Process for preparing benzoic acid esters and their intermediates

Abstract

The present invention relates to a compound of formula (I), a pharmaceutically or cosmetically acceptable salt thereof, or any stereoisomer thereof, wherein R’ is selected from the group consisting of H, (C1-C6)-alkyl, and (C3-C6)-cycloalkyl; R1, R2, R4, R5, R6, R7, R9, and R 10 are independently radicals selected from the group consisting of H, hydroxy, amino, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkylamino, and (C1-C6)-dialkylamino; R3 and R8 are independently selected from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy, hydroxy, amino, (C1-C6)-alkylamino, and (C1-C6)-dialkylamino), and relates to a process for preparing the same, which process comprises a beta-elimination reaction of the corresponding alkyl halide precursor in the presence of DBU and a suitable solvent. The present invention also relates to intermediates useful in such a preparation process. [Chemical 1] TIFF2025522152000022.tif95160

Description

Technical Field

[0001] This application claims the benefit of European Patent Application No. EP22382681, filed on July 15, 2022.

[0002] Field of the Invention The present invention relates to a process for the preparation of benzoic acid ester compounds and to some novel intermediates useful in said process.

Background Art

[0003] Several benzoic acids are described as photochemical precursors of ultraviolet absorbers. These photoprotective activities are due to the fact that they are readily photochemically converted in situ to sunscreen compounds with high UV protection ability.

[0004] The compounds of formula (I) can be obtained by various methods disclosed in the art. Thus, International Patent Publication No. 2006 / 100225 discloses benzoic acid ester compounds and a process for their preparation based on the reaction of an acyl halide with an intermediate silyl enol ether according to the following scheme, where R1-R21 and R' have defined values.

Chemical Formula

[0005] Another process for the preparation of a specific benzoic acid ester compound, 1-(4-methoxyphenyl)vinyl 4-(tert-butyl)benzoate, is disclosed in “Dose-dependent progressive sunscreens. A new strategy for photoprotection?”, Photochemical & Photobiological Sciences (2010), 9(4), 530-534 (D2), and the following scheme illustrates this process:

Chemical Formula

[0006] Another process for preparing certain benzoic acid ester compounds has been disclosed by Noriko et al. and relates to the reaction of an alkyne having an aromatic substituent with NXS (X is selected from Cl, Br, and I) and AcOH, followed by multi-substituted enol ester synthesis based on a coupling reaction (see Noriko Okamoto et al, ,, Regio- and Stereoselective Multisubstituted Enol Ester Synthesis” JOC, 2011, vol. 76, pp. 9133-9138).

[0007] A process for preparing 2-chloroethyl benzoate based on a carbonylative synthesis co-catalyzed by palladium / aluminum from an epoxide and an aryl iodide has been disclosed in the art (see Qi Xinxin et al.; “Palladium / aluminium-cocatalyzed carbonlylative synthesis of 2-chloroethyl benzoates from epoxides and aryl iodides”, Journal of Organometallic Chemistry, 2020, vol. 910, 121114).

[0008] However, research on novel preparation processes for these benzoic acid esters with good yields and purity and that can be carried out on an industrial scale remains an active field. Therefore, the provision of a novel preparation process for such compounds is highly desirable.

Summary of the Invention

[0009] The inventors have found a novel process for preparing benzoic acid esters that proceeds with good yields, good purity, and can be carried out on an industrial scale.

[0010] Accordingly, a first aspect of the present invention is a compound of formula (I): [Chemical formula] (wherein, R’ is selected from the group consisting of H; (C 1- C6)-alkyl and (C 3- C6)-cycloalkyl, R1, R2, R4, R5, R6, R7, R9, and R 10 are each independently a radical selected from the group consisting of H, hydroxy, amino, (C 1- C6)-alkyl, (C 1- C6)-alkoxy, (C 1- C6)-alkylamino, and (C 1- C6)-dialkylamino, R3 and R8 are each independently (C 1- C6)-alkyl, (C 1- C6)-alkoxy, hydroxy, amino, (C 1- C6)-alkylamino, and (C 1- C6)-dialkylamino selected from the group consisting of), a process for preparing a pharmaceutically or cosmetically acceptable salt thereof, or any stereoisomer or mixture thereof, which comprises reacting a compound of formula (II) or a suitable salt thereof: [Chemical formula] (wherein, R’, R 1- R 10 are as defined for the compound of formula (I) and X is halogen) with a strong non-nucleophilic base. The process is related to this step.

