 0.18 mm and 0.20 mm. The transmission spectrum of the film can be measured by a UV spectrophotomer, and each UV spectrum (UV sepctrum) is shown in detail in FIG. Among them, the solid line ( ) for recipe 1, dotted line ( ) is Formula 2. In the application experiment results, the novel polymerizable water-soluble or alcohol-soluble ultraviolet light absorber monomer of the present invention has an excellent ultraviolet light shielding effect in a contact lens by the ultraviolet light transmission pattern.

In summary, the present invention can achieve the object of the invention by the disclosed technical idea, which is novel, progressive and available for industrial use, and is in conformity with the patent requirements of the invention. However, those disclosed above are preferred embodiments, and those that are modified or modified in part and derived from the technical idea of the present invention are easily inferred by those skilled in the art, and do not depart from the scope of the patent.

The above-mentioned embodiments are merely examples for convenience of description, and the scope of the claims is intended to be limited to the above embodiments.

1 is a commercially available Benzotriazole A and a compound (I)-a, a compound (I)-b, a compound (I)-c, a compound (I)-d and a compound (I) in the sixth embodiment of the present invention. The result of the e-solution test.

Figure 2 is a graph showing the ultraviolet penetrating spectrum of Formulation 1 containing no compound of the present invention and Formulation 2 containing Compound (I)-e of the present invention in Example 7 of the present invention.

Claims (11)

A polymerizable water-soluble or alcohol-soluble ultraviolet light absorber monomer, which is represented by the formula (I): Wherein R ₁ is hydrogen or C ₁ -C ₅ alkyl, R ₂ is hydrogen, chlorine, bromine or iodine, R ₃ is hydrogen or methyl, and m is from 3 to 12. The ultraviolet light absorber monomer according to claim 1, wherein the formula (I) is The ultraviolet light absorber monomer according to claim 1, wherein the formula (I) is The ultraviolet light absorber monomer according to claim 1, wherein the formula (I) is A polymer having ultraviolet light absorbing properties, comprising: a polymerizable monomer, which is represented by the following formula (I): Wherein R ₁ is hydrogen or C ₁ -C ₅ alkyl, R ₂ is hydrogen, chlorine, bromine or iodine, R ₃ is hydrogen or methyl, and m is 3 to 12; and at least one polymerizable copolymer body. A method for producing a polymerizable water-soluble ultraviolet light absorber monomer, comprising: a compound of the following formula (II), Reacting with polyethylene glycol (PEG) of formula (III), Obtaining a compound of formula (IV), Further reacting a compound of formula (IV) with an acrylic compound of formula (V), Obtaining a compound represented by the following formula (I), Wherein R ₁ is hydrogen or C ₁ -C ₅ alkyl, R ₂ is hydrogen, chlorine, bromine or iodine, R ₃ is hydrogen or methyl, and x and m are 3 to 12. A method for producing a polymerizable water-soluble ultraviolet light absorber monomer, comprising: a compound of the following formula (II), Reacting with a compound of the following formula (VI), And obtaining a compound represented by the following formula (I), Wherein R ₁ is hydrogen or C ₁ -C ₅ alkyl, R ₂ is hydrogen, chlorine, bromine or iodine, R ₃ is hydrogen or methyl, and n and m are 3 to 12, but no polymerization is used. Starter and chain transfer agent. An ultraviolet-shielding contact lens obtained by dissolving in a hydrophilic material as the monomer described in claim 1 of the patent application. The contact lens of claim 8, wherein the hydrophilic material comprises a hydrogel or a silicone hydrogel. An ultraviolet-protectable artificial crystal, which is produced by dissolving in a hydrophilic material as the monomer described in the first application of the patent application. The artificial crystal according to claim 10, wherein the hydrophilic material comprises a hydrogel or a silicone hydrogel.