Process for the preparation of oxyresveratrol and derivatives thereof

Abstract

The present disclosure relates to novel methods for producing resveratrol-type compounds (e.g., oxyresveratrol), salts thereof, hydrates thereof, and physical compositions thereof without the use of protecting group chemistry.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 597,698, filed November 10, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Resveratrol and its derivatives, including oxidized resveratrol, are associated with anticancer and anti-aging properties. In particular, resveratrol-type compounds have been shown to possess inhibitory tyrosinase activity, melanin production, antioxidant, and anti-inflammatory activities. Currently, resveratrol and its derivatives can be obtained naturally or synthesized from biological sources. Isolation of compounds from biological sources requires at least extraction and chromatographic separation from plant materials. Conventional methods for the synthesis of resveratrol-type compounds involve multiple synthetic steps involving protection / deprotection chemistry, the use of metal catalysis, and combinations thereof. The synthesis of resveratrol-type compounds depends on the formation of a central olefin. Classical synthetic methods for olefin formation include metal-catalyzed coupling chemistry (i.e., Suzuki coupling, Heck coupling, and the McMurray reaction), which requires the chemistry of protecting the phenolic hydroxyl groups of the reactant species. Therefore, improved methods for obtaining resveratrol-type compounds are still needed. Summary of the Invention

[0004] This disclosure is based, at least in part, on the synthesis of compounds of formula (I) as disclosed herein. For example The present invention describes the development of a method for oxidizing resveratrol, which produces oxidized resveratrol compounds in high yield. The synthesized oxidized resveratrol described herein also exhibits different (e.g., higher) biological activities compared to commercially available bio-extracted oxidized resveratrol.

[0005] In some respects, this disclosure provides a method for preparing compounds of formula (I): (Formula I), or a salt thereof. In Formula I, each of R1, R2, R3, and R4 may independently be H, -OH, -OMe, and -OEt; and at least one of R1, R2, R3, and R4 is -OH (unprotected). In specific examples, the compound of Formula I can be... (Compound 1).

[0006] The method includes: making compound I-3: (Formula I-3) or its salts and aldehyde A1: (A1); Contact under conditions suitable for forming a compound of formula I or its salt. In formula I-3, X is a halogen ( For exampleCl or Br, Br (optionally).

[0007] In some implementations, R1 and R2 are each -OH. Alternatively or additionally, in some implementations, R3 and R4 are each -OH.

[0008] In some embodiments, the molar ratio of compound I-3 to aldehyde A1 in the reaction system can be from 3:1 to 1:3. In some examples, the molar ratio of compound I-3 to aldehyde A1 in the reaction system can be from 2:1 to 1:2. In one example, the molar ratio between the two compounds can be about 1:1.5.

[0009] In some embodiments, the compound of formula I-3 is: Alternatively or additionally, aldehyde A1 is: .

[0010] Exemplary suitable conditions in the contact step for producing compounds of formula I in good yield include one or more of the following: (a) In the contact step for producing compound I, a suitable inorganic base is used ( For example The inorganic bases are NaOC6H5, Na2SiO3, Ca(OH)2, Mg(OH)2, LiOH, Cs2CO3, K3PO4, t-buOK, K2CO3, and Na2CO3 (e.g., K2CO3 or Na2CO3). In one example, the inorganic base may be Na2CO3. In some examples, the compound of formula I-3 is contacted with the base before contacting aldehyde Al. In other examples, the compound of formula I-3 is contacted with the base after contacting aldehyde Al. In still other examples, the compound of formula I-3 is contacted with the base simultaneously with contacting aldehyde Al.

[0011] (b) Using a suitable organic solvent, such as n-methyl-2-pyrrolidone (NMP).

[0012] (c) The reaction is carried out at a temperature of about 70-100 degrees Celsius, such as about 85-95 degrees Celsius. In some examples, the compound of formula I-3 and aldehyde A1 can be heated to a temperature of about 85-95 degrees Celsius. In other examples, the compound of formula I-3 and aldehyde A1 can be heated to a temperature of about 70-100 degrees Celsius. For example (to a temperature of approximately 85-95℃).

[0013] In the specific instance, the contact steps for producing the compound of formula I are carried out under all conditions (a)-(c).

[0014] In some embodiments, compounds of formula I-3 used in the reaction to produce compounds of formula I disclosed herein can be prepared by a method comprising the following steps: At approximately 25-30 degrees Celsius, compound I-2 is: Or its salt is contacted with triphenylphosphine (PPh3) under conditions suitable for forming a compound of formula I-3 or its salt.

[0015] In some embodiments, the compound of formula I-2 can be prepared by a method including the following steps: At approximately 25 degrees Celsius, compound I-1 is: Or its salt is contacted with boron tribromide (BBr3) under conditions suitable for forming a compound of formula I-2 or its salt. In formula I-1, each of R3' and R4' may independently be H, -OH, -OMe or -OEt, and at least one of R3' and R4' is -OMe or -OEt, for example -OMe.

[0016] In some embodiments, the compound of formula I-1 is: .

[0017] Compounds of Formula I prepared by any of the synthetic methods disclosed herein are also within the scope of this disclosure.

[0018] Details of one or more embodiments of the invention are set forth in the following description. Other features or advantages of the invention will become apparent from the following drawings and the following detailed description of several embodiments, and also from the appended claims. Attached Figure Description

[0019] The following figures form part of this specification and are included to further illustrate certain aspects of this disclosure, which can be better understood by referring to the combination of the figures and the detailed description of the specific embodiments presented herein.

[0020] Figure 1A-1B The particle size distribution (PSD) of oxidized resveratrol, evaluated using particle size distribution method, is shown. Figure 1A Commercially available oxidized resveratrol (extracted from plants). Figure 1B Oxidized resveratrol was synthesized by the synthesis method disclosed in Example 1 below.

[0021] Figure 2A-2B Commercially available resveratrol oxide (SVO2+) is shown. Figure 2A ) and oxidized resveratrol synthesized using the method described in Example 1 below. Figure 2B Differential scanning calorimetry (DSC) spectra of .

[0022] Figures 3A-3B Commercially available resveratrol oxide (SVO2+) is shown. Figure 3A ) and oxidized resveratrol synthesized using the method described in Example 1 below. Figure 3B Thermogravimetric analysis (TGA) spectra. Detailed Implementation

[0023] definition

[0024] All definitions defined and used in this document should be understood as controls over dictionary definitions, definitions incorporated by reference in other documents, and / or the general meaning of the defined terms.

[0025] All references, patents and patent applications disclosed herein are incorporated by reference in relation to their respective subjects, and in some cases may cover the entire document.

[0026] Unless expressly indicated to the contrary, the indefinite article “a / an” as used in this specification and claims shall be understood to mean “at least one / an”.