[0011] Another aspect of the present invention is the compound of formula (II) or a salt thereof as described above (wherein R’ is H, and R1, R2, R4, R5, R6, R7, R9, and R 10is, independently, a radical selected from the group consisting of H, hydroxy, amino, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkylamino, and (C1-C6)-dialkylamino, R3 and R8 are, independently, selected from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy, hydroxy, amino, (C1-C6)-alkylamino, and (C1-C6)-dialkylamino, and X is a halogen selected from the group consisting of Cl, Br, and I).

BEST MODE FOR CARRYING OUT THE INVENTION

[0012] For the purposes of the present invention, all ranges provided include both the upper and lower endpoints of that range. Ranges provided, for example, of temperature, time, size, etc., are considered approximate values unless otherwise specified.

[0013] The term "room temperature", as disclosed herein, represents the temperature of an environment without heating or cooling and generally consists of 20 to 25 °C.

[0014] Throughout this specification and the claims, the terms (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkylamino, and (C1-C6)-dialkylamino are to be construed as being straight-chain or branched.

[0015] As described above, a compound of formula (I), a pharmaceutically or cosmetically acceptable salt thereof, or any stereoisomer or mixture thereof (wherein R’ is H; (C 1- C6)-alkyl and (C 3- C6)-cycloalkyl selected from the group consisting of R1, R2, R4, R5, R6, R7, R9, and R 10 are, independently, H, hydroxy, amino, (C 1- C6)-alkyl, (C 1- C6)-alkoxy, (C 1- C6)-alkylamino, and (C 1-a radical selected from the group consisting of (C6)-dialkylamino, and R3 and R8 are independently (C 1- C6)-alkyl, (C 1- C6)-alkoxy, hydroxy, amino, (C 1- C6)-alkylamino, and (C 1- C6)-dialkylamino) and a process for preparing the same, said process comprising reacting a compound of formula (II) (wherein R′, R 1- R 10 is as defined for the compound of formula (I) and X is a halogen as defined above) with a strong non-nucleophilic base in the presence of a suitable solvent, the process is part of the present invention.

[0016] When R′ is different from H, the compound of formula (I) exhibits cis-trans isomerism. The process according to the present invention for preparing any one or a mixture of the isomers of the compound of formula (I) as defined above forms part of the present invention. Generally, a mixture of isomers is obtained. If desired, the isomers can be separated by conventional purification means.

[0017] In a particular embodiment, the process is a process in which R′ is H in the compound of formula (I).

[0018] In another particular embodiment, the process is a process in which in the compound of formula (I) and the compound of formula (II), R1, R2, R4, R5, R6, R7, R9, and R 10 are independently radicals selected from the group consisting of H, hydroxy, amino, and methyl.

[0019] In another particular embodiment, the process is a process in which in the compound of formula (I) and the compound of formula (II), R2, R4, R7, and R9 are H.

[0020] In another specific embodiment, the process is a process in which X is bromine in the compound of formula (II). In another specific embodiment, in the compounds of formula (I) and formula (II), R’, R1, R2, R4, R5, R6, R7, R9, and R 10 are H, R3 is tert-butyl, and R8 is methoxyl. Preferred compounds produced by the process of the present invention are: 1-phenylvinyl 4-methoxybenzoate; 1-(4-methoxyphenyl)-vinyl 4-tert-butylbenzoate; 1-(4-tert-butylphenyl)vinyl 4-methoxybenzoate; and 1-phenylvinyl 4-tert-butylbenzoate.

[0021] A non-nucleophilic strong base, as used herein, refers to a sterically hindered organic base that is an insufficient nucleophile. Common non-nucleophilic bases are bulky, so that protons can bind to the base center, but alkylation and complexation are inhibited. Examples of non-nucleophilic strong bases are 1,8-diazabicycloundec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), lithium diisopropylamide; silicon-based amides such as sodium and potassium bis(trimethylsilyl)amide (NaHMDS and KHMDS, respectively), lithium tetramethylpiperidide (LiTMP). Other non-nucleophile strong bases can be inorganic bases such as sodium hydride and potassium hydride.

[0022] In a specific embodiment, the non-nucleophilic strong base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, IIIa) and 1,1,3,3-tetramethylguanidine (TMG, IIIb).

Chemical formula

[0023] Generally, the amount of the non-nucleophilic strong base is in the range of 1 to 3 equivalents per equivalent of the compound (II).

[0024] Suitable solvents for this reaction are, for example, (C6-C8) aromatic hydrocarbons such as toluene or xylene, or (C1-C3)-chlorine-containing solvents such as dichloromethane or dichloroethane.

[0025] Generally, the reaction is carried out at a temperature in the range of 20 to 90 °C. In certain embodiments, the reaction is carried out at a temperature in the range of 60 to 80 °C. In another specific embodiment, the reaction is carried out at a temperature in the range of 70 to 75 °C.

[0026] The term "suitable salt" refers to a non-toxic salt. Since some of the compounds of formula (I) are basic compounds, the salts can be prepared with pharmaceutically or cosmetically acceptable non-toxic acids.

[0027] Also, the compounds of formula (II) can be in the form of non-toxic salts. In certain embodiments, the salts are pharmaceutically or cosmetically acceptable salts, similar to the compounds of formula (I).

[0028] The term "pharmaceutically or cosmetically acceptable salt", when used herein with respect to either of the compounds (I) and (II), encompasses any salt formed from organic and inorganic acids such as hydrobromic acid, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, adipic acid, aspartic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, glutamic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, oxalic acid, pivalic acid, propionic acid, p-toluenesulfonic acid, succinic acid, tartaric acid, etc.

[0029] The preparation of a pharmaceutically or cosmetically acceptable salt of a compound of formula (I) or a compound of formula (II) can be carried out by methods known in the art. For example, they can be prepared from the parent compound containing a basic moiety by conventional chemical methods. Generally, such salts are prepared, for example, by reacting the free base form of these compounds with a stoichiometric amount of a suitable pharmaceutically or cosmetically acceptable acid in water or an organic solvent or a mixture thereof.

[0030] When preparing a compound of formula (I) using a non-toxic salt of a compound of formula (II), if desired, this can be converted to the free base in advance by reaction with a suitable base. Alternatively, this can be used in the reaction in salt form.

[0031] The compounds of formula (I) may be in any crystalline form of the free solvate or solvate (e.g., hydrate), and both forms are intended to be within the scope of the present invention. Methods of solvation are generally known within the art.

[0032] The term "solvate" refers to a molecular complex containing a compound of formula (I) or a salt thereof and a stoichiometric or non-stoichiometric amount of one or more solvent molecules bound by non-covalent intermolecular forces. When one or more solvent molecules forming part of the molecular complex are water, the solvate is a hydrate.

[0033] The compound of formula (I) or a salt thereof can be further purified, for example, by crystallization in a suitable solvent. Examples of suitable solvents are (C2-C6) alcohols such as ethanol or 2-propanol. The compound of formula (I) can be obtained with a purity of more than 99% by HPLC. In certain embodiments, the compound of formula (I) is obtained with a purity of 99.5% or more. Other solvents suitable for the purification step are (C6-C8) aromatic hydrocarbons such as toluene or xylene, (C1-C3)-chlorine-containing solvents such as dichloromethane, dichloroethane, or a mixture of (C6-C8) aromatic hydrocarbon and (C2-C6)-alcohol. In certain embodiments, the solvent mixture is 2-propanol / toluene.

[0034] Compound (II) can be prepared by a process comprising reacting a compound of formula (IV) with a compound of formula (V) or a stereoisomer or a mixture thereof as defined below, in the presence of a suitable solvent (wherein R’, R1-R 10 are as defined for the compound of formula (I) and X is a halogen selected from the group consisting of Cl, Br, and I).

Chemical formula

[0035] Thus, when R’ is different from H, the compound of formula (V) also exhibits cis-trans isomerism. The process according to the invention for preparing the compound of formula (II) from any of the isomers or mixtures thereof of the compound of formula (V) as defined above forms part of the present invention. For the compound of formula (I), generally a mixture of isomers is obtained. If desired, the isomers can be separated by conventional purification means.

[0036] In certain embodiments, the process for preparing the compound of formula (II) is a process carried out in the presence of a coupling agent capable of intervening in the conversion of an acyl halide to an ester. In certain embodiments, the coupling agent is selected from the group consisting of 4-dimethylaminopyridine (DMAP), pyridine, 4-pyrrolidinopyridine (PPY), collidine isomers, i.e., trimethyl derivatives of pyridine, such as 3,4,5-collidine, 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine, and N-methylimidazole. In another particular embodiment, the coupling agent is N,N-dimethylaminopyridine (DMAP).

[0037] Generally, an amount contained in the range of 1 to 1.5 equivalents of the coupling agent is used. In certain embodiments, this step is carried out in the presence of an amount contained in the range of 1.2 to 1.5 equivalents per equivalent of the compound of formula (IV). Optionally, a tertiary amine that can assist in the in-situ regeneration of the catalyst can also be present. In certain embodiments, an amount of 1 equivalent of DAMP is used and a tertiary amine is also present. An example of a suitable tertiary amine is triethylamine. When using a tertiary amine, DMAP can be used in a sub-stoichiometric amount such as 0.2 equivalent.

[0038] Suitable solvents for the reaction are, for example, (C6-C8) aromatic hydrocarbons such as toluene or xylene, and (C1-C3)-chlorine-containing solvents such as dichloromethane or dichloroethane.

[0039] Generally, the reaction is carried out at a temperature contained in the range of 0 °C to 50 °C. In certain embodiments, the reaction is carried out at a temperature contained in the range of 10 to 40 °C. In another particular embodiment, the reaction is carried out at a temperature contained in the range of 25 to 40 °C.

[0040] The compound of formula (IV) is, in the presence of a suitable solvent, the following formula (VI):

Chemical formula

[0041] with a halogenating agent. The halogenating agent can be selected from the group consisting of SO2Cl2, SOCl2, PBr3, and PBr5, which gives a compound of formula (IV) where X is Cl or Br. In certain embodiments, the halogenating agent is SOCl2.

[0042] Acyl chlorides can react with HF to provide acyl fluorides. They can also be prepared directly from carboxylic acids using PPh3, NBS and Et3N-3HF. Acyl iodides can be obtained, for example, by the reaction of acetyl iodide with a monocarboxylic acid.

[0043] Suitable solvents are, for example, (C6-C8) aromatic hydrocarbons such as toluene or xylene, or (C1-C3)-chlorine-containing solvents such as dichloromethane or dichloroethane.

[0044] The reaction of the compound of formula (VI) with the halogenating agent is generally carried out at a temperature in the range of 50 °C to 120 °C. In certain embodiments, the reaction is carried out at a temperature in the range of 60-90 °C. In another particular embodiment, the reaction is carried out at a temperature in the range of 70 °C to 90 °C.

[0045] After termination of the reaction, the excess halogenating agent can be separated, for example, by successive cycles of toluene addition followed by its distillation. The product can also be purified, for example, by distillation.

[0046] ​The compound of formula (V) can be prepared by a process comprising the step of reacting a compound of formula (VII) with a reducing agent in the presence of a solvent in either its isomeric form or a mixture thereof to yield the compound of formula (V), where R’, R6, R7, R8, R9, and R 10 are as defined in any of the embodiments of the compound of formula (I) and X is a halogen). [Chemical formula]

[0047] Suitable solvents are, for example, protic solvents such as (C1-C6) alcohols. In certain embodiments, the solvent is methanol. In another specific embodiment, the reducing agent used in the process for preparing compound (V) is sodium borohydride or lithium aluminum hydride.

[0048] The reaction of the compound of formula (VII) with the reducing agent is generally carried out at a temperature in the range of -10 °C to 15 °C. In certain embodiments, the reaction is carried out at a temperature within the range of -10 °C to 0 °C. In certain embodiments, the reaction is carried out at a temperature within the range of -10 to (-5) °C.

[0049] The product can be isolated by extraction with a solvent such as toluene followed by evaporation to dryness. Alternatively, the organic solution can be used directly in the next step, and preferably, the water that may be present in the solution is removed, for example, by evaporation.

[0050] This process may include the step of performing a preparation step for preparing the compound (VII) and a further step for its conversion with the compound (II) without isolating the compound of formula (VII).

[0051] Some of the intermediates (IV) - (VII) for preparing the compounds of formula (I), other than the compounds of formula (II), may also be in the form of non-toxic salts. These salts can be the salts disclosed above. In certain embodiments, intermediates (IV) - (VII) are used in the form of the free base.

[0052] The preparation of salts of these intermediates involved in the process of the present invention can be carried out by methods known in the art. For example, they can be prepared from the parent compounds containing basic moieties by conventional chemical methods. Generally, these salts are prepared, for example, by reacting the free base form of these compounds with a stoichiometric amount of a suitable non-toxic acid in a suitable solvent.

[0053] Regarding the specific conditions for carrying out the steps of the process of the present invention, those skilled in the art are aware of how to adjust the respective parameters of the above steps from the perspective of the description and examples of the present invention.

[0054] The provision of a single reaction step for preparing compound (I) from compound (II) of the overall process of the present invention, as well as the provision of a combination of two or more consecutive steps of the overall process including the step of converting compound (II) to compound (I), are part of the present invention.

[0055] Scheme I illustrates the overall process for preparing a specific compound of formula (I) wherein R’, R1, R2, R4, R5, R6, R7, R9, and R 10 is H, R3 is tert-butyl, and R8 is methoxyl).

Chemical formula

[0056] The process of the present invention can be carried out in consecutive steps where the resulting intermediates are isolated, or alternatively, some of the steps of the present invention can be carried out in one pot.

[0057] The intermediate compound of formula (II) above or a salt thereof is novel. Thus, providing a novel compound of formula (II) or a salt thereof, which is an intermediate useful in the preparation of the benzoic acid ester according to the present invention, also forms part of the present invention.

[0058] The use of the compound of formula (II) as an intermediate for preparing the compound of formula (I) or a salt thereof is regarded as part of the present invention. The intermediate compound of formula (II) itself as a product is also part of the present invention. In formula (II), R’ is selected from the group consisting of H, (C1-C6)-alkyl, and (C3-C6)-cycloalkyl, and R1, R2, R4, R5, R6, R7, R9, and R 10 are independently radicals selected from the group consisting of H, hydroxy, amino, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkylamino, and (C1-C6)-dialkylamino, and R3 and R8 are independently selected from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy, hydroxy, amino, (C1-C6)-alkylamino, and (C1-C6)-dialkylamino, and X is a halogen selected from the group consisting of Cl, Br, and I.

Chemical formula

[0059] The term halogen means any of Cl, Br, and I. In certain embodiments, the compound of formula (II) is a compound in which X is bromine. In another embodiment, the compound of formula (II) is a compound in which R3 is tert-butyl. In another specific embodiment, the compound of formula (II) is a compