WO2018177329A1 - Polymerizable dye compound and preparation method therefor, and polymer containing dye, and use thereof - Google Patents

Abstract

Provided are a new polymerizable dye compound and a preparation method therefor, and a polymer comprising the dye compound, a preparation method therefor and the use thereof. The present invention pertains to the field of ocular medical devices. The above-described dye compound is a polymerizable compound, does not easily migrate and diffuse in a polymer, and has excellent absorption properties with regard to ultraviolet rays and blue light, and a polymer polymerized with the involvement of same is suitable for ocular medical devices.

Description

Polymerizable dye compound, preparation method, polymer containing the same and use thereof Technical field

The present invention relates to the field of ocular medical devices, and in particular to polymerizable dyes having the ability to absorb ultraviolet and blue light regions.

Background technique

Cataract is caused by turbidity or pigment formation and deposition in the natural lens of the human eye. It changes from transparent to opaque, hindering the entry of light into the eye, leading to a decline in vision or even blindness. Currently recognized as the most effective method for the treatment of cataract is phacoemulsification intraocular lens implantation, that is, after removing the opaque natural lens, the intraocular lens (IOL: intraocular Lens) is implanted and placed in the lens capsule. The natural lens has the property of not transmitting ultraviolet light and visible light in the blue region near 400 to 500 nm. In contrast, the conventional transparent crystal for artificial crystals transmits ultraviolet light and blue region light, resulting in intraocular lens implantation. After the patient has dizziness and blue vision, and the short-wavelength, high-energy blue region light reaches the eye, it will cause serious damage to the retina and cause diseases such as macular degeneration.

Therefore, most of the intraocular lens polymers developed in recent years have been copolymerized with ultraviolet absorbers and blue light absorbers. US 7,074,117 B2, published on Dec. 14, 2007, discloses a novel azo yellow dye having a vinyl polymerizable group, and copolymerizing it with an acrylic monomer or a siloxane oligomer to prepare for absorption of blue light , soft, foldable, high refractive index intraocular lens. CN103026267B, published Apr. 29, 2015, discloses an ophthalmic material comprising a combination of a benzotriazole-based ultraviolet absorber and a azo-based chromophore blue-absorbing agent. Recently, a monomer compound capable of copolymerizing with other artificial crystal material monomers having an ultraviolet absorbing portion having an azo blue chromophore and a benzophenone skeleton in the molecule has been developed, for example, WO2013162042A1, 2013 On October 31, a dye compound having a benzophenone skeleton and a blue light absorbing azobenzene skeleton having both ultraviolet absorbing properties in the molecule was disclosed. Although these materials with UV and blue transmission cutoff characteristics have particular advantages for many existing materials, these materials also have limitations, such as flexibility and solubility in ophthalmic device materials, providing a variety of different transmissions. Features such as features require higher availability of ophthalmic device materials.

Summary of the invention

The present invention aims to solve at least one of the technical problems in the related art at least to some extent.

To this end, the present invention proposes a novel polymerizable dye compound having a benzophenone skeleton having ultraviolet absorption properties in the molecule and an azobenzene skeleton having absorption properties in a blue region, and thus the dye compound has better properties. Ultraviolet light and blue light interception performance; and the compound has a vinyl polymerizable group, can be copolymerized with monomers used in other ophthalmic medical device materials, is difficult to migrate and dissolve in the polymer, and thus is used as an eye part The medical device such as the ultraviolet blue light absorber of the intraocular lens is highly safe to use; in addition, the novel polymerizable dye compound of the present invention has an asymmetric alkoxy group as a linking group, so that the compound has excellent solubility and flexibility. Not only is it easier to carry out polymerization with other monomer materials, but the polymer obtained by polymerizing it as a monomer is still expected to maintain flexibility, thereby making handling at the time of surgery easy.

The novel polymerizable dye compound of the present invention is a compound represented by the following formula (I) or a stereoisomer or tautomer of the compound of the formula (I).

In the general formula (I):

R ¹ is hydrogen or an alkyl group, preferably hydrogen or methyl;

R ² is an alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl; R ^3a , R ^3b , R ^3c and R ⁴ are each independently hydrogen, fluorine, chlorine , bromine, iodine, aldehyde, cyano, nitro, hydroxy, -NR ^a R ^b , -C(=O)R ^c , -S(=O) ₂ R ^c , -C(=O)NR ^a R ^b , -S(=O) ₂ NR ^a R ^b , alkyl, alkoxy, halo C _1-6 alkyl, halo C _1-6 alkoxy, C _1-6 alkoxy C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-12 aryl, C _6-12 aryl C _1-6 alkyl, C _6-12 aryloxy, C _6-12 An aryloxy C _1-6 alkyl group or a C _6-12 aryl C _1-6 alkoxy group;

Each of R ^a , R ^b and R ^{c is} independently hydrogen, hydroxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _6-10 aryl Or a C _6-10 aryl C _1-6 alkyl group; each of R ^3a , R ^3b , R ^3c and R ⁴ is preferably hydrogen, fluorine, chlorine, bromine, iodine, aldehyde, cyano, nitro, hydroxy, -NH ₂ , -N(CH ₃ ) ₂ , -C(=O)CH ₃ , -C(=O)OH, -C(=O)OCH ₃ , -CONH ₂ , -CON(CH ₃ ) ₂ , C _1-8 alkyl, C _1-8 alkoxy, halo C _1-4 alkyl, halo C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, C _6-10 aryloxy, C _6-10 aryloxy C _{1- 4} alkyl or C _6-10 aryl C _1-4 alkoxy; further, each of R ^3a , R ^3b , R ^3c and R ⁴ is preferably hydrogen, fluorine, chlorine, bromine, iodine, aldehyde, cyano , nitro, hydroxy, -NH ₂ , -N(CH ₃ ) ₂ , -C(=O)CH ₃ , -C(=O)OH, -C(=O)OCH ₃ , -CONH ₂ , -CON (CH ₃ ) ₂ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-Butoxy, isobutoxy, trifluoromethyl, trifluoroethyl , trifluoromethoxy, trifluoroethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, benzene Base, phenylmethyl, phenethyl, phenylpropyl, phenoxy, phenoxymethyl, phenoxyethyl, phenylmethoxy or phenylethoxy.

Another aspect of the present invention also provides a polymer comprising the above polymerizable dye compound and thus having a function of blocking ultraviolet light and blue light. Further, since the above dye is a polymerizable compound, it can be copolymerized with a monomer used for other ophthalmic medical device materials, and diffusion diffusion does not easily occur in the polymer.

Another aspect of the invention also provides the use of the polymer of the invention in the preparation of an ocular medical device. The ocular medical device prepared by using the polymer has the characteristics of low hardness, good flexibility, easy folding, and ability to intercept blue light and ultraviolet light. The above-mentioned ocular medical device includes an intraocular lens, an intraocular lens, a contact lens, a corneal correction, an intracorneal lens, a corneal inlay, a corneal ring, or a glaucoma filter device.

Further, the present invention also provides a process for producing the novel polymerizable dye compound and a process for preparing a polymer comprising the dye.

The above objects and advantages of the present invention will become apparent from the Detailed Description.

DRAWINGS

1 is a graph showing the ultraviolet-visible absorption spectrum of the polymer sheet A1 obtained in Example 12;

Figure 2 is a graph showing the ultraviolet-visible absorption spectrum of the polymer sheet A2 obtained in Example 13;

Figure 3 is a graph showing the ultraviolet-visible absorption spectrum of the polymer sheet A3 obtained in Example 14;

4 is a graph showing the ultraviolet-visible absorption spectrum of the polymer sheet A4 obtained in Example 15;

Figure 5 is a graph showing the ultraviolet-visible absorption spectrum of the polymer sheet A5 obtained in Example 16;

Figure 6 is a graph showing the ultraviolet-visible absorption spectrum of the polymer sheet A6 obtained in Example 17;

Figure 7 is a graph showing the ultraviolet-visible absorption spectrum of the polymer sheet A7 obtained in Example 18;

Figure 8 is a graph showing the ultraviolet-visible absorption spectrum of the polymer sheet A8 obtained in Example 19;

Figure 9 is a graph showing the ultraviolet-visible absorption spectrum of the polymer sheet A9 obtained in Example 20;

Figure 10 is a graph showing the ultraviolet-visible absorption spectrum of the polymer sheet A10 obtained in Example 21;

Fig. 11 is a graph showing the UV-visible absorption spectrum of the polymer sheets A12 obtained in Comparative Example 1 and the polymer sheets A13 and A6 obtained in Comparative Example 2.

Detailed description of the invention

Definitions and general terms

Embodiments of the invention are described in detail below, examples of which are illustrated in the accompanying drawings. The embodiments described below with reference to the drawings are intended to be illustrative of the invention and are not to be construed as limiting.

Unless otherwise stated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. All patents and publications related to the present invention are hereby incorporated by reference in their entirety. The term "comprising" or "including" is an open-ended expression that includes the content of the invention, but does not exclude other aspects. In the present invention, all numbers disclosed herein are approximate, whether or not the words "about" or "about" are used. The value of each number may have a difference of less than 10% or a reasonable difference considered by those in the field, such as a difference of 1%, 2%, 3%, 4% or 5%.

In the present invention, the dye compound proposed by the present invention has a formula represented by the formula (I), and also includes a stereoisomer or a tautomer conforming to the compound of the formula represented by the formula (I). "Stereoisomer" refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, and atropisomers and the like.

The stereochemical definitions and rules used in the present invention generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stere Stereochemical definitions and rules described in Hemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light. In describing optically active compounds, the prefixes D and L, or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

Depending on the choice of starting materials and methods, the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.

The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.

The racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E .Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed . Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.

In the present invention, the term "ultraviolet light" means visible light having a wavelength in the range of 300 to 400 nm, "intercepting ultraviolet light", "absorbing ultraviolet light" and the like means visible light containing ultraviolet light, a polymerizable dye compound proposed by the present invention or When a material such as a polymer is incident on one side of the material and passes through the material, the intensity of the ultraviolet light in the outgoing light on the other side of the material is significantly lower than that of the ultraviolet light in the incident light, even The emitted light does not contain ultraviolet light.

In the present invention, the term "blue light" means visible light having a wavelength in the range of 400 to 550 nm, and the terms "intercepting blue light" and "absorbing blue light" refer to a visible light containing blue light, a polymerizable dye compound or polymer proposed by the present invention. When the material surface of the material is incident on one side and passes through the material, the intensity of blue light in the outgoing light on the other side of the material is significantly lower than that of the blue light in the incident light, and is not included in the emitted light. Blu-ray.

The "room temperature" in the present invention refers to a temperature which can be attained by subjecting, for example, a reaction liquid, a mixed liquid or the like to an indoor environment for a certain period of time during the synthesis, preparation, and the like without performing additional cooling or heat treatment. For example, in some embodiments, the "room temperature" temperature is from about 10 degrees Celsius to about 40 degrees Celsius. In some embodiments, "room temperature" refers to a temperature of from about 20 degrees Celsius to about 30 degrees Celsius; in other embodiments, "room temperature" refers to 20 degrees Celsius, 22.5 degrees Celsius, 25 degrees Celsius, 27.5 degrees Celsius, and the like.

In the present invention, the term "optional" or "optionally" means that the subsequently described event or situation may, but does not necessarily, occur, and the description includes the case in which the event or situation occurs and in which it does not occur. . For example, "optionally substituted alkylene" means that the alkylene group may be unsubstituted by any substituent, or alkyl, halogen, nitro, cyano, aldehyde, amino, alkoxy, haloalkyl, haloalkane Substituted by a substituent such as an oxy group.

In each part of the specification, the substituents of the compounds disclosed herein are disclosed in terms of the type or range of groups. In particular, the invention includes each individual sub-combination of each member of the group and range of such groups. For example, the term "C ₁₆ alkyl" refers particularly to the disclosure independently methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

The term "alkyl" or "alkyl group" denotes a saturated straight or branched chain hydrocarbyl group. In one embodiment, the alkyl group contains from 1 to 20 carbon atoms; in another embodiment, the alkyl group contains from 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 -8 carbon atoms; in yet another embodiment, the alkyl group contains 1-6 carbon atoms; and in one embodiment, the alkyl group contains 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH) (CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl -2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) _2), 2-methyl-3-pentyl _{(-CH (CH 2 CH 3)} CH (CH 3) 2), 2,3- dimethyl 2-butyl _{(-C (CH 3) 2 CH} (CH 3) 2), 3,3- dimethyl-2-butyl _{(-CH (CH 3) C (} CH 3) 3), n-heptyl Base, just octyl, and so on.

The term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains from 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains from 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains from 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group is optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propyloxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), and the like.

The term "alkenyl" denotes a straight or branched chain hydrocarbon radical having at least one carbon-carbon sp ² double bond, which includes the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2-20 carbon atoms; in another embodiment, the alkenyl group contains 2-12 carbon atoms; in yet another embodiment, the alkenyl group comprises 2 -8 carbon atoms; also in one embodiment, the alkenyl group contains 2-6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH = CH _2), allyl (-CH ₂ CH = CH ₂₎ and the like.

The term "alkynyl" denotes a straight or branched chain hydrocarbon radical having at least one carbon-carbon sp triple bond. In one embodiment, the alkynyl group contains 2-20 carbon atoms; in another embodiment, the alkynyl group contains 2-12 carbon atoms; in yet another embodiment, the alkynyl group comprises 2 -8 carbon atoms; also in one embodiment, the alkynyl group contains 2-6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), 1-propynyl (-C≡C-CH ₃ ), and the like. .

The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "haloalkyl", "haloalkenyl" or "haloalkoxy" denotes an alkyl, alkenyl or alkoxy group, respectively, substituted by one or more halogen atoms, wherein alkyl, alkenyl and alkoxy The radicals have the meanings described herein, and such examples include, but are not limited to, difluoromethyl, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2 , 2,3,3-tetrafluoropropoxy, and the like. The haloalkyl, haloalkenyl or haloalkoxy group is optionally substituted with one or more substituents described herein.

The term "alkoxyalkyl" denotes an alkyl group substituted by one or more alkoxy groups, wherein the alkyl group and the alkoxy group have the meanings as described herein, such examples include However, it is not limited to methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and the like.

The term "aryl" denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring system is aromatic Of the family, wherein each ring system comprises a ring of 3-7 atoms and one or more attachment points are attached to the remainder of the molecule. Examples of the aryl group may include a phenyl group, a naphthyl group, and an anthracenyl group. When the aryl group may be optionally substituted, the substituted group may be fluorine, chlorine, bromine, iodine, cyano, azide, nitro, amino, hydroxy, decyl, alkylamino, alkoxy, alkylthio, Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl.

The term "aryloxy" or "aryloxy" refers to an optionally substituted aryl group, as defined herein, attached to an oxygen atom and attached to the remainder of the molecule by an oxygen atom, wherein the aryl group Has the meaning as described in the present invention. Examples of aryloxy groups include, but are not limited to, phenoxy, halophenoxy, cyano substituted phenoxy, hydroxy substituted phenoxy, and the like.

The term "arylalkyl" denotes an alkyl group substituted with one or more aryl groups; wherein the alkyl group and the aryl group have the meaning as described herein, and examples of arylalkyl include , but not limited to, benzyl, phenethyl and the like.

The term "aryloxyalkyl" refers to an alkyl group substituted with one or more aryloxy groups; wherein the aryloxy group and the alkyl group have the meanings as described herein. Examples of aryloxyalkyl groups include, but are not limited to, phenoxymethyl, fluorophenoxymethyl (such as (2-fluorophenoxy)methyl, (3-fluorophenoxy)methyl or (4-Fluorophenoxy)methyl), chlorophenoxymethyl, and the like.

The term "arylalkoxy" means that the alkoxy group is substituted by one or more aryl groups; wherein the alkoxy group and the aryl group have the meanings as described herein. Examples of arylalkoxy groups include, but are not limited to, benzyloxy, fluorobenzyloxy, chlorobenzyloxy, cyano substituted benzyloxy, methylsulfonyl substituted benzyloxy, phenylethoxy Base, and so on.

Detailed content of the invention

(1) The novel polymerizable dye compound of the present invention

The novel polymerizable dye compound of the present invention is a compound represented by the following formula (I) or a stereoisomer or tautomer of the compound of the formula (I).

In the formula (I), R ¹ is hydrogen or an alkyl group;

Preferably, R ¹ is hydrogen or a C _1-6 alkyl group;

Preferably, R ¹ is hydrogen or a C _1-3 alkyl group;

Preferably, R ¹ is hydrogen or methyl;

In the formula (I), R ² is an alkyl group;

Preferably, R ² is a C _1-6 alkyl group;

Preferably, R ² is a C _1-4 alkyl group;

From the viewpoint of reaction efficiency in production, preferably, R ² is a methyl group or an ethyl group;

In the formula (I), R ^3a , R ^3b , R ^3c and R ⁴ are each independently hydrogen, fluorine, chlorine, bromine, iodine, aldehyde, cyano, nitro, hydroxy, -NR ^a R ^b , C(=O)R ^c , -S(=O) ₂ R ^c , -C(=O)NR ^a R ^b , -S(=O) ₂ NR ^a R ^b , alkyl, alkoxy, halogen C _1-6 alkyl, halo C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-12 , C _6-12 aryl C _1-6 alkyl, C _6-12 aryloxy, C _6-12 aryloxy C _1-6 alkyl or C _6-12 aryl C _1-6 alkoxy ;with

Each of R ^a , R ^b and R ^{c is} independently hydrogen, hydroxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _6-10 aryl Or a C _6-10 aryl C _1-6 alkyl group;

Preferably, R ^3a , R ^3b , R ^3c and R ⁴ are each independently hydrogen, fluorine, chlorine, bromine, iodine, aldehyde, cyano, nitro, hydroxy, -NH ₂ , -N(CH ₃ ) ₂ , -C(=O)CH ₃ , -C(=O)OH, -C(=O)OCH ₃ , -CONH ₂ , -CON(CH ₃ ) ₂ , C _1-8 alkyl, C _1-8 Alkoxy, halo C _1-4 alkyl, halo C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, C _6-10 aryloxy, C _6-10 aryloxy C _1-4 alkyl or C _6-10 aryl C _1-4 alkoxy;

Preferably, R ^3a , R ^3b , R ^3c and R ⁴ are each independently hydrogen, fluorine, chlorine, bromine, iodine, aldehyde, cyano, nitro, hydroxy, -NH ₂ , -N(CH ₃ ) ₂ , -C(=O)CH ₃ , -C(=O)OH, -C(=O)OCH ₃ , -CONH ₂ , -CON(CH ₃ ) ₂ , methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, trifluoromethyl, trifluoro Ethyl, trifluoromethoxy, trifluoroethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl , phenyl, phenylmethyl, phenethyl, phenylpropyl, phenoxy, phenoxymethyl, phenoxyethyl, phenylmethoxy or phenylethoxy.

From the viewpoint of light absorption characteristics, R ^{3a is} particularly preferably hydrogen, hydroxy, methoxy, ethoxy or octyloxy;

R ^{3b is} particularly preferably hydrogen or a hydroxyl group from the viewpoint of light absorption characteristics; R ^{3c is} particularly preferably hydrogen or a hydroxyl group from the viewpoint of light absorption characteristics; R ^{4 is} particularly preferably considered from the viewpoint of reaction efficiency in production. It is hydrogen, hydroxy, methyl or ethyl.

In the dye compound of the formula (I), the benzophenone skeleton is a chromophore that absorbs ultraviolet light, and the azobenzene skeleton is a chromophore that absorbs blue light, both of which are present in the dye molecule, so that The dye compound of the present invention exhibits good intercepting performance in the ultraviolet light-blue region of 300 to 550 nm.

In the dye compound of the formula (I), the (meth)acryloyl group is bonded to the azobenzene through an asymmetric ether bond, wherein the (meth)acryloyl group is a reaction site participating in the copolymerization, so that the present invention can be used. The polymeric dye compound can be copolymerized with other polymerizable monomers to greatly reduce the risk of migration of the dye compound in the polymer and improve the safety of the device directly in contact with the human body prepared from the polymer. In addition, the asymmetric ether linkage group can increase the solubility of the dye compound, greatly improve the polymerization efficiency when the copolymerization reaction is carried out, and can maintain the flexibility of the polymer molecule obtained after the polymerization, and the polymer is used. The prepared ophthalmic medical device such as intraocular lens has the characteristics of low hardness, flexibility and easy folding, and can intercept blue light and ultraviolet light.

The dye compound of the present invention represented by the formula (I) is not particularly limited, but a compound having the following structure is exemplified as a preferred embodiment:

The compounds represented by the above formulas (1) to (11) or the stereoisomers or tautomers of the compounds represented by the formulae (1) to (11) have an effect of intercepting blue light and ultraviolet light. Specifically, when the ultraviolet-visible absorption spectrum is measured, the spectral transmittance is almost zero at 400 nm or less, that is, the ultraviolet ray is almost completely blocked, and the rise of the graph sharply occurs around 420 to 500 nm, that is, blue. The light in the color region can be suitably suppressed, and thus can be added as an additive to the raw material of the synthetic ophthalmic medical device, and the above compound does not have optical (refractive index, etc.) and mechanical properties on the ophthalmic medical device. The tensile strength, elongation at break, and elastic modulus, etc., have a negative effect and can therefore be used to prepare flexible ophthalmic medical devices such as foldable intraocular lenses.

In addition, the novel polymerizable dye compound of the present invention can be further combined with other ultraviolet absorbers and/or blue light absorbers in terms of fine-tuning the hue of the ophthalmic medical device and imparting better ultraviolet and blue light absorption properties to the ophthalmic product. Use together.

Another aspect of the present invention also provides a process for the preparation of the above novel polymerizable dye compound, which is mainly used as a starting material or an intermediate of the compound represented by the following formula (II) or (III), including a diazotization step and In the esterification step, the synthesis step is not particularly limited, and for example, the dye compound of the present invention can be produced by the following synthesis method.

Wherein R is hydrogen or a protecting group and R ² has the definitions described herein.

Synthesis method one:

The compound of the above formula (II) or formula (III) is reacted with an acrylic compound or a methacrylic compound or the like to introduce a polymerizable group; then the amino group is exposed, and the amino protecting group can be removed by a deprotection reaction. Or reducing the nitro group to an amino group by a reduction reaction; finally, the above-obtained polymerizable aminoaryl compound is diazotized to obtain a diazonium salt, and then the diazonium salt is subjected to a diazo coupling reaction with a benzophenone compound having a different structure. Thereby, the polymerizable dye compound of the present invention is obtained. The synthesis method 1 is represented by a chemical reaction formula as follows:

Wherein R represents hydrogen or a protecting group, R ⁵ represents a hydroxyl group or a halogen, and R ¹ , R ² , R ^3a , R ^3b , R ^3c and R ⁴ are the same as defined above for the substituent.

Synthesis method two:

The compound of the above formula (II) or formula (III) is deprotected by a deprotection reaction, or the nitro group is reduced by a reduction reaction to obtain an aminoaryl compound; the obtained aminoaryl compound is diazotized to obtain The diazonium salt is further subjected to diazo coupling with a benzophenone compound of a different structure to obtain the dye compound of the present invention.

The synthesis method 2 is represented by a chemical reaction formula as follows:

Wherein R represents hydrogen or a protecting group, R ⁵ represents a hydroxyl group or a halogen, and R ¹ , R ² , R ^3a , R ^3b , R ^3c and R ⁴ are the same as defined above for the substituent.

The amino protecting group R may be tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, A protecting group such as a tosyl group or a 2-nitrobenzenesulfonyl group.

The diazotization reaction, the diazo coupling reaction, the esterification reaction, the nitro reduction reaction, and the deprotection reaction in the above synthesis method can be carried out by a known method.

(2) The polymer of the present invention

Another aspect of the invention provides a polymer formed by copolymerizing a polymerizable dye compound of the invention with one or more bulk monomers or other polymerizable comonomers. Thus, since the above polymerizable dye compound has an effect of blocking ultraviolet rays and blue light, the compound containing the above polymerizable dye thus has an effect of absorbing ultraviolet light and blue light. In addition, since the above polymerizable dye compound has a group which can participate in polymerization, it can copolymerize with other monomers in the bulk monomer or the raw material of the synthetic polymer, thereby greatly reducing the risk of migration of the dye compound in the polymer. In turn, the safety performance of the device directly in contact with the human body prepared from the polymer can be improved. For example, the polymer can be used to prepare an ocular medical device such as an artificial lens, so that the artificial lens can also have the function of intercepting blue light and ultraviolet light, thereby reducing the damage of blue light and ultraviolet light in the visible light to the human eye.

In the present invention, "bulk monomer" specifically refers to the main monomer material used to form the polymer body. The bulk monomer can be polymerized to constitute a main component of the above-mentioned polymer proposed by the present invention, which can be copolymerized with the above polymerizable dye compound in a polymerization reaction. The type of the bulk monomer of the present invention is not particularly limited, and in some embodiments of the present invention, the bulk monomer is an acrylate or methacrylate monomer. It may include, but is not limited to, at least one of the following monomers: methyl (meth)acrylate, ethyl (meth)acrylate, propyl (meth)acrylate, isopropyl (meth)acrylate, butyl methacrylate Ester, tert-butyl (meth)acrylate, isobutyl (meth)acrylate, amyl (meth)acrylate, t-amyl (meth)acrylate, hexyl (meth)acrylate, (meth)acrylic acid Heptyl ester, octyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, decyl (meth)acrylate, sunflower (meth)acrylate, dodecyl (meth)acrylate, Linear or branched (meth) such as stearyl (meth) acrylate, cyclopentyl (meth) acrylate, cyclohexyl (meth) acrylate or phenoxy (meth) acrylate Methoxyethyl acrylate, ethoxyethyl (meth)acrylate, methoxydiglycol (meth)acrylate, 2-ethylphenoxy (meth)acrylate, (methyl) 2-ethylthiophene acrylate, 2-ethylaminophenyl (meth)acrylate, phenyl (meth)acrylate, benzyl (meth)acrylate, 2-phenylethyl (meth)acrylate Ester, 2-phenylethyl (meth)acrylate, (A) 3-phenylpropyl acrylate, 4-phenylbutyl (meth)acrylate, 4-methylphenyl (meth)acrylate, 4-methylbenzyl (meth)acrylate, 2,2-methylphenylethyl (meth)acrylate, 2,3-methylphenylethyl (meth)acrylate, 2,4-methylphenylethyl (meth)acrylate , 2-(4-propylphenyl)ethyl (meth)acrylate, 2-(4-(1-methylethyl)phenyl)ethyl (meth)acrylate, (meth)acrylic acid -2-(4-methoxyphenyl)ethyl ester, 2-(4-cyclohexylphenyl)ethyl (meth)acrylate, 2-(2-chlorophenyl)(meth)acrylate Ester, 2-(3-chlorophenyl)ethyl (meth)acrylate, 2-(4-chlorophenyl)ethyl (meth)acrylate, 2-(4-bromo)(meth)acrylate Phenyl)ethyl ester, 2-(3-phenylphenyl)ethyl (meth)acrylate, 2-(4-phenylphenyl)ethyl (meth)acrylate, (meth)acrylic acid- 2-(4-Benzylphenyl)ethyl ester. In another embodiment of the present invention, the bulk monomer may include at least one of 2-phenylethyl acrylate, 2-phenylethyl methacrylate, and ethoxyethyl methacrylate. In other embodiments of the invention, the bulk monomer is a vinyl-based monomer, which may include, but is not limited to, at least one of the following monomers: styrene, 4-butylstyrene, styrene, vinyl acetate, 4-ethoxymethylstyrene, 4-hexyloxymethylstyrene, 4-hexyloxyethylstyrene, vinyl ether, n-butyl vinyl ether, isobutyl vinyl ether, uncle Butyl vinyl ether, cyclohexene vinyl ether, butanediol divinyl ether, N-vinyl caprolactam, dodecyl vinyl ether, octadecyl vinyl ether, divinyl glycol divinyl Ether ether, trivinyl glycol divinyl ether. In still other embodiments of the present invention, the bulk monomer is an allyl monomer, which may include, but is not limited to, at least one of the following monomers: methyl crotonate, ethyl crotonate, benzene crotonate. Ethyl ester, propylene acetate, propylene propionate, propylene butyrate, propylene valerate, propylene hexanoate, 3-phenyl-2-propenyl butyrate. The above bulk monomer has better optical and mechanical properties, and can further improve the performance of the polymer.

In the present invention, the "other polymerizable monomer" specifically means other polymerizable monomers constituting the polymer raw material proposed by the present invention in addition to the bulk monomer, such as a polymerizable ultraviolet absorber, a blue light absorber, Crosslinking agent, initiator, and the like.

In the preparation of the raw material of the polymer of the present invention, at least one of a crosslinking agent, an initiator, and an ultraviolet absorber may be further included. The above-mentioned crosslinking agent, initiator, and bulk monomer, and the above-mentioned dye compound which absorbs the ultraviolet/blue light region are mixed, and the polymer proposed by the present invention is formed by polymerization.

In some embodiments of the invention, the crosslinking agent may include, but is not limited to, ethylene glycol dimethacrylate, diethylene glycol dimethacrylate, polyethylene glycol dimethacrylate, 1,3-propanediol. Dimethacrylate, 1,6-hexanediol dimethacrylate, 1,3-butanediol dimethacrylate, 1,4-butanediol dimethacrylate, 1,4-butyl Diol diacrylate, trimethylolpropane trimethacrylate, 1,5-bis(methacryloyloxy) 2,2,3,3,4,4-hexafluorohexane, 1,6 Bis(acryloyloxy) 2,2,3,3,4,4,5,5-octafluorohexane and pentaerythritol tetraacrylate.

In some embodiments of the invention, the initiator may include, but is not limited to, benzoyl peroxide, t-butyl hydroperoxide, cumyl hydroperoxide, bis(4-tert-butylcyclohexyl)peroxydicarbonate. , azobisisobutyronitrile and azobis(2,4-dimethylvaleronitrile). Thereby, the performance of the polymer can be further improved.

In the raw material constituting the polymer of the present invention, a known polymerizable ultraviolet absorber (a substance mainly absorbing an ultraviolet ray portion), a blue absorbing agent (a substance mainly absorbing light in a blue region), or a material may be further used in combination. At the same time, it absorbs substances in the ultraviolet/blue light region. By using these polymeric ultraviolet absorbers, blue light absorbers, and materials that absorb both the ultraviolet and blue light regions in combination, it is possible to finely adjust the balance between the ultraviolet absorption property of the finally obtained polymer and the light absorption property of the blue region. For example, if the polymer proposed by the present invention is used as an artificial crystal material, it can be used to adjust the color tone, ultraviolet absorbing ability, blue light absorbing ability, and the like of the artificial crystal. Polymeric UV absorbers may include, but are not limited to, 2-(2'-hydroxy-3'-methallyl-5'-methylphenyl)benzotriazole, 2-[3-(2H-benzo) Triazol-2-yl)-4-hydroxyphenyl]ethyl 2-methacrylate, 2-(2H-benzotriazol-2-yl)-4-methyl-6-(2-propenyl) Phenol, 2-(5-chloro-2H-benzo[d][1,2,3]triazole)-4-methyl-6-(2-allyl)phenol, 4-allyl- 2-(5-chloro-2H-benzo[d][1,2,3]triazole)-6-methoxyphenol, 2-(5-chloro-2H-1,2,3-benzo[ d][1,2,3]triazole)-4-methyl-6-allylphenol, 2-hydroxy-4-(methacryloyloxy)benzophenone, and 2-acrylic acid-2- (4-Benzoyl-3-hydroxyphenoxy)ethyl ester. The blue light absorber may include, but is not limited to, an azo system, an anthracene system, a nitro group, a phthalocyanine system, or the like, and these may be used alone or in combination of two or more. The material having the ultraviolet/blue light absorption region at the same time may include, but is not limited to, benzophenone or 2-hydroxy-4-(p-styrene) such as 2,4-dihydroxy-3(p-styreneazo)benzophenone. A benzoic acid such as benzoic acid phenyl group or the like absorbs a dye compound in an ultraviolet/blue light region. They may be used singly or in combination of two or more.

Alternatively, suitable comonomers may be selected to impart various functional properties to the polymers proposed herein.

When oxygen permeability is imparted to the polymer proposed by the present invention, as the comonomer, a silicon-containing monomer such as a silicon-containing (meth) acrylate or a silicon-containing styrene derivative or a fluorine-containing monomer may be selected. Alkyl (meth) acrylates or the like may be used.

When the strength of the polymer is increased or the hardness is adjusted, as the comonomer, an alkyl (meth) acrylate or a styrene-containing styrene derivative (meth) acrylate or the like may be selected.

When a fluorine-containing monomer such as an alkyl group (meth) acrylate containing fluorine or a styrene derivative containing fluorine is selected as a comonomer, a polymer is provided to have a function of preventing lipid contamination.

When hydrophilicity is imparted to the polymer of the present invention, as the comonomer, only (meth)acrylic acid hydroxyesters, (meth)acrylamides, (meth)acrylic acid aminoalkyl esters, (A) are selected. The monomer having a hydrophilic group such as an acrylate or an N-ethyl lactam may be used.

When a monomer having an aromatic ring group, such as a styrene monomer or an aromatic ring-containing (meth) acrylate, is selected as the comonomer, the polymer of the present invention can be used as a lens having a high refractive index. material.

As described above, the polymerizable dye compound proposed by the present invention has excellent absorption characteristics in ultraviolet light (wavelength below 400 nm) and blue light region (wavelength: 400 nm to 500 nm), and the polymer proposed by the present invention contains a dye compound having the above properties. Therefore, the polymer of the present invention also has excellent absorption properties in the ultraviolet light and blue light regions. Specifically, the ultraviolet visible absorption spectrum of the polymer proposed by the present invention is as shown in FIGS. 1 to 10, and is below 400 nm. The light transmittance reaches 0%, almost completely blocking the ultraviolet light, and the sharp rise of the graph appears around 420-500 nm, which weakens the intensity of the blue region to some extent. Further, the dye compound proposed by the present invention has a polymerizable group and can be copolymerized with other monomers in the polymer, so that the phenomenon that the dye compound migrates and elutes from the polymer does not occur. In addition, the dye compound proposed by the present invention has an asymmetric ether bond as a linking group, which greatly increases the solubility of the dye compound, greatly improves the polymerization efficiency when the copolymerization reaction is carried out, and enables the polymer obtained after the polymerization. Molecules remain fairly compliant and are suitable for use in eye medical devices such as intraocular lenses for specific functions.

In yet another aspect of the invention, the invention provides a method of making the polymers described above. The method comprises: subjecting the raw material mixture to a gradient heating or a photocuring treatment to obtain a polymer. Among them, the raw material mixture contains the bulk monomer described above and a dye compound that absorbs ultraviolet light and blue light. The specific types of the bulk monomer and the dye compound have been described in detail above and will not be described herein. In the method proposed by the present invention, the ratio of the bulk monomer and the dye compound is also not particularly limited. One skilled in the art can make adjustments to the above ratios based on the requirements for the specific physicochemical properties of the particular polymer being prepared, as well as the particular type of bulk monomer, dye compound selected. In order to further improve the properties of the polymer prepared by the method, at least one of a crosslinking agent, an initiator, and an ultraviolet absorber may be further included in the raw material mixture. The method has simple operation steps, short production cycle, and the obtained polymer has ideal physical and chemical properties (such as optical and mechanical properties and intercepting blue light function).

In an embodiment, the gradient heat treatment described above may include:

The first reaction stage:

In the first reaction stage, the raw material mixture is heated to 40 to 102 degrees Celsius for reaction, preferably at 40 to 70 degrees Celsius, and the reaction time may be from 1 to 48 hours. The reaction at a lower temperature prevents the reaction rate from being too fast, which is advantageous for forming a sample having a uniform appearance, thereby improving the performance of the polymer.

Second reaction stage:

In the second reaction stage, the raw material mixture passing through the first reaction stage is heated to 40 to 140 ° C for the reaction, preferably at 80 to 120 ° C, and the reaction time may be from 1 to 48 hours. Thereby, it is advantageous to promote further reaction of the remaining raw materials, promote the conversion of the raw materials, and further improve the properties of the polymer prepared by the method.

(3) The ophthalmic medical device of the present invention

In another aspect of the invention, the invention provides an ocular medical device comprising the polymer as set forth above in the present invention. Thus, the ocular medical device has all of the features and advantages of the foregoing polymers, and will not be described again. Specifically, the ocular medical device has ideal mechanical and optical properties, and can intercept ultraviolet light and blue light components in visible light, thereby reducing damage of ultraviolet rays and blue light to human eyes and the like; the ocular medical device has better The safety performance is because the ultraviolet/blue light absorbing dye compound in the polymer proposed by the present invention is not easily migrating and diffusing in the polymer, thereby preventing the dye compound from coming into direct contact with the human body. The eye medical treatment also has the characteristics of low hardness, good flexibility, and easy folding, which makes handling at the time of surgery easier.

The above-mentioned ocular medical device may be an intraocular lens, an intraocular lens, a contact lens, a corneal correction, an intracorneal lens, a corneal inlay, a corneal ring or a glaucoma filter device. More preferably, the polymer of the present invention can be used as a material for an artificial crystal. When the polymer of the present invention is used as a material for an artificial crystal, it can be molded by a known method. For example, a polymerization method can be carried out in a suitable mold or container to obtain a rod-shaped, block-shaped, or plate-shaped polymer, and then processed into a desired shape by a processing method such as cutting, polishing, or laser processing. After the polymer is formed into a shape or a polymerization reaction in a mold corresponding to the desired shape, finer processing is performed as needed.

The solution of the present invention will be explained below in conjunction with the embodiments. Those skilled in the art will appreciate that the following examples are merely illustrative of the invention and are not to be considered as limiting the scope of the invention. Where specific techniques or conditions are not indicated in the examples, they are carried out according to the techniques or conditions described in the literature in the art or in accordance with the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are conventional products that can be obtained commercially.

The examples described below are all set to degrees Celsius unless otherwise stated. The reagents used are all commercially available or can be prepared by the methods described herein.

In the present invention, if there is any difference between the chemical name and the chemical structure, the structure is dominant.

The following abbreviations are used throughout the present invention.

g g

mL ml

Mm mmol

h hours

Min minute

s seconds

Boc tert-butoxycarbonyl

EtOAc ethyl acetate

n-Hex n-hexane

Example 1

Synthesis of the compound 1-(4-((3-benzoyl-4-hydroxyphenyl)diazenyl)phenoxy)-3-methoxypropan-2-yl methacrylate

Step 1: Synthesis of the compound 1-methoxy-3-(4-nitrophenoxy)propan-2-ol

4-Nitrophenol (41.7 g, 0.3 mol), potassium carbonate (56.5 g, 0.1 mol) and absolute ethanol (200 mL) were successively added to a three-necked flask, and the mixture was stirred under reflux for 1 hour, and then slowly added dropwise thereto 1- Chloro-3methoxy-2-propanol (25 g, 0.2 mol) and stirring was continued for 24 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated to ethyl ether. The crude product was diluted with methylene chloride (250mL) and washed with aqueous sodium hydroxide (5% wt, 150mLx2). The organic phase was dried with EtOAc EtOAc EtOAc. The mass spectrum of the obtained product and the nuclear magnetic resonance spectrum data are as follows:

LC-MS (ESI, pos.) m/z: 250 [M+Na] ⁺

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 8.21-8.19 (m, 2H), 7.01-6.98 (m, 2H), 4.24-4.18 (m, 1H), 4.16-4.09 (m, 2H), 3.62-3.55 (m, 2H), 3.43 (s, 3H), 2.74-2.73 (d, 1H).

Step 2: Synthesis of the compound 1-(4-aminophenoxy)-3-methoxypropan-2-ol

1-methoxy-3-(4-nitrophenoxy)propan-2-ol (27 g, 118.9 mmol), 5% palladium on carbon (25.2 g, 11.9 mmol), ammonium formate ( 44.9 g, 713.4 mmol) and tetrahydrofuran (100 mL), the mixture was stirred at room temperature for 5 minutes, then the reaction was transferred to a 60 ° C oil bath for 2 h. The reaction was filtered, and the filter cake was washed with THF (100 mL). The collected filtrate was washed with saturated aqueous sodium hydrogen carbonate (100 mL×1), and the aqueous phase was extracted with dichloromethane (100 mL×3). After washing (100 ml×2), the aqueous layer was extracted with methylene chloride (100 mL×1). 99%). The mass spectrum of the obtained product and the nuclear magnetic resonance spectrum data are as follows:

LC-MS (ESI, pos.) m/z: 198 [M+H] ⁺

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 6.79-6.76 (m, 2H), 6.66-6.64 (m, 2H), 4.17-4.12 (m, 1H), 3.99-3.92 (m, 2H), 3.60-3.52 (m, 2H), 3.42 (s, 3H).

Step 3: Synthesis of the compound 1-(4-tert-butoxycarbonylaminophenoxy)-3-methoxypropan-2-ol

1-(4-Aminophenoxy)-3-methoxypropan-2-ol (22 g, 111.7 mmol) and methanol (200 mL) were sequentially added to a one-neck flask. BOC anhydride (37.4 g, 171.3 mmol) was diluted with MeOH (30 mL) and then evaporated. The mixture was concentrated to dryness (3 mL), EtOAc (EtOAc) , 87.6%). The mass spectrum of the obtained product and the nuclear magnetic resonance spectrum data are as follows:

LC-MS (ESI, pos.) m/z: 320 [M+Na] ⁺

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 7.28-7.27 (m, 2H), 6.88-6.85 (m, 2H), 6.41 (s, 1H), 4.20-4.14 (m, 1H), 4.04- 3.97 (m, 2H), 3.61-3.53 (m, 2H), 3.43 (s, 3H), 2.60-2.59 (d, 1H), 1.53 (s, 9H).

Step 4: Synthesis of the compound 1-(4-tert-butoxycarbonylaminophenoxy)-3-methoxypropan-2-yl methacrylate

1-(4-tert-Butoxycarbonylaminophenoxy)-3-methoxypropan-2-ol (15 g, 50.5 mmol), triethylamine (10.1 g, 100 mmol), 4- After dimethylaminopyridine (1.22 g, 5 mmol) and tetrahydrofuran (150 mL) were dissolved, methacryloyl chloride (10.5 g, 100.9 mmol) was slowly added dropwise thereto, and stirred at 0 ° C for 1 h, then transferred to room temperature and stirring was continued. 24h. The reaction was quenched by the addition of 50% aqueous sodium bicarbonate (10 mL), and the mixture was stirred for 10 min, then filtered and filtered and evaporated to EtOAc EtOAc (EtOAc) 1) The title compound was obtained as a colorless transparent viscous liquid (17 g, 92.4%). The mass spectrum of the obtained product and the nuclear magnetic resonance spectrum data are as follows:

LC-MS (ESI, pos.ion) m / z: 388 [M + Na] +;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 7.28-7.26 (m, 2H), 6.87-6.85 (m, 2H), 6.46 (s, 1H), 6.16 (s, 1H), 5.60 (s, 1H), 5.37-5.32 (m, 1H), 4.12-4.11 (m, 2H), 3.71-3.70 (d, 2H), 3.41 (s, 3H), 1.96 (s, 3H), 1.52 (s, 9H) .

Step 5: Synthesis of the compound 1-(4-aminophenoxy)-3-methoxypropan-2-yl methacrylate

1-(4-tert-Butoxycarbonylaminophenoxy)-3-methoxypropan-2-yl methacrylate (17 g, 46.6 mmol) and dichloromethane (100 mL) were sequentially added to a single-necked flask. After dissolution, trifluoroacetic acid (70 mL) was added and stirred at room temperature for 15 min. After the reaction was completed, it was neutralized with aqueous sodium hydroxide, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjj Liquid (12.5 g, 98%). The mass spectrum of the obtained product and the nuclear magnetic resonance spectrum data are as follows:

LC-MS (ESI, pos.) m/z: 266 [M+H] ⁺

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 6.79-6.77 (m, 2H), 6.65-6.64 (m, 2H), 6.16 (s, 1H), 5.61 (s, 1H), 5.37-5.32 ( m, 1H), 4.13-4.12 (m, 2H), 3.71-3.70 (d, 2H), 3.41 (s, 3H), 1.97 (s, 3H).

Step 6: Synthesis of the compound 1-(4-((3-benzoyl-4-hydroxyphenyl)diazenyl)phenoxy)-3-methoxypropan-2-yl methacrylate

1-(4-Aminophenoxy)-3-methoxypropan-2-yl methacrylate (1.0 g, 3.77 mmol) and potassium bromide (0.45 g, 3.77 mmol) were sequentially added to a three-necked flask. Concentrated hydrochloric acid (1.9g, 18.8mmol) and acetone / water (v / v = 1 / 1, 20mL), the mixture was stirred in a low temperature bath of -5 ° C, when the internal temperature reached below 0 ° C, sodium nitrite ( 0.31 g, 4.50 mmol) was dissolved in water (20 mL), slowly added dropwise to the mixture and stirred for 0.5 h. 2-Hydroxybenzophenone (0.75 g, 3.77 mmol), sodium hydroxide (0.38 g, 9.43 mmol), anhydrous sodium carbonate (0.5 g, 4.7 mmol) were dissolved in water (20 mL) and added dropwise The diazonium salt solution is maintained during the dropwise addition to a temperature of not higher than 5 °C. Stirring was continued overnight, and the mixture was poured into dichloromethane (100 mL). The mass spectrum of the obtained product and the nuclear magnetic resonance spectrum data are as follows:

LC-MS (ESI, pos.ion) m / z: 475 [M + H] +;

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.23 (m, 1H), 8.16-8.13 (m, 1H), 7.86-7.57 (m, 7H), 7.21-7.19 (s, 1H), 7.04- 7.01(s,2H), 6.18(s,1H), 5.62(s,1H),5.42-5.36(m,1H), 4.29-4.27(d,2H),3.74-3.73(d,2H),3.43( s, 3H), 1.98 (s, 3H).

Example 2

Synthesis of 1-(4-((5-benzoyl-2,4-dihydroxyphenyl)diazenyl)phenoxy)-3-methoxypropan-2-ylmethacrylate

The remaining steps were the same as in Example 1, except that in the step (6), 1-(4-aminophenoxy)-3-methoxypropan-2-yl methacrylate was sequentially added to a three-necked flask. (3g, 11.3mmol), potassium bromide (1.35g, 11.3mmol), concentrated hydrochloric acid (5.7g, 56.5mmol) and water (20mL), the mixture was stirred in a low temperature bath at -5 °C, when the internal temperature reached 0 °C In the following, sodium nitrite (0.93 g, 13.5 mmol) was dissolved in water (20 mL), and slowly added dropwise to the above reaction mixture, and stirring was continued for 0.5 h. 2,4-dihydroxybenzophenone (2.42 g, 11.3 mmol), sodium hydroxide (1.13 g, 28.3 mmol), anhydrous sodium carbonate (1.5 g, 14.1 mmol), dissolved in water (20 mL) It is added to the above diazonium salt solution, and the dropping process keeps the solution temperature not higher than 5 °C. Stirring was continued overnight, the mixture was poured into dichloromethane (1 mL). The mass spectrum of the obtained product and the nuclear magnetic resonance spectrum data are as follows:

LC-MS (ESI, pos.ion) m / z: 491 [M + H] +;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 8.02 (s, 1H), 7.79-7.75 (m, 4H), 7.67-7.64 (m, 1H), 7.60-7.56 (m, 2H), 7.04- 7.02 (m, 2H), 6.59 (s, 1H), 6.18 (s, 1H), 5.63 (s, 1H), 5.42-5.37 (m, 1H), 4.29-4.28 (d, 2H), 3.74-3.72 ( d, 2H), 3.43 (s, 3H), 1.98 (s, 3H).

Example 3

Synthesis of 1-(4-((3-benzoyl-2,6-dihydroxyphenyl)diazenyl)phenoxy)-3-methoxypropan-2-ylmethacrylate

The remaining steps were the same as in Example 1, except that in the step (6), 1-(4-aminophenoxy)-3-methoxypropan-2-yl methacrylate was sequentially added to a three-necked flask. (2g, 7.5mmol), potassium bromide (0.89g, 7.5mmol), concentrated hydrochloric acid (3.8g, 37.7mmol) and deionized water (20mL), the mixture was stirred in a low temperature bath at -5 °C, when the internal temperature reached Sodium nitrite (0.62 g, 9 mmol) was dissolved in water (20 mL), slowly added dropwise to the above reaction mixture, and stirring was continued for 0.5 h. 2,4-dihydroxybenzophenone (1.61 g, 7.5 mmol), sodium hydroxide (0.75 g, 18.7 mmol), anhydrous sodium carbonate (0.99 g, 9.4 mmol), dissolved in water (20 mL) It is added to the above diazonium salt solution, and the dropping process keeps the solution temperature not higher than 5 °C. Stirring was continued overnight, the mixture was poured into dichloromethane (100 mL). The mass spectrum of the obtained product and the nuclear magnetic resonance spectrum data are as follows:

LC-MS (ESI, pos.ion) m / z: 491 [M + H] +;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 7.92-7.90 (d, 2H), 7.70-7.68 (d, 2H), 7.62-7.60 (m, 2H), 7.55-7.53 (m, 2H), 7.08-7.06(m,2H), 6.49-6.47(d,1H), 6.19(s,1H), 5.64(s,1H),5.43-5.40(m,1H),4.33-4.28(m,2H), 3.76-3.72 (m, 2H), 3.44 (s, 3H), 1.99 (s, 3H).

Example 4

Compound 1-(4-((5-benzoyl-4-hydroxy-2-methoxyphenyl)diazenyl)phenoxy)-3-methoxypropan-2-yl methacrylate Synthesis

The remaining steps were the same as in Example 1, except that in the step (6), 1-(4-aminophenoxy)-3-methoxypropan-2-yl methacrylate was sequentially added to a three-necked flask. (1.0g, 3.77mmol), potassium bromide (0.45g, 3.77mmol), concentrated hydrochloric acid (1.9g, 18.8mmol) and acetone/water (v/v=1/1, 20mL), mixture at -5°C Stir in a low temperature bath. When the internal temperature reached below 0 ° C, sodium nitrite (0.31 g, 4.50 mmol) was dissolved in water (20 mL), slowly added dropwise to the above reaction mixture, and stirring was continued for 0.5 h. 2-Hydroxy-4methoxybenzophenone (0.75 g, 3.77 mmol), sodium hydroxide (0.38 g, 9.43 mmol), anhydrous sodium carbonate (0.5 g, 4.7 mmol), dissolved in water (20 mL). And adding to the above diazonium salt solution, the dropping process keeps the solution temperature not higher than 5 °C. Stirring was continued overnight, the mixture was poured into dichloromethane (1 mL). The mass spectrum of the obtained product and the nuclear magnetic resonance spectrum data are as follows:

LC-MS (ESI, pos.) m/z: 505 [M+H] ⁺

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 8.03 (s, 1H), 7.82-7.80 (m, 2H), 7.74-7.72 (m, 2H), 7.65-7.61 (m, 1H), 7.57- 7.53 (m, 2H), 7.01-6.99 (m, 2H), 6.72 (s, 1H), 6.18 (s, 1H), 5.62 (s, 1H), 5.42-5.36 (m, 1H), 4.27-4.25 ( m, 2H), 4.11 (s, 3H), 3.73-3.72 (m, 2H), 3.43 (s, 3H), 1.98 (s, 3H).

Example 5

Compound 1-(4-((4-hydroxy-3-(4-hydroxybenzoyl)phenyl)diazenyl)phenoxy)-3-methoxypropan-2-yl methacrylate synthesis

The remaining steps were the same as in Example 1, except that in the step (6), 1-(4-aminophenoxy)-3-methoxypropan-2-yl methacrylate was sequentially added to a three-necked flask. (2g, 7.5mmol), potassium bromide (0.89g, 7.5mmol), concentrated hydrochloric acid (3.8g, 37.7mmol) and acetone/water (v/v=1/1, 20mL), the mixture is low at -5°C Stirring in a warm bath, when the internal temperature reached below 0 ° C, sodium nitrite (0.62 g, 8.98 mmol) was dissolved in water (20 mL), and slowly added dropwise to the above reaction mixture, and stirring was continued for 0.5 h. 2,4'-dihydroxybenzophenone (1.61 g, 7.5 mmol), sodium hydroxide (0.75 g, 18.7 mmol), anhydrous sodium carbonate (1.00 g, 9.4 mmol) were dissolved in water (20 mL). The above diazonium salt solution is added dropwise, and the dropping process keeps the solution temperature not higher than 5 °C. Stirring was continued overnight, and the mixture was poured into dichloromethane (100 mL). The mass spectrum of the obtained product and the nuclear magnetic resonance spectrum data are as follows:

LC-MS (ESI, pos.ion) m / z: 491 [M + H] +;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 8.26-8.25 (d, 1H), 8.13-8.11 (m, 1H), 7.86-7.84 (m, 2H), 7.79-7.77 (m, 2H), 7.20-7.18(m,1H), 7.04-6.98(m,4H), 6.18(s,1H), 5.63(s,1H),5.44-5.39(m,1H), 4.29-4.28(m,2H), 3.75-3.74 (d, 2H), 3.44 (s, 3H), 1.98 (s, 3H).

Example 6

Compound 1-(4-((5-benzoyl-4-hydroxy-2-(octyloxy)phenyl)diazenyl)phenoxy)-3-methoxypropan-2-ylmethyl Acrylate synthesis

The remaining steps were the same as in Example 1, except that in the step (6), 1-(4-aminophenoxy)-3-methoxypropan-2-yl methacrylate was sequentially added to a three-necked flask. (2g, 7.5mmol), potassium bromide (0.89g, 7.5mmol), concentrated hydrochloric acid (3.8g, 37.7mmol) and acetone/water (v/v=1/1, 20mL), the mixture is low at -5°C Stirring in a warm bath, when the internal temperature reached below 0 ° C, sodium nitrite (0.62 g, 8.98 mmol) was dissolved in water (20 mL), and slowly added dropwise to the above reaction mixture, and stirring was continued for 0.5 h. 2-Hydroxy-4'-n-octyloxybenzophenone (1.61 g, 7.5 mmol), sodium hydroxide (0.75 g, 18.7 mmol), anhydrous sodium carbonate (1.00 g, 9.4 mmol) were dissolved in water ( 20 mL) was added dropwise to the above diazonium salt solution, and the dropping process kept the solution temperature not higher than 5 °C. Stirring was continued overnight, and the mixture was poured into dichloromethane (100 mL). The nuclear magnetic resonance spectrum data of the obtained product are as follows:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 8.02 (s, 1H), 7.82-7.81 (m, 2H), 7.73-7.72 (m, 2H), 7.63-7.61 (m, 1H), 7.56- 7.53 (m, 2H), 7.01-7.00 (d, 2H), 6.99 (s, 1H), 6.18 (s, 1H), 5.62 (s, 1H), 5.42-5.38 (m, 1H), 4.29-4.24 ( m,4H), 3.74-.373 (m, 2H), 3.43 (s, 3H), 1.98 (s, 3H), 1.58-1.53 (m, 2H), 1.45-1.28 (m, 10H), 0.92-0.89 (t, 3H).

Example 7 Compound 1-(4-((5-Benzoyl-4-hydroxy-2-methoxyphenyl)diazenyl)phenoxy)-3-methoxyprop-2-ylacrylic acid Ester synthesis

Step 1: Synthesis of the compound 1-(4-tert-butoxycarbonylaminophenoxy)-3-methoxyprop-2-yl acrylate

1-(4-tert-Butoxycarbonylaminophenoxy)-3-methoxypropan-2-ol (8.00 g, 26.94 mmol) and triethylamine (5.45 g, 53.96 mmol) were sequentially added to a one-neck flask. After 4-dimethylaminopyridine (0.65 g, 2.5 mmol) and tetrahydrofuran (150 mL) were dissolved, acryloyl chloride (4.80 g, 46.12 mmol) was slowly added dropwise thereto, stirred at 0 ° C for 1 h, then transferred to room temperature and continued. Stir for 24 h. The reaction was quenched by the addition of 50% aqueous sodium hydrogencarbonate (10 mL), and the mixture was stirred for 10 min, then filtered and filtered, and then evaporated to EtOAc (EtOAc) 1) The title compound was obtained as a pale red transparent viscous liquid (8.05 g, 81.9%). Mass spectrometry and nuclear magnetic resonance data are as follows:

LC-MS (ESI, pos.ion) m / z: 374 [M + Na] +;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 7.28-7.26 (m, 2H), 6.88-6.86 (m, 2H), 6.49-6.45 (d, 1H), 6.22-6.15 (m, 1H), 5.89-5.86 (d, 1H), 5.41-5.36 (m, 1H), 4.19-4.13 (m, 2H), 3.71-3.70 (d, 2H), 3.41 (s, 3H), 1.52 (s, 9H).

Step 2: Synthesis of the compound 1-(4-aminophenoxy)-3-methoxyprop-2-yl acrylate

1-(4-tert-Butoxycarbonylaminophenoxy)-3-methoxyprop-2-yl acrylate (8.0 g, 31.87 mmol) and dichloromethane (100 mL) were sequentially added to a single-necked flask to dissolve well. Trifluoroacetic acid (70 mL) was added and stirred at room temperature for 15 min. After the reaction was completed, it was neutralized with aqueous sodium hydroxide, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjj Liquid (4.60 g, 80%). Mass spectrometry and nuclear magnetic resonance data are as follows:

LC-MS (ESI, pos.ion) m / z: 252 [M + H] +;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 6.79-6.77 (m, 2H), 6.65-6.63 (m, 2H), 6.49-6.45 (d, 1H), 6.23-6.16 (m, 1H), 5.88-5.86(d,1H), 5.39-5.34(m,1H),4.13-4.11(m,2H),3.71-3.70(d,2H), 3.41(s,3H).

Step 3: Compound 1-(4-((5-benzoyl-4-hydroxy-2-methoxyphenyl)diazenyl)phenoxy)-3-methoxypropan-2-ylacrylic acid Ester synthesis

1-(4-Aminophenoxy)-3-methoxyprop-2-yl acrylate (1.48 g, 5.90 mmol), potassium bromide (0.70 g, 5.90 mmol), concentrated hydrochloric acid were added to a three-necked flask. (2.99g, 29.5mmol) and acetone/water (v/v=1/1, 20mL), the mixture is stirred in a low temperature bath at -5 °C, when the internal temperature reaches below 0 °C, sodium nitrite (0.54g) , 7.80 mmol) was dissolved in water (20 mL), slowly added dropwise to the above reaction mixture, and stirring was continued for 0.5 h. 2-Hydroxy-4-methoxybenzophenone (1.34 g, 5.90 mmol), sodium hydroxide (0.59 g, 14.75 mmol), anhydrous sodium carbonate (0.78 g, 7.34 mmol) dissolved in water (20 mL) And added dropwise to the above diazonium salt solution, and the dropping process keeps the solution temperature not higher than 5 °C. Stirring was continued overnight, and the mixture was poured into dichloromethane (100 mL). The mass spectrum of the obtained product and the nuclear magnetic resonance spectrum data are as follows:

LC-MS (ESI, pos.ion) m / z: 491 [M + H] +;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 8.20 (s, 1H), 7.79-7.75 (m, 4H), 7.67-7.53 (m, 4H), 7.04-7.02 (d, 2H), 6.59 ( s,1H), 6.18(s,1H), 5.63(s,1H),5.42-5.37(m,1H), 4.29;-4.25(m,2H),3.74-.372(d,2H),3.43( s, 3H), 1.98 (s, 3H).

Example 8

1-(4-((5-benzoyl-4-hydroxy-2-(octyloxy)phenyl)diazenyl)phenoxy)-3-methoxyprop-2-yl acrylate

The remaining steps were the same as in Example 7, except that in the step (3), 1-(4-aminophenoxy)-3-methoxyprop-2-yl acrylate (2 g) was sequentially added to a three-necked flask. , 7.97 mmol), potassium bromide (0.89 g, 7.50 mmol), concentrated hydrochloric acid (3.8 g, 37.70 mmol) and acetone/water (v/v = 1/1, 20 mL), mixture in a low temperature bath at -5 ° C After stirring, when the internal temperature reached below 0 ° C, sodium nitrite (0.62 g, 8.99 mmol) was dissolved in water (20 mL), and slowly added dropwise to the above reaction mixture, and stirring was continued for 0.5 h. 2-Hydroxy-4-n-octyloxybenzophenone (2.60 g, 7.97 mmol), sodium hydroxide (0.75 g, 18.75 mmol), anhydrous sodium carbonate (0.99 g, 9.33 mmol) dissolved in water (20 mL) And dripping into the above diazonium salt solution, the dropping process keeps the solution temperature not higher than 5 °C. Stirring was continued overnight, and the mixture was poured into dichloromethane (100 mL). Mass spectrometry and nuclear magnetic resonance data are as follows:

LC-MS (ESI, </RTI>^</RTI> ^m .

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 8.01 (s, 1H), 7.82-7.80 (m, 2H), 7.73-7.71 (m, 2H), 7.64-7.60 (m, 1H), 7.56- 7.52 (m, 2H), 7.01-6.99 (m, 2H), 6.69 (s, 1H), 6.51-6.47 (d, 1H), 6.23-6.16 (m, 1H), 5.91-5.88 (d, 1H), 5.45-5.40 (m, 1H), 4.27-4.23 (m, 4H), 3.73-3.72 (d, 2H), 3.43 (s, 3H), 2.00-1.93 (m, 2H), 1.46-1.28 (m, 10H) ), 0.92-0.89 (t, 3H).

Example 9

Compound 1-(4-((5-benzoyl-4-hydroxy-2-methoxyphenyl)diazenyl)phenoxy)-3-ethoxypropan-2-yl methacrylate Synthesis

Step 1: Synthesis of compound 1-ethoxy-3-(4-nitrophenoxy)propan-2-ol

4-Nitrophenol (41.7 g, 0.30 mol), potassium carbonate (56.5 g, 0.41 mol) and absolute ethanol (200 mL) were successively added to a three-necked flask, and the mixture was stirred under reflux for 1 hour, and then slowly added thereto 1- Chloro-3ethoxy-2-propanol (25 g, 0.18 mol) was stirred for 24 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated to ethyl ether. The crude product was diluted with methylene chloride (250mL) and washed with aqueous sodium hydroxide (5% wt, 150mLx2). The organic phase was dried with EtOAc EtOAc EtOAc EtOAc. Mass spectrometry and nuclear magnetic resonance data are as follows:

LC-MS (ESI, pos.ion) m / z: 242 [M + H] +;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 8.23-8.21 (m, 2H), 7.02-7.00 (m, 2H), 4.25-4.11 (m, 3H), 3.67-3.55 (m, 4H), 2.63-2.62(d,1H), 1.26-1.23(t,3H).

Step 2: Synthesis of the compound 1-(4-aminophenoxy)-3-ethoxypropan-2-ol

1-Ethoxy-3-(4-nitrophenoxy)propan-2-ol (27 g, 0.11 mol), 5% palladium on carbon (1.18 g, 0.56 mmol), ammonium formate (into a single-necked flask) 4.49 g, 71.34 mmol) and tetrahydrofuran (100 mL), the mixture was stirred at room temperature for 5 minutes, then the reaction was transferred to a 60 ° C oil bath for 2 h. The reaction was filtered, and the filter cake was washed with THF (100 mL). The collected filtrate was washed with saturated aqueous sodium hydrogen carbonate (100 mL×1), and the aqueous phase was extracted with dichloromethane (100 mL×3). After washing (100 ml×2), the aqueous layer was extracted with methylene chloride (100 mL×1). 96%). Mass spectrometry and nuclear magnetic resonance data are as follows:

LC-MS (ESI, pos.ion) m / z: 212 [M + H] +;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 6.80-6.78 (m, 2H), 6.69-6.66 (m, 2H), 4.18-4.12 (m, 1H), 4.01-3.94 (m, 2H), 3.65-3.55 (m, 4H), 1.26-1.22 (t, 3H).

Step 3: Synthesis of the compound 1-(4-tert-butoxycarbonylaminophenoxy)-3-ethoxypropan-2-ol

1-(4-Aminophenoxy)-3-ethoxypropan-2-ol (22 g, 0.10 mol) and methanol (200 mL) were sequentially added to a one-neck flask. BOC anhydride (37.4 g, 0.17 mmol) was diluted with MeOH (30 mL) and then evaporated. The mixture was concentrated to dryness (3 mL), EtOAc (EtOAc) , 92.5%). Mass spectrometry and nuclear magnetic resonance data are as follows:

LC-MS (ESI, pos.ion) m / z: 334 [M + Na] +;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 7.28-7.27 (m, 2H), 6.88-6.86 (m, 2H), 6.40 (s, 1H), 4.20-4.13 (m, 1H), 4.04- 3.97 (m, 2H), 3.65-3.55 (m, 4H), 2.60-2.59 (d, 1H), 1.53 (s, 9H), 1.26-1.22 (t, 3H).

Step 4: Synthesis of the compound 1-(4-tert-butoxycarbonylaminophenoxy)-3-ethoxypropan-2-yl methacrylate

1-(4-tert-Butoxycarbonylaminophenoxy)-3-ethoxypropan-2-ol (15 g, 48.2 mmol), triethylamine (10.1 g, 100.0 mmol), 4 were sequentially added to a one-neck flask. Dimethylaminopyridine (1.22 g, 5.0 mmol) and tetrahydrofuran (150 mL) were dissolved, and then methacryloyl chloride (10.5 g, 100.9 mmol) was slowly added dropwise thereto, and stirred at 0 ° C for 1 h, then transferred to room temperature. Stirring was continued for 24 h. The reaction was quenched by the addition of 50% aqueous sodium bicarbonate (10 mL), and the mixture was stirred for 10 min, then filtered and filtered and evaporated to EtOAc EtOAc (EtOAc) 1) The title compound was obtained as a colorless transparent viscous liquid (17 g, 93.0%). Mass spectrometry and nuclear magnetic resonance data are as follows:

LC-MS (ESI, pos.ion) m / z: 402 [M + Na] +;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 7.28-7.26 (m, 2H), 6.89-6.86 (m, 2H), 6.37 (s, 1H), 6.16 (s, 1H), 5.60 (s, 1H), 5.37-5.32 (m, 1H), 4.21-4.15 (m, 2H), 3.74-3.73 (d, 2H), 3.62-3.51 (m, 2H), 1.97 (s, 3H), 1.53 (s, 9H), 1.22-1.19 (t, 3H).

Step 5: Synthesis of the compound 1-(4-aminophenoxy)-3-ethoxypropan-2-yl methacrylate

1-(4-tert-Butoxycarbonylaminophenoxy)-3-ethoxypropan-2-yl methacrylate (17 g, 44.9 mmol) and dichloromethane (100 mL) were sequentially added to a one-neck flask. After dissolution, trifluoroacetic acid (70 mL) was added and stirred at room temperature for 15 min. After the reaction was completed, it was neutralized with aqueous sodium hydroxide, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjj Liquid (12.5 g, 98%). Mass spectrometry and nuclear magnetic resonance data are as follows:

LC-MS (ESI, pos.) m/z: 280 [M+H] ⁺

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 6.79-6.77 (m, 2H), 6.67-6.63 (m, 2H), 6.16 (s, 1H), 5.60 (s, 1H), 5.35-5.30 ( m,1H), 4.17-4.10 (m, 2H), 3.74-3.72 (d, 2H), 3.62-3.51 (m, 2H), 1.97 (s, 3H), 1.22-1.19 (t, 3H).

Step 6: Compound 1-(4-((5-benzoyl-4-hydroxy-2-methoxyphenyl)diazenyl)phenoxy)-3-ethoxyprop-2-ylmethyl Synthesis of acrylate

1-(4-Aminophenoxy)-3-ethoxypropan-2-yl methacrylate (2 g, 7.2 mmol) and potassium bromide (0.89 g, 7.5 mmol) were added to a three-necked flask. Hydrochloric acid (3.8g, 37.7mmol) and acetone/water (v/v=1/1, 20mL), the mixture is stirred in a low temperature bath at -5 °C, when the internal temperature reaches below 0 °C, sodium nitrite (0.62) g, 9.0 mmol) was dissolved in water (20 mL) and slowly added dropwise to the above mixture and stirring was continued for 0.5 h. 2-Hydroxy-4'-methoxybenzophenone (1.64 g, 7.2 mmol), sodium hydroxide (0.75 g, 18.7 mmol), anhydrous sodium carbonate (0.99 g, 9.3 mmol) dissolved in water (20 mL) And dripping into the above diazonium salt solution, the dropping process keeps the solution temperature not higher than 5 °C. Stirring was continued overnight, and the mixture was poured into dichloromethane (100 mL). Mass spectrometry and nuclear magnetic resonance data are as follows:

LC-MS (ESI, pos.ion) m / z: 519 [M + H] +;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 8.03 (s, 1H), 7.82-7.53 (m, 7H), 7.01-6.99 (m, 2H), 6.72 (s, 1H), 6.17 (m, 1H), 5.62 (m, 1H), 5.40-5.35 (m, 1H), 4.29-4.27 (m, 2H), 4.11 (s, 3H), 3.76-3.74 (m, 2H), 3.61-3.56 (m, 2H), 1.98 (s, 3H), 1.23-1.20 (m, 3H).

Example 10

Synthesis of 1-(4-((3-benzoyl-4-hydroxyphenyl)diazenyl)phenoxy)-3-ethoxypropan-2-ylmethacrylate

The remaining steps were the same as in Example 9, except that in the step (6), 1-(4-aminophenoxy)-3-ethoxypropan-2-yl methacrylate was sequentially added to a three-necked flask. (2g, 7.2mmol), potassium bromide (0.89g, 7.5mmol), concentrated hydrochloric acid (3.8g, 37.7mmol) and acetone/water (v/v=1/1, 20mL), the mixture is low at -5°C Stirring in a warm bath. When the internal temperature reached below 0 ° C, sodium nitrite (0.62 g, 9.0 mmol) was dissolved in water (20 mL), and slowly added dropwise to the above reaction mixture, and stirring was continued for 0.5 h. 2-Hydroxybenzophenone (1.43 g, 7.2 mmol), sodium hydroxide (0.75 g, 18.7 mmol), anhydrous sodium carbonate (0.99 g, 9.3 mmol) were dissolved in water (20 mL) and added dropwise The diazonium salt solution is maintained during the dropwise addition to a temperature of not higher than 5 °C. Stirring was continued overnight, and the mixture was poured into dichloromethane (100 mL). Mass spectrometry and nuclear magnetic resonance data are as follows:

LC-MS (ESI, </RTI>^</RTI> ^m .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.24 - 8.23 (d, 1H), 8.15-8.13 (m, 1H), 7.86-7.79 (m, 4H), 7.69-7.66 (m, 1H), 7.60-7.57 (m, 2H), 7.22-7.19 (d, 1H), 7.04-7.02 (m, 2H), 6.17 (s, 1H), 5.62 (s, 1H), 5.41-5.36 (m, 1H), 4.33-4.26 (m, 2H), 3.76-3.75 (d, 2H), 3.62-3.55 (m, 2H), 1.98 (s, 3H), 1.24-1.20 (t, 3H).

Example 11

Synthesis of 1-(4-((5-benzoyl-2,4-dihydroxyphenyl)diazenyl)phenoxy)-3-ethoxypropan-2-ylmethacrylate

The remaining steps were the same as in Example 9, except that in the step (6), 1-(4-aminophenoxy)-3-ethoxypropan-2-yl methacrylate was sequentially added to a three-necked flask. (2g, 7.2mmol), potassium bromide (0.89g, 7.5mmol), concentrated hydrochloric acid (3.8g, 37.7mmol) and acetone/water (v/v=1/1, 20mL), the mixture is low at -5°C Stirring in a warm bath. When the internal temperature reached below 0 ° C, sodium nitrite (0.62 g, 9.0 mmol) was dissolved in water (20 mL), and slowly added dropwise to the above reaction mixture, and stirring was continued for 0.5 h. 2,4-dihydroxybenzophenone (1.54 g, 7.2 mmol), sodium hydroxide (0.75 g, 18.7 mmol), anhydrous sodium carbonate (0.99 g, 9.3 mmol), dissolved in water (20 mL) It is added to the above diazonium salt solution, and the dropping process keeps the solution temperature not higher than 5 °C. Stirring was continued overnight, and the mixture was poured into dichloromethane (100 mL). Mass spectrometry and nuclear magnetic resonance data are as follows:

LC-MS (ESI, pos.) m/z: 505 [M+H] ⁺

_{^{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 8.03 (s, 1H), 7.75-7.73 (m, 2H), 7.68-7.67 (m, 2H), 7.62-7.59 (m, 1H), 7.54- 7.51 (m, 2H), 6.99-6.97 (m, 2H), 6.45 (s, 1H), 6.17 (s, 1H), 5.63 (s, 1H), 5.41-5.36 (m, 1H), 4.33-4.26 ( m, 2H), 3.76-3.75 (d, 2H), 3.62-3.55 (m, 2H), 1.98 (s, 3H), 1.24-1.20 (t, 3H).

Example 12 Preparation of Polymer A1

0.3500 g of 2-phenylethyl acrylate, 0.2500 g of 2-phenylethyl methacrylate, 0.3500 g of ethoxyethyl methacrylate, 0.0350 g of 1,4-butanediol diacrylate, and double 0.0200 g of (4-tert-butylcyclohexyl)peroxydicarbonate and 0.0010 g of the dye compound prepared in Example 1 were uniformly mixed, and then transferred to a mold composed of two layers of glass and one polytetrafluoroethylene sheet, and then the mold was The reaction was carried out in an oven at 60 ° C for 3 hours, and the oven was elevated to 100 ° C and maintained for 3 hours to obtain a transparent and elastic polymer. The obtained material was ultrasonically cleaned in absolute ethanol and vacuum dried at 60 ° C for 24 hours. That is, the polymer A1 was obtained.

Examples 13-22 Preparation of Polymers A2 to A11

The rest of the procedure was the same as in Example 12 except that the dye compounds prepared in Examples 2 to 11 were used in place of the dye compounds prepared in Example 1, respectively, to obtain polymers A2 to A11.

Comparative Example 1 Preparation of Polymer A12

0.3500 g of 2-phenylethyl acrylate, 0.2500 g of 2-phenylethyl methacrylate, 0.3500 g of ethoxyethyl methacrylate, 0.0350 g of 1,4-butanediol diacrylate, and double 0.0100g (4-tert-butylcyclohexyl)peroxydicarbonate (with no dye compound and UV absorber added), uniformly mixed, then transferred to a mold consisting of two layers of glass and a sheet of polytetrafluoroethylene, and then the mold The reaction was carried out in an oven at 60 ° C for 3 hours, and the oven was elevated to 100 ° C and maintained for 3 hours to obtain a transparent and elastic polymer. The obtained material was ultrasonically washed in absolute ethanol and vacuum dried at 60 ° C for 24 hours. The polymer A12 was obtained.

Comparative Example 2 Preparation of Polymer A13

0.3500 g of 2-phenylethyl acrylate, 0.2500 g of 2-phenylethyl methacrylate, 0.3500 g of ethoxyethyl methacrylate, and 1,4-butanediol diacrylate 0.0350 g, 2 -100 mg of (2'-hydroxy-3'-methallyl-5'-methylphenyl)benzotriazole and 0.0100 g of bis(4-tert-butylcyclohexyl)peroxydicarbonate (no dye added) The compound was uniformly mixed, then transferred to a mold consisting of two layers of glass and a piece of polytetrafluoroethylene. The mold was placed in an oven at 60 ° C for 3 hours, and the oven was elevated to 100 ° C and continued to maintain. After 3 hours, a transparent and elastic polymer was obtained, and the obtained material was ultrasonically washed in absolute ethanol and vacuum dried at 60 ° C for 24 hours.

Spectral transmittance measurement

(1) Test method: The spectral transmittance of the material in the range of 200 nm to 800 nm light wave was measured by an Agilent Cary 60 ultraviolet-visible spectrophotometer at room temperature.

(2) Test results:

1 to 10 show the results of spectral transmittance of the polymers A1 to A10 prepared in Examples 12 to 21. Figure 11 is a graph showing the spectral transmittance of the polymer A12 prepared in Comparative Example 1, the polymer A13 prepared in Comparative Example 2, and the polymer A6 prepared in Example 17.

As can be seen from the drawing, the polymer A12 prepared in Comparative Example 1 without any other ultraviolet absorber and the dye compound proposed by the present invention has a strong transmittance at 310 nm and a permeation at 370 nm. The ratio is higher than 90%, and there is no absorption of ultraviolet light and blue light; and the polymer A13 prepared by adding the conventional ultraviolet absorber but not adding the dye compound proposed by the present invention has a spectrum of ultraviolet rays of 400 nm or less. The better absorption, the transmittance is almost 0%, and the transmittance is higher at 400 nm and above, the transmittance in the blue region at 450 nm to 550 nm is higher than 90%, and there is almost no absorption of blue light; The polymers A1 to A10 prepared in Examples 12 to 21 of the dye compound of the present invention can completely absorb ultraviolet light of 400 nm or less, and can also significantly reduce the spectral transmission of wavelengths of 400 to 500 nm. The blue light has a good absorption rate, and in the visible light range, the maximum value of the spectral transmittance is higher than 91%. Therefore, the polymer added with the dye compound proposed by the invention can not only intercept the ultraviolet light better. Blue light, and can maintain good transparency.

Solubility test of dye compounds

(1) Test method:

The dye compounds prepared in the above Examples 1 to 10 were weighed in five portions for each dye, 20 mg each, and then 2-phenylethyl acrylate 80 mg, 180 mg, 380 mg, 780 mg, and 1980 mg were sequentially added to obtain a mass fraction of 20%. , 10%, 5.0%, 2.5%, 1.0% of five different concentrations of the solution, the dissolution of the dye compounds prepared in the above Examples 1 to 10 in the monomer was observed. The mixture of each group was sonicated for one minute, and shaken. If a clear transparent solution was obtained, it was considered to be soluble, a liquid-solid homogeneous mixed phase was obtained, or a solid precipitate was still insoluble. The test results are shown in Table 1.

(2) Test results:

It can be seen from Table 1 that all the dye compounds except the compound (2), the compound (3), and the compound (5) are well dissolved at a mass fraction of 20% or less; among them, the compound (3) When the mass fraction of the compound (5) is reduced to 5.0%, the compound (2) dissolves well, and the compound (2) dissolves well at a mass fraction of 1.0%. Since the dye is used in the material in an amount of not more than 0.2 w/w%, in the dye compound prepared in the examples of the present invention, even the compound (2) having the worst solubility has a solvency of 5 times.

Table 1 Solubility of the dye compounds prepared in Examples 1 to 10 in bulk monomers

In the description of the present specification, the description of the terms "one embodiment", "another embodiment", "an example" or the like means that a specific feature, structure, material or characteristic described in connection with the embodiment or example is included in the present invention. At least one embodiment or example. In the present specification, the schematic representation of the above terms is not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples. In addition, various embodiments or examples described in the specification, as well as features of various embodiments or examples, may be combined and combined.

While the embodiments and the embodiments of the present invention have been shown and described, it is understood that the foregoing embodiments and examples are illustrative and not restrictive Variations, modifications, substitutions and variations of the above-described embodiments and embodiments may be made within the scope of the invention.

Claims (16)

1. A polymerizable dye compound, characterized in that the compound has the following general formula (I) or a stereoisomer or tautomer of the compound of the formula (I):

   

   among them:

   R ¹ is hydrogen or an alkyl group;

   R ² is an alkyl group;

   R ^3a , R ^3b , R ^3c and R ⁴ are each independently hydrogen, fluorine, chlorine, bromine, iodine, aldehyde, cyano, nitro, hydroxy, -NR ^a R ^b , -C(=O)R ^c , -S(=O) ₂ R ^c , -C(=O)NR ^a R ^b , -S(=O) ₂ NR ^a R ^b , alkyl, alkoxy, halogenated C _1-6 alkyl, Halogenated C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-12 aryl, C _6-12 aryl a C _1-6 alkyl group, a C _6-12 aryloxy group, a C _6-12 aryloxy C _1-6 alkyl group or a C _6-12 aryl C _1-6 alkoxy group;

   Each of R ^a , R ^b and R ^{c is} independently hydrogen, hydroxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _6-10 aryl Or a C _6-10 aryl C _1-6 alkyl group.
2. The polymerizable dye compound according to claim 1, wherein the R ¹ is hydrogen or a methyl group.
3. The polymerizable dye compound according to claim 1 or 2, wherein the R ² is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or an isobutyl group.
4. The polymerizable dye compound according to any one of claims 1 to 3, wherein each of R ^3a , R ^3b , R ^3c and R ^{4 is} independently hydrogen, fluorine, chlorine, bromine, iodine or an aldehyde group. , cyano, nitro, hydroxy, -NH ₂ , -N(CH ₃ ) ₂ , -C(=O)CH ₃ , -C(=O)OH, -C(=O)OCH ₃ , -CONH ₂ , -CON(CH ₃ ) ₂ , C _1-8 alkyl, C _1-8 alkoxy, halo C _1-4 alkyl, halo C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, C _6-10 aryloxy, C _6-10 aryloxy C _1-4 alkyl or C _6-10 aryl C _1-4 alkoxy.
5. The polymerizable dye compound according to any one of claims 1 to 4, wherein each of R ^3a , R ^3b , R ^3c and R ^{4 is} independently hydrogen, fluorine, chlorine, bromine, iodine or an aldehyde group. , cyano, nitro, hydroxy, -NH ₂ , -N(CH ₃ ) ₂ , -C(=O)CH ₃ , -C(=O)OH, -C(=O)OCH ₃ , -CONH ₂ , -CON(CH ₃ ) ₂ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropyl Oxyl, n-butoxy, isobutoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, methoxymethyl, methoxyethyl, methoxy Propyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, phenyl, phenylmethyl, phenethyl, phenylpropyl, phenoxy, phenoxymethyl, phenoxy Ethyl, phenylmethoxy or phenylethoxy.
6. The polymerizable dye compound according to any one of claims 1 to 5, wherein the compound is a compound represented by the formula (1) to (11), or a stereoisomer or a mutual Isomers:

   
7. A polymer characterized by copolymerizing a compound according to any one of claims 1 to 6 with one or two or more bulk monomers or/and other polymerizable monomers. .
8. The polymer according to claim 7, wherein the bulk monomer comprises at least one of a (meth) acrylate monomer, a vinyl monomer, and an allyl monomer.
9. The polymer according to claim 7 or 8, wherein the raw material for preparing the polymer further comprises at least one of an initiator, a crosslinking agent, and an ultraviolet absorber.
10. An ophthalmic medical device comprising the polymer of any of claims 7-9.
11. The ocular medical device according to claim 10, wherein the ocular medical device is an intraocular lens, an intraocular lens, a contact lens, a corneal correction, an intracorneal lens, a corneal insert, a corneal ring, or a glaucoma filter. Optical device.
12. A process for the preparation of a compound according to any one of claims 1 to 6, wherein a compound represented by the following formula (II) or formula (III) is used as a starting material or an intermediate:

    

    Wherein: R is hydrogen or a protecting group.
13. The process according to claim 12, which comprises the step of obtaining an amino compound represented by the following formula (IV):

    
14. The process according to claim 12, which comprises the step of obtaining a compound represented by the following formula (V):

    
15. A method of preparing a polymer according to any one of claims 7-9, comprising:

    The raw material mixture is subjected to a gradient heating or photocuring treatment to obtain the polymer, wherein the raw material mixture contains a bulk monomer, the polymerizable dye compound according to any one of claims 1 to 6, and optionally cross-linking At least one of a agent, an initiator, and an ultraviolet absorber.
16. The preparation method according to claim 15, wherein the gradient heat treatment comprises:

    In the first reaction stage, the temperature of the first reaction stage is 40 to 120 degrees Celsius, the reaction time is 1 to 48 hours; and the second reaction stage, the temperature of the second reaction stage is 40 to 140 degrees Celsius, and the reaction time is 1 ~48 hours.

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