[0027] As used herein in this specification and claims, the phrase “and / or” should be understood to mean “any one or two” of the elements so combined, that is, these elements coexist in some cases and exist separately in others. Multiple elements listed with “and / or” should be interpreted in the same way, that is, “one or more” of the elements so combined. In addition to the elements specifically identified by the “and / or” clause, other elements may optionally be present, whether related to or unrelated to those specifically identified. Thus, as a non-limiting example, when used in conjunction with open-ended language such as “comprising,” a reference to “A and / or B” may refer only to A in one embodiment (optionally including elements other than B); only to B in another embodiment (optionally including elements other than A); both A and B in yet another embodiment (optionally including other elements); and so on.

[0028] As used herein in this specification and claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when items in a list are separated, “or” or “and / or” should be interpreted as inclusive, i.e., including multiple elements or at least one element in a list of elements, but further including more than one element, as well as optional additional items not listed. Terms that are clearly indicated only in reverse, such as “only one of…” or “exact one of…” or, when used in a claim, “consisting of…” will refer to multiple elements or exactly one element in a list of elements. In general, when preceded by an exclusive term such as “any one,” “one of…,” “only one of…,” or “exact one of…,” the term “or” as used herein should be interpreted only as indicating an exclusive alternative (i.e., “one or the other, not two”). When used in a claim, “consisting substantially of…” should have the ordinary meaning as used in the field of patent law.

[0029] As used in this specification and claims, the phrase "at least one" relating to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of every element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase "at least one," whether or not they are related to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B," or equivalently, "at least one of A and / or B") can: in one embodiment, mean at least one, optionally including more than one A, without B (and optionally including elements other than B); in another embodiment, mean at least one, optionally including more than one B, without A (and optionally including elements other than A); in yet another embodiment, mean at least one, optionally including more than one A and at least one, optionally including more than one B (and optionally including other elements); and so on.

[0030] It should also be understood that, unless expressly indicated to the contrary, in any method claimed herein that includes more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are described.

[0031] As used herein, the term “treatment” refers to the application or administration of a composition comprising one or more active agents to a subject who suffers from a target disease or condition, symptoms of the disease / condition, or is susceptible to the disease / condition, with the aim of treating, curing, alleviating, relieving, altering, remedying, improving, modifying, or influencing the condition, symptoms of the disease, or susceptibility to the disease or condition.

[0032] Reducing the severity of a target disease / symptom includes delaying the development or progression of the disease, or reducing its severity or prolonging survival. Reducing the severity of the disease or prolonging survival does not necessarily require a cure. As used herein, “delaying” the development of a target disease or symptom means postponing, hindering, slowing, stabilizing, and / or delaying the progression of the disease. This delay can vary in length, depending on the history of the disease and / or the individual being treated. Methods of delaying or reducing the development of the disease or delaying the onset of the disease include reducing the likelihood of developing one or more symptoms of the disease within a given time frame and / or reducing the degree of symptom reduction within a given time frame compared to not using this method. Such comparisons are typically based on clinical studies using a large number of subjects sufficient to give statistically significant results.

[0033] The term "development" or "progression" of a disease refers to the initial presentation and / or subsequent progression of the disease. The development of a disease can be detectable and can be assessed using standard clinical techniques well known in the art. However, development also refers to progression that may not be detectable. For the purposes of this disclosure, development or progression refers to the biological process of symptoms. "Development" includes occurrence, relapse, and onset. As used herein, an "onset" or "occurrence" of a target disease or condition includes an initial onset and / or relapse.

[0034] As used herein, "effective amount" means the amount of each active agent required, alone or in combination with one or more other active agents, to impart a therapeutic effect to a subject. Determining whether a given amount of antibody achieves a therapeutic effect will be apparent to those skilled in the art. As will be recognized by those skilled in the art, the effective amount varies depending on the specific condition being treated, the severity of the condition, individual patient parameters (including age, physical condition, body type, sex, and weight), the duration of treatment, the nature of concurrent therapies (if present), the specific route of administration, and similar factors within the knowledge and expertise of a healthcare professional. These factors are well known to those skilled in the art and can be resolved through routine experimental procedures alone. Generally, it is preferred to use the maximum dose of the individual component or its combination, i.e., the highest safe dose based on reasonable medical judgment.

[0035] As used herein, the term “extracorporeal” includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrasheath, intralesional, and intracranial injection or infusion techniques.

[0036] The compounds disclosed herein and the methods for preparing the compounds disclosed herein include those generally described above, and are illustrated by the categories, subclasses, and species disclosed herein. Unless otherwise indicated, the following definitions shall apply as used herein. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. Furthermore, the general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0037] "Alkyl" refers to a straight-chain, saturated, acyclic, monovalent hydrocarbon radical or a branched, saturated, acyclic, monovalent hydrocarbon radical having one to three carbon atoms connected to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, or 1-methylethyl (isopropyl). Optionally substituted alkyl radicals are alkyl radicals that are optionally substituted with one, two, three, four, or five substituents, where the valence allows, and these substituents are independently selected from the group consisting of: halogen, cyano, nitro, oxygen, hydroxyl, thio, or amino.

[0038] "Alkenyl" refers to a straight-chain, acyclic, monovalent hydrocarbon radical or a branched, acyclic, monovalent hydrocarbon radical, such as vinyl or propenyl, containing a carbon-carbon double bond and having two or three carbon atoms connected to the rest of the molecule by single bonds. Optionally substituted alkenyl radicals are alkenyl radicals that are optionally substituted with one, two, or three substituents, where the valence allows, and these substituents are independently selected from the group consisting of: halogen, cyano, nitro, hydroxyl, thio, or amino.

[0039] "Alynyl" refers to a straight-chain, acyclic, monovalent hydrocarbon radical or a branched, acyclic, monovalent hydrocarbon radical containing a triple bond and having two or three carbon atoms connected to the rest of the molecule by single bonds, such as ethynyl or propynyl. Optionally substituted alkynyl radicals are alkynyl radicals optionally substituted with a substituent selected from the group consisting of: halogen, cyano, nitro, hydroxyl, thio, or amino.

[0040] "Alkoxy" refers to a group of the formula -ORa, where Ra is hydrogen or an alkyl radical containing one to three carbon atoms as defined above. Optionally substituted alkyl radicals may have their alkyl portion substituted as defined above for alkyl radicals.

[0041] "Amino" refers to a group of the formula -NRbRc, where Rb and Rc are each hydrogen or an alkyl radical containing one to three carbon atoms as defined above. The alkyl portion of an optionally substituted amino radical may be optionally substituted as defined above for alkyl radicals.

[0042] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. In cases containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be single-point connected (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may optionally be substituted at any connection point with one or more substituents, for example, one to five substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, (C2-C6)alkenyl, (C2-C6)ynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, and -OC(O)O(C1-C6)alkyl.

[0043] "Carbonyl" refers to the formula . group.

[0044] "Halogen" refers to a free radical of chlorine, bromine, fluorine, or iodine atoms. The term "halogen" also encompasses the terms "halogen group" or "halogenated compound".

[0045] The "optionally substituted" portion may be substituted by one to four, preferably one to three, or more preferably one or two non-hydrogen substituents. Unless otherwise stated, when the substituent is on carbon, it is selected from the group consisting of: -OH, -CN, -NO2, halogen, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide, and amino, none of which are further substituted. Unless otherwise stated, when the substituent is on nitrogen, it is selected from the group consisting of: alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl, sulfonate, and sulfonamide, none of which are further substituted.

[0046] The compounds disclosed herein can exist as stereoisomers, wherein an asymmetric or chiral center is present. Stereoisomers are designated as (R) or (S) depending on the configuration of the substituents surrounding the chiral carbon atom. The terms (R) and (S) as used herein refer to configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45: 13-30, which is hereby incorporated by reference. Various stereoisomers and mixtures thereof are contemplated in this disclosure and are expressly included within the scope of this disclosure. Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers.

[0047] A tautomer is one of two or more structural isomers that exist in equilibrium and readily transform from one isomeric form to another. This transformation results in the migration of hydrogen atoms, accompanied by the conversion of adjacent double bonds. Tautomers exist as a mixture of tautomers in solution. In solutions where tautomerism is possible, tautomers will reach chemical equilibrium. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert through tautomerism is called the phenomenon of tautomerism.

[0048] As used herein, a "reagent" is a common partner of reactants in many chemical reactions. It can be organic or inorganic; small or large; gaseous, liquid, or solid. The reagent portion that is ultimately incorporated into the product can range from all to very little or none.

[0049] "Thio" refers to a group of the formula -SRd, where Rd is hydrogen or an alkyl radical containing one to three carbon atoms as defined above. Optionally substituted alkyl moieties may have their alkyl portions substituted as defined above for alkyl radicals.

[0050] As used in this paper, "hydrophilicity" refers to one or more molecules having a hydrophilic-lipophilic balance greater than 10, for example, using the Griffin method.

[0051] I. Synthesis Method

[0052] This disclosure aims to develop methods for producing resveratrol compounds such as oxidized resveratrol and its derivatives. For exampleThe improved synthetic method for compound (I) disclosed herein offers improved yields compared to known methods in the literature. Conventional synthetic methods for oxidized resveratrol typically involve protecting the -OH moiety in the reactants. Such methods have failed to yield satisfactory oxidized resveratrol yields. Furthermore, synthetic routes involving conventional Wittig reactions in the presence of bases (such as MeONa, HMDSLi, LiOH, Cs2CO3, etc.) also result in low yields of oxidized resveratrol.

[0053] The synthetic method presented herein involves the use of a reactant with an unprotected -OH moiety and / or an inorganic base such as Na₂CO₃. Surprisingly, the synthetic method described herein leads to the successful production of the desired oxidized resveratrol compound in high yield. The synthesized product also exhibits higher bioactivity compared to the commercially available oxidized resveratrol (extracted from a natural source) reported herein. In summary, the synthetic method presented herein demonstrates at least the following advantageous features: (a) high reaction efficiency; (b) high purity of the synthesized compound (…). For example (c) low cost; and (d) does not involve heavy metal catalysts such as palladium, thereby reducing or avoiding safety issues for therapeutic use.

[0054] Resveratrol compounds

[0055] The resveratrol compounds provided in this article may have the structure of formula (I) or a salt thereof: (I), where R 1 R 2 R 3 and R 4 Each of them is independently H, halogen ( For example (F, Cl, or Br), hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, thioyl, or amine. In some embodiments, R 1 R 2 R 3 and R 4 One or more of them can be hydroxyl groups.

[0056] In some instances, resveratrol compounds can have the structure of formula (Ia) or a salt thereof: (Ia), where R 1 R 2 and R 3 Each of these is as defined above.

[0057] In one example, the resveratrol compound is resveratrol (where R... 1 -R 3 Both are -OH, and R 4(For –H). In another example, the resveratrol compound is oxidized resveratrol (where R is –H). 1 -R 4 (All are -OH). As is known to those skilled in the art, the resveratrol compounds disclosed herein may have suitable substitutions at one or more suitable positions in resveratrol.

[0058] Synthesis method

[0059] In some aspects, this disclosure provides a synthetic method for preparing compounds of formula (I) as described herein, or salts thereof. An example of a synthetic scheme for a compound of formula (I) (e.g., resveratrol oxide), scheme 1, is given in Example 1 below.

[0060] In some implementations, the synthesis method provided herein includes using formula I-3 Compounds or their salts with having formula A1 The steps of the aldehyde A1 reaction (step 3 illustrated in Scheme 1). In these formulas, each of R1, R2, R3, and R4 is independently H, -OH, -OMe, or -OEt, and at least one of R1, R2, R3, and R4 is -OH ( Right now (Unprotected). In some cases, at least two of R1, R2, R3, and R4 are unprotected -OH moieties. In some cases, at least three of R1, R2, R3, and R4 are unprotected -OH moieties. In one instance, R1, R2, R3, and R4 are all unprotected -OH moieties. In Formula I-3, X is a halide. In some instances, X is Cl. In other instances, X is Br, as illustrated in Scheme 1.

[0061] Step 3 described herein can be performed under conditions that allow for the formulation of compounds of Formula I or their salts as provided herein. In some embodiments, a suitable molar ratio of Formula I-3 to aldehyde A1 can be used to ensure successful production of the Formula I compound in the desired yield. For example, the molar ratio of Formula I-3 to aldehyde A1 can be from 3:1 to 1:3, such as from 2:1 to 1:2. In one example, the molar ratio of Formula I-3 to aldehyde A1 is 2:1. In another example, the molar ratio of Formula I-3 to aldehyde A1 is 1.5:1. In yet another example, the molar ratio of Formula I-3 to aldehyde A1 is 1:1. In some specific examples, the molar ratio of Formula I-3 to aldehyde A1 is 1:1.5. In other specific examples, the molar ratio of Formula I-3 to aldehyde A1 is 1:2.

[0062] Step 3 can be carried out in the presence of an inorganic base. Suitable inorganic bases for use in any of the synthetic methods provided herein include LiOH, Cs₂CO₃, K₃PO₄, t-buOK, K₂CO₃, or Na₂CO₃. In one specific example, the inorganic base is Na₂CO₃. The use of Na₂CO₃ as an inorganic base in the synthetic methods provided herein results in high levels of oxidized resveratrol and low levels of byproducts, as described in the following examples.

[0063] In some cases, the compound of formula I-3 as disclosed herein can be mixed with a suitable inorganic base as disclosed herein, and then aldehyde A1 can be added in step 3 to allow the production of compound I. Alternatively, aldehyde A1 as disclosed herein can be mixed with a suitable inorganic base, also as disclosed herein, and then the compound of formula I-3 can be added in step 3 to allow the production of compound I. In one specific example, the compound of formula I-3, aldehyde A1, and a suitable inorganic base are mixed together simultaneously in step 3 to allow the production of compound I.

[0064] Furthermore, step 3 can be performed at a suitable temperature, for example, approximately 70-100 degrees Celsius. In some instances, step 3 is performed at approximately 70-85 degrees Celsius. In other instances, step 3 is performed at approximately 85-95 degrees Celsius. In yet another instance, step 3 is performed at approximately 90-100 degrees Celsius.

[0065] In a specific example, the compound of formula I-3 has the structure Furthermore, aldehyde A1 has a structure Step 3 is carried out in a molar ratio of 1:1.5 between the compound of formula I-3 and aldehyde A1. Alternatively or additionally, step 3 is carried out in the presence of an inorganic base (which may be Na2CO3) at a temperature of about 85-95 degrees Celsius.

[0066] Any suitable organic solvent can be used to dissolve the reagents used in step 3. Exemplary solvents include, but are not limited to, n-methyl-2-pyrrolidone (NMP), acetonitrile, etc. N,N -Dimethylformamide (DMF), 1,4-dioxane, dimethoxyethane, tetrahydrofuran (THF), Also known as The solvents are oxacyclopentane (2-methyloxacyclopentane) and 2-methyloxacyclopentane (2-MeTHF). In one example, n-methyl-2-pyrrolidone (NMP) is used as the organic solvent in step 3.

[0067] The reagents used in step 3 described herein, including compounds of formula I-3 and aldehyde A1, can be prepared by conventional methods or by the methods provided herein. In some embodiments, they can be prepared by using formula I-2... The compound or its salt is reacted with triphenylphosphine (PPh3) to obtain the compound of formula I-3, as illustrated in step 2 of scheme 1 below. In formula I-2, X can be any halide provided herein. In one example, X is Br. R3 and R4 are as defined herein. In some cases, R3 or R4 or both can be an unprotected -OH moiety. The molar ratio between the compound of formula I-2 and PPh3 can be from 2:1 to 1:2. In one example, the molar ratio between the two reagents can be about 1:1 (…). For example (1:1.1). In some implementations, this can be achieved by making formula I-2 The compound or its salt reacts with a phosphite or tributylphosphine (TBUP) to obtain the compound of formula I-3, as illustrated in step 2 of scheme 1 below. In formula I-2, X can be any halide provided herein. In one example, X is Br. R3 and R4 are as defined herein. In some cases, R3 or R4, or both, can be an unprotected -OH moiety. The molar ratio between the compound of formula I-2 and the phosphite or tributylphosphine (TBUP) can be from 5:1 to 1:5. In one example, the molar ratio between the two reagents can be about 1:2 (e.g., 1:2.5). In other examples, the molar ratio between the two reagents can be about 1:3 (e.g., 1:2.9). The reaction in step 2 can be carried out at a suitable temperature, for example, about 20-35 degrees Celsius. In some examples, step 2 is carried out at a temperature of about 25-30 degrees Celsius. Organic solvents such as acetonitrile (ACN), toluene, or dichloromethane (DCM) can be used in the reaction in step 2.

[0068] Any compound of formula I-2 used as a substrate in step 2 can be prepared by conventional synthetic methods or methods disclosed herein. In some embodiments, the compound of formula I-2 can be prepared by making a compound of formula I-1... The compound or its salt reacts with boron tribromide (BBr3) to produce a compound of formula I-2, as described in step 1 of scheme 1 below. R3' and R4' are each independently H, -OH, -OMe, or -OEt, and at least one of R3' and R4' is -OMe or -OEt. In some instances, both R3' and R4' are -OMe. The molar ratio between the compound of formula I-1 and BBr3 can be from 2:1 to 1:5. In some instances, the molar ratio between the compound of formula I-1 and BBr3 can be from 1:1 to 1:4. In one instance, the molar ratio between the two reagents can be about 1:3.

[0069] In some embodiments, the compound of formula I-2 can be prepared by making the compound of formula I-1... The compound or its salt reacts with EtSNa, TMSI, MsOH, HBr, or BCl3 to produce a compound of formula I-2, as described in step 1 of Scheme 1 below. R3' and R4' are each independently H, -OH, -OMe, or -OEt, and at least one of R3' and R4' is -OMe or -OEt. In some instances, both R3' and R4' are -OMe. The molar ratio between the compound of formula I-1 and EtSNa, TMSI, MsOH, HBr, or BCl3 can be from 5:1 to 1:10. In some instances, the molar ratio between the compound of formula I-1 and EtSNa, TMSI, MsOH, HBr, or BCl3 can be from 1:1 to 1:6. In one instance, the molar ratio between the two reagents can be about 1:2. In other instances, the molar ratio between the two reagents can be about 1:3. In still other instances, the molar ratio between the two reagents can be about 1:4. In yet another example, the molar ratio between the two reagents can be approximately 1:5. Step 1 can be carried out at a suitable temperature, for example, approximately 20-30 degrees Celsius. In some examples, Step 2 is carried out at approximately 25 degrees Celsius. Organic solvents such as dichloromethane (DCM), n-methyl-2-pyrrolidone (NMP), methanesulfonic acid, acetic acid, or combinations thereof can be used in Step 1.

[0070] In some embodiments, after each step of the reaction (e.g., steps 1, 2, and / or 3 as described herein), the resulting compound can be isolated from the reaction mixture and purified. For example (by column chromatography). Alternatively, after the preceding step (e.g., step 1 and / or step 2), the resulting intermediate compound can be used directly in the next reaction step without separation or purification.

[0071] Unless explicitly described, one or more steps of the synthetic methods provided herein may include various bases and acids depending on the reactions performed. For example, Brønsted or Lewis bases or acids may also be used in the preparation methods of the present invention. Exemplary bases include, but are not limited to, triethylamine, pyridine, piperidine, 2,6-dimethylpyridine, pyrrolidine, toluene, diisopropylamine, diisopropylethylamine, sodium hydride, sodium hydroxide, and sodium carbonate. Exemplary Lewis acids according to the present invention include, but are not limited to, titanium tetrachloride, aluminum chloride, boron trifluoride, boron tribromide, dimethylboron bromide, phosphorus pentachloride, tin dichloride, and tin tetrachloride. In some embodiments, for example, alkylation or alkenylation processes are carried out with one or more bases. Similarly, in some embodiments, certain reaction steps of the methods of this disclosure may be carried out with a base ( For example The process is carried out in the presence of sodium hydride.

[0072] In further embodiments, the nucleophilic or electrophilic addition and substitution identified in the methods for preparing the compounds (including synthetic intermediates) of this disclosure have utilized various leaving groups or electrophilic groups. Such groups include, but are not limited to, halogens, methanesulfonyl groups, trifluoromethanesulfonates, acetyl groups, or p-toluenesulfonyl groups.

[0073] In some embodiments, certain substrates used in each step of the reactions involved in the synthetic method can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. By way of example, such substrate compounds used in the synthetic methods of this disclosure can be synthesized using the methods described herein, together with synthetic methods known in the field of synthetic organic chemistry, or by variations thereof as understood by those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules, as well as functional group transformations and manipulations, are available from relevant scientific literature or from standard textbooks in the art. Although not limited to any one or more sources, the classic texts incorporated herein, such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette (ed.), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), are known and recognized as useful and widely accepted reference textbooks in organic synthesis.

[0074] It should be understood that the synthetic methods disclosed herein are tolerant of a wide range of functional groups, and therefore a variety of substituted starting materials can be used. These methods typically provide the desired final compound at or near the end of the process, although in some cases it may be necessary to further convert the compound into its pharmaceutically acceptable salt.

[0075] In the synthetic schemes described herein, for simplicity, compounds may be drawn in a specific configuration. Such a specific configuration should not be construed as limiting this disclosure to one or another isomer, tautomer, regio isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regio isomers, or stereoisomers. However, it should be understood that a given isomer, tautomer, regio isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regio isomer, or stereoisomer.

[0076] Compound of formula (I) produced by the synthetic method disclosed herein For example Resveratrol oxide is also within the scope of this disclosure. Compounds of formula (I) synthesized in this manner (…) For example The synthesized resveratrol oxide can be a mixture of compounds in both the amorphous and hydrated forms. Compared to commercially available resveratrol oxide derived from plant sources, the synthesized compound was observed to have a lower proportion of the hydrated form.

[0077] II. Compositions containing resveratrol-type compounds

[0078] In some embodiments, the composition comprises a resveratrol-type compound, such as a resveratrol-type compound produced by any of the synthetic methods disclosed herein. In some embodiments, the resveratrol-type compound is resveratrol oxide. In some embodiments, the resveratrol-type compound is a salt of resveratrol oxide. In some embodiments, the resveratrol-type compound is a hydrate of resveratrol oxide. In some embodiments, the resveratrol-type compound is a crystalline form of resveratrol oxide. In some embodiments, the composition comprises at least one crystalline form of resveratrol oxide.

[0079] In some embodiments, the composition is a cosmetic composition. In some embodiments, the composition is a pharmaceutical composition.

[0080] Pharmaceutical Composition

[0081] In some embodiments, the composition is a pharmaceutical composition comprising the compounds described herein and pharmaceutically acceptable excipients, diluents, or carriers.

[0082] In some embodiments, the compounds described herein are active agents. In some embodiments, any active agent (optionally a hydrophilic therapeutic agent) and a nonionic surfactant (which can form micelles with the active agent and optionally a hydrophilic therapeutic agent) can be formulated into a pharmaceutical composition for the therapeutic applications disclosed herein.

[0083] In some embodiments, the pharmaceutical compositions disclosed herein comprise one or more resveratrol-type compounds. In some embodiments, the pharmaceutical compositions described herein comprise a compound wherein the compound is used to alleviate symptoms caused by abnormal subcutaneous deposition of adipose tissue or fat. For example An active agent for lipomas or liposarcomas. See also For example WO2023 / 221945, the relevant disclosures of which are incorporated herein by reference for the purposes and purposes of this document. As disclosed herein, the active agents can form micelles (a first plurality of micelles) with suitable nonionic surfactants (such as those disclosed herein). The pharmaceutical compositions disclosed herein may also comprise a second plurality of micelles formed from a hydrophilic agent and a suitable nonionic surfactant.

[0084] The pharmaceutical composition used in the method of the present invention may comprise a pharmaceutically acceptable carrier, excipient, or stabilizer in the form of a lyophilized formulation or an aqueous solution. (Remington: The Science and Practice of Pharmacy, 20th edition (2000), Lippincott Williams and Wilkins, edited by KE Hoover). The acceptable carrier, excipient, or stabilizer is non-toxic to the recipient at the dose and concentration used and may include: buffers, such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexahydroquinone quaternary ammonium chloride; benzyl alkyl ammonium chloride, benzyl chloride; phenolic alcohols, butanol, or benzyl alcohol; alkyl parabens, such as methyl or propyl parabens; catechol; resorcinol; cyclohexanol; 3-pentanol; and... m-Cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextran; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes ( For example (Zn-protein complex); and / or nonionic surfactants, such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[0085] In other instances, the pharmaceutical compositions described herein may be formulated into sustained-release forms. Suitable examples of sustained-release formulations include a semi-permeable matrix of a solid hydrophobic polymer containing an antibody, in the form of a molded article, such as a membrane or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides (US Patent No. 3,773,919), copolymers of L-glutamic acid and 7-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate)), sucrose isobutyrate acetate, and poly-D-(-)-3-hydroxybutyric acid.

[0086] For in vivo The administered pharmaceutical composition must be sterile. This is easily achieved, for example, by filtration through a sterile filter membrane. Therapeutic antibody compositions are typically placed in containers with sterile access ports, such as intravenous solution bags or vials with stoppers that can be punctured by a hypodermic needle.

[0087] The pharmaceutical compositions described herein may be in unit dosage forms, such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral, or rectal administration, or for administration by inhalation or blowing. For example, such pharmaceutical compositions may be formulated in a manner suitable for administration via appropriate routes, such as oral, parenteral, topical, intravenous, rectal, oral, vaginal, or via implantable receptacle.

[0088] Sterile injectable compositions, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents (such as polysorbate 80) and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, for example, in the form of a solution in 1,3-butanediol. Acceptable solvents and media that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are routinely used as solvents or suspension media (e.g., synthetic mono- or diglycerides of glycerol). Fatty acids such as oleic acid and their glyceride derivatives can be used to prepare injectable formulations, as can naturally occurring, pharmaceutically acceptable oils (such as olive oil or castor oil, especially in their polyoxyethyleneized form). These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersants. Other commonly used surfactants (such as Tween or Span) or other similar emulsifiers or bioavailability enhancers commonly used to manufacture pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.

[0089] In some embodiments, the compositions described herein can be formulated into topical preparations, such as creams, lotions, or gels for topical application. Such creams, lotions, or gels can be formulated using ingredients known in the art as suitable for topical pharmaceuticals.

[0090] The carrier in a pharmaceutical composition must be "acceptable" in the sense of compatibility with the active ingredient of the formulation (and preferably, the ability to stabilize the active ingredient), and harmless to the subject to be treated. For example, solubilizers such as cyclodextrin (which form more soluble complexes with oxadiazole compounds) or more solubilizers may be used as pharmaceutical carriers to deliver oxadiazole compounds. Examples of other carriers include colloidal silica, magnesium stearate, sodium dodecyl sulfate, and D&C Yellow #10.

[0091] In some embodiments, the pharmaceutical compositions disclosed herein may also contain antioxidants. Examples include, but are not limited to, beta-carotene, lutein, lycopene, bilirubin, vitamin A, vitamin C (ascorbic acid), vitamin E, uric acid, nitric oxide, nitrogen oxides, pyruvate, catalase, superoxide dismutase, glutathione peroxidase, N-acetylcysteine, and naringenin, or combinations thereof.

[0092] III. Therapeutic uses of Formula I compounds

[0093] In some respects, this article provides methods for alleviating (e.g., treating) symptoms caused by abnormal subcutaneous deposition of adipose tissue and / or fat using any of the pharmaceutical compositions disclosed herein.

[0094] In some implementations, symptoms caused by abnormal subcutaneous deposition of adipose tissue and / or fat can be tumors of adipose tissue, which may lead to abnormal deposition of fat cells / tissue (adipose tissue) and / or fat under skin patches (subcutaneous tissue). In some instances, tumors of adipose tissue can be benign, such as lipomas. In other instances, tumors of adipose tissue can be malignant, such as liposarcomas. See also For example The relevant public information in WO2023 / 221945 is incorporated herein by reference for the purposes and purposes of this paper.

[0095] For the purposes of this disclosure, the appropriate dosage of the pharmaceutical composition described herein will depend on the specific active agent and optional hydrophilic agent used, the type and severity of the disease / symptom, whether the composition is administered for prophylactic or therapeutic purposes, prior therapy, the patient's clinical history and response to the active agent, and the judgment of the attending physician. Typically, clinicians will administer the pharmaceutical compositions disclosed herein until a dosage is reached to achieve the desired outcome.

[0096] In some implementations, the desired outcome is a reduction or elimination of lipomas or liposarcomas, or a reduction in at least one symptom associated with lipoma-related conditions (e.g., pain) or liposarcoma-related conditions. Methods for determining whether a dose produces the desired outcome will be apparent to those skilled in the art. The specific dosing regimen used in the methods described herein—i.e., the dose, timing, and repetition—will depend on the specific subject and the subject's medical history. The therapeutic efficacy of the target disease / condition can be evaluated using methods well-known in the art.

[0097] Depending on the type or location of the disease to be treated, the pharmaceutical composition may be administered to the subject using conventional methods known to those skilled in the art in the medical field. The composition may also be administered via other conventional routes, such as parenteral administration, topical administration, or administration via an implantable receptacle. Alternatively, it may be administered to the subject via an injectable receptacle route, such as using injectable or biodegradable materials and methods with 1-month, 3-month, or 6-month receptacles.

[0098] In one embodiment, the pharmaceutical compositions disclosed herein are administered via site-specific or targeted local delivery techniques. Examples of site-specific or targeted local delivery techniques include various implantable reservoir sources or local delivery catheters (such as infusion catheters, indwelling catheters or needle catheters, synthetic grafts, outer membrane wrappings, shunts and stents or other implantable devices), site-specific loads, direct injection, or direct application.

[0099] In some instances, the pharmaceutical compositions disclosed herein are administered to subjects by injection, such as intramuscular (IM), subcutaneous (SC), intravenous (IV), intraosseous, epidural, intradermal (ID), or any other form of injection.

[0100] Without further elaboration, it is believed that those skilled in the art can utilize the invention to the fullest extent based on the foregoing description. Therefore, the following specific embodiments should be interpreted as illustrative only and do not limit the remainder of this disclosure in any way. All publications cited herein for the purposes or subject matter are incorporated herein by reference.

[0101] Example

[0102] Unless otherwise instructed, the practice of this disclosure will employ conventional molecular biology (including recombinant technologies), microbiology, cell biology, biochemistry, chemistry, and immunology techniques.

[0103] Example 1 Synthetic resveratrol oxide

[0104] Introducing protecting groups into the hydroxyl groups of the reaction substrate presents challenges during the Wittig reaction and deprotection phases. Therefore, this example investigates the use of unprotected substrates in the synthesis of oxidized resveratrol via the Wittig reaction. Protecting groups such as methyl groups on the hydroxyl groups of the reaction substrate are removed beforehand. The synthetic scheme is illustrated in Scheme 1 below.

[0105] Option 1:

[0106] Step 1: Preparation of ORV-SM7B

[0107] ORV-SM7 (1.0 equivalent), BBr3 (3.0 equivalent), and DCM (10.0 v) were reacted at 25 °C. Then, under nitrogen protection, dichloromethane (5 L, 5.0 v) and ORV-SM7 (1.0 kg, 1.0 equivalent) were added to the reaction mixture. The reaction was then cooled to 0 ± 5 °C, and boron tribromide (2.3 kg, 2.1 equivalent) was added dropwise. After the addition was complete, the temperature was raised to 25 ± 5 °C and maintained for approximately 2 hours. Purified water (5.0 L, 5.0 v) was added to another reaction flask, and the mixture was cooled to 0 ± 5 °C. The reaction mixture was then added dropwise to ice water, where a white solid gradually precipitated. The reaction efficiency was analyzed by HPLC. For comparison, ORV-SM7 was used as a standard, where the peak area of ​​ORV-SM7 was ≤1%.

[0108] ORV-SM7B was separated from the reaction mixture without further purification by adding it to ice water, stirring the mixture, and filtering. The precipitate contained ORV-SM7B.

[0109] Step 2: Preparation of ORV-SM7C

[0110] ORV-SM7B (1.0 equivalent), PPh3 (1.1 equivalent), and ACN (10.0 v) were reacted at 25–30 °C. Under nitrogen protection, ACN (10 L, 10.0 v) and ORV-SM7B (wet filter cake, 1.0 equivalent) were added sequentially to the reaction flask. The mixture was maintained at 25 ± 5 °C and stirred for 10–20 minutes. The mixture was filtered, and the filter cake was washed twice with ACN (2 L, 2.0 v). The filtrate was collected, and PPh3 (1.25 kg, 1.1 equivalent) was added. The temperature was adjusted to 25 ± 5 °C, and the mixture was stirred for at least 2 hours. The mixture was filtered, and the filter cake was washed twice with ACN (1 L, 1.0 v). The filter cake was collected and vacuum dried at 25 ± 5 °C until the LOD ≤ 2%. The collected off-white solid was ORV-SM7C.

[0111] For HPLC sampling, the standard is that the peak area of ​​ORV-SM7B is ≤1%.

[0112] ORV-SM7C was isolated and purified as follows. The reaction system was directly filtered, and the filter cake contained ORV-SM7C. ORV-SM7C was further purified by crystallization with NMP and MTBE. The NMR characterization of ORV-SM7C is as follows: 1 H NMR (300 MHz, methanol-) d 4) δ 7.95 – 7.82 (m, 3H), 7.79 – 7.64 (m, 9H), 7.69 – 7.59 (m, 4H), 6.21 (q, J = 2.2 Hz, 1H), 5.94 (t, J = 2.3 Hz, 2H), 4.72 (d, J = 14.8 Hz, 2H).

[0113] Step 3: Preparation of ORV

[0114] The reaction in step 3 is described in detail below: 1. Under nitrogen protection, NMP (12 L, 10.0 v), ORV-SM4 (534 g, 1.5 equivalent) and ORV-SM7C (1.2 Kg, 1.0 equivalent) were added sequentially to the reactor.

[0115] 2. Stir for 5-10 minutes to dissolve and clarify the system, then add Na2CO3 (1.37 kg, 5.0 equivalent).

[0116] 3. Heat the reaction system to 100±5℃ and keep it away from light for at least 16 hours.

[0117] 4. For sampling and testing, the standard is that the peak area of ​​ORV-SM7C is ≤5%.

[0118] 5. Prepare a 20% acetic acid solution (12 L, 10.0 v) and a 36% sodium chloride aqueous solution (12 L, 10.0 v).

[0119] 6. Add the two solutions prepared above to 2-MeTHF (12 L, 10.0 v) and cool to 5±5℃.

[0120] 7. Control the temperature at 5±5℃, add the reaction system dropwise to the three mixed solutions for quenching, separate the liquids and collect the organic phase.

[0121] 8. Use 2-MeTHF (9.6 L) 2,8.0 v 2) Extract the aqueous phase.

[0122] 9. Take samples for aqueous phase analysis and testing. The standard is that the ORV-0 content is ≤2%. If it is not qualified, continue extraction with 2-MeTHF (9.6L, 8.0 v) until it is qualified.

[0123] 10. Combine all organic phases and mix with 20% sodium chloride solution (12 L) 2, 10.0 v 2) Wash and collect the organic phase by liquid separation.

[0124] 11. Concentrate the organic phase to 2-3 volumes and take a sample for H-NMR analysis to calculate the volume of NMP relative to ORV-0.

[0125] 12. Add NMP to a volume of 4 and slowly drop it into MTBE (24 L, 20.0 v).

[0126] 13. Cool the system to 0±5℃ and continue stirring for at least 2 hours to crystallize.

[0127] 14. Filter and rinse MTBE (2.4 L) 2, 2.0 v 2) Filter cake and take samples to ensure that the peak area of ​​TPPO is ≤0.5% according to HPLC detection standard.

[0128] 15. If the filter cake is not up to standard, add the filter cake to NMP (2.4 L, 2.0 v), raise the temperature to 45-50°C, dissolve and clarify, and add MTBE (12 L, 10.0 v) dropwise to crystallize until it is up to standard.

[0129] 16. Dissolve the qualified filter cake in 2-MeTHF (6 L, 5.0 v) and use 5% sodium chloride aqueous solution (6 L) 2,5.0 v 2) Washing.

[0130] 17. Collect the washed organic phase and react it with EtOH (6 L) 3, 5.0 v 3) Concentrate to 10 volumes.

[0131] 18. Add activated carbon (0.36 kg, 0.3 wt.) to decolorize for at least 2 hours and then filter.

[0132] 19. Concentrate the filtrate to 2-3 volumes.

[0133] 20. Maintain the temperature at 35±5℃ and slowly add H2O (16.8 kg, 14.0 v). After the addition is complete, cool to 0±5℃.

[0134] 21. Filter and use H2O (1.2 kg) 2,1.0 v 2) Rinse the filter cake.

[0135] 22. Collect the filter cake, heat it to 50±5℃, and vacuum dry the material to LOD=2.0%.

[0136] The reaction efficiency was analyzed by HPLC sampling. The standards were: ORV-0 ≥ 98.0%; single impurity ≤ 0.5%.

[0137] ORV-0 purification conditions: First purification: Add the crude product to NMP (2.0 v), raise the temperature to 45-50°C, dissolve and clarify, add MTBE (10.0 v) dropwise, and cool to 0±5°C for crystallization.

[0138] Second purification: The crude product was dissolved in ethanol (2.0 v), the temperature was raised to 35 ± 5 °C, and H₂O (14.0 v) was slowly added dropwise. After the addition was complete, the mixture was cooled to 0 ± 5 °C to allow for crystallization.

[0139] ORV-0 NMR characterization: 1 H NMR (300 MHz, DMSO- d 6) δ 9.59 (s, 1H), 9.41 (s, 1H), 9.16 (s, 2H), 7.35 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 16.5 Hz, 1H), 6.77 (d, J = 16.5 Hz, 1H), 6.34 (dd, J = 6.0, 2.2 Hz, 3H), 6.25 (dd, J = 8.4, 2.4 Hz, 1H), 6.08 (t, J = 2.1 Hz, 1H).

[0140] Table 1 summarizes the synthesis efficiency.

[0141] Table 1. Reaction tests and % yield ORV-0A (structure shown below) refers to the byproduct 5-methylphenyl-1,3-diol.

[0142]

[0143] Example 2: Solid form analysis of oxidized resveratrol

[0144] The bio-extracted resveratrol samples were characterized and analyzed compared to the resveratrol samples synthesized using the methods described herein. The resveratrol samples contained both crystalline form I and crystalline form III, but in different proportions. Crystalline form I was anhydrous crystals, while crystalline form III was hydrated crystals. Commercially available extraction sources had a higher proportion of hydrated crystals, and the water of crystallization signal in the raw materials was visible in the DSC spectrum.

[0145] XRPD data

[0146] X-ray powder diffraction (XRPD) measurements were performed to evaluate the comparison between bio-extracted oxidized resveratrol (C) and oxidized resveratrol (D) synthesized using the methods described herein. Measurements were performed after dynamic vapor adsorption (DVS) and drying at 150 °C. Table 2 below lists the peaks (2-θ) for sample A (type III), sample B (type I), sample C (commercially available), and sample D (synthesized by the method described above).

[0147] Table 2. Characteristic XRPD peaks

[0148] PSD data

[0149] like Figure 1A and 1B As shown, the particle size distribution (PSD) of oxidized resveratrol (bottom) synthesized using the methods described herein and bio-extracted oxidized resveratrol (top) were evaluated using particle size analysis.

[0150] DSC data

[0151] Differential scanning calorimetry (DSC) was also used to determine the crystallinity of C and D. For example... Figure 2A The figure shows the normalized enthalpy of 44.403 J / g at a peak temperature of 82.92 degrees Celsius, and... Figure 2B The normalized enthalpy of crystallization (113.51 J / g) is shown at temperatures above 200°C. A signal of water of crystallization in sample C is observed at approximately 83°C in the DSC spectrum. The descending peak near 83°C is a characteristic signal indicating the presence of the hydrate crystal form.

[0152] TGA data

[0153] like Figure 3A and 3BAs shown, thermogravimetric analysis (TGA) was performed on C and D. C shows a weight percentage loss of 1.228% at 190.00 degrees Celsius, and D shows a weight percentage loss of 0.540% at 200 degrees Celsius.

[0154] Example 3: Bioactivity in inhibiting melanin production

[0155] This embodiment explores the bioactivity of the synthesized oxidized resveratrol compound relative to commercially available oxidized resveratrol extracted from plant sources in inhibiting melanin production. The test conditions are summarized in Table 3 below.

[0156] Table 3. Test Group

[0157] As shown in Tables 4 and 5 below, both commercially available and synthetic oxidized resveratrol inhibited α-MSH-induced melanin production. Compared to commercially available resveratrol, synthetic resveratrol exhibited greater inhibitory activity, for example, at 128 μM.

[0158] Table 4. Inhibition of melanin by oxidized resveratrol at 32 μM

[0159] Table 5. Inhibition of melanin by oxidized resveratrol at 128 μM

[0160] All features disclosed in this specification can be combined in any combination. Each feature disclosed in this specification can be replaced by an alternative feature for the same, equivalent, or similar purpose. Therefore, unless otherwise expressly stated, each disclosed feature is merely an example of an equivalent or similar feature in a general series.

[0161] From the above description, those skilled in the art can readily determine the essential characteristics of the present invention, and various changes and modifications can be made to adapt it to various uses and conditions without departing from the spirit and scope of the invention. Therefore, other embodiments are also within the scope of the claims.

[0162] equivalent

[0163] While several inventive embodiments have been described and illustrated herein, various other means and / or structures will readily conceive of those skilled in the art for performing the functions described herein and / or obtaining these results and / or one or more of these advantages, and each of such variations and / or modifications is considered to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily understand that all parameters, dimensions, materials, and configurations described herein are exemplary, and actual parameters, dimensions, materials, and / or configurations will depend on one or more specific applications using the teachings of this invention. Those skilled in the art will recognize or be able to identify many equivalents of the specific inventive embodiments described herein using only conventional experiments. Therefore, it should be understood that the foregoing embodiments are presented by way of example only, and that the inventive embodiments may be practiced in ways other than those specifically described and claimed within the scope of the appended claims and their equivalents. The inventive embodiments disclosed herein relate to each individual feature, system, article, material, kit, and / or method described herein. Furthermore, any combination of two or more such features, systems, articles, materials, toolkits and / or methods that does not contradict each other is included within the scope of this invention disclosure.

Claims

1. A preparative compound of formula I: (Formula I), or a salt thereof, the method comprising: Compound I-3: (Formula I-3) or its salts and aldehyde A1: (A1); contact under conditions suitable for forming a compound of formula I or a salt thereof; and R1, R2, R3, and R4 are each independently selected from the following groups: H, -OH, -OMe, and -OEt; At least one of R1, R2, R3, and R4 is -OH; and Where X is a halide.

2. The method according to claim 1, wherein R1 and R2 are each -OH.

3. The method according to claim 1, wherein R3 and R4 are each -OH.

4. The method according to claim 1, wherein the molar ratio of the compound of formula I-3 to aldehyde Al is about 3:1 to 1:3, optionally about 1:1.

5.

5. The method according to claim 1, wherein the compound of formula I-3 is: 。 6. The method according to claim 1, wherein the aldehyde A1 is: 。 7. The method according to claim 1, wherein the compound of formula I is: (Compound 1).

8. The method of claim 1, wherein the contact step is carried out in the presence of an inorganic base.

9. The method according to claim 8, wherein the inorganic base is selected from the group consisting of: NaOC6H5, Na2SiO3, Ca(OH)2, Mg(OH)2, LiOH, Cs2CO3, K3PO4, t-buOK, K2CO3 and Na2CO3.

10. The method according to claim 8, wherein the inorganic base is Na2CO3 or K2CO3, optionally Na2CO3.

11. The method of claim 8, wherein the compound of formula I-3 is contacted with the base prior to contact with the aldehyde Al.

12. The method of claim 8, wherein the compound of formula I-3 is contacted with the base after being contacted with the aldehyde Al.

13. The method according to claim 8, wherein the compound of formula I-3 is contacted with the base while simultaneously contacting the aldehyde Al.

14. The method of claim 1, wherein the contacting step is carried out in the presence of an organic solvent.

15. The method according to claim 14, wherein the organic solvent is n-methyl-2-pyrrolidone (NMP).

16. The method of claim 1, wherein the contact step is performed at a temperature of about 70-100 degrees Celsius.

17. The method of claim 16, wherein the contacting step is performed at a temperature of about 85-95 degrees Celsius.

18. The method according to claim 1, wherein the compound of formula I-3 is prepared by a method comprising the following steps: At approximately 25-30 degrees Celsius, compound I-2 is: Or its salt is contacted with triphenylphosphine (PPh3) under conditions suitable for forming compounds of formula I-3 or their salts.

19. The method according to claim 18, wherein, The compound of formula I-2 is prepared by a method comprising the following steps: At approximately 25 degrees Celsius, compound I-1 is: Or its salt is contacted with BBr3 under conditions suitable for forming a compound of formula I-2 or its salt, wherein R3' and R4' are each independently H, -OH, -OMe or -OEt, and wherein at least one of R3' and R4' is -OMe or -OEt.

20. The method according to claim 19, wherein the compound of formula I-1 is: .

21. A compound of formula (I), (Formula I), or a salt thereof, prepared by the method according to claim 1; R1, R2, R3, and R4 are each independently selected from the following groups: H, -OH, -OMe, and -OEt; and At least one of R1, R2, R3, and R4 is -OH.

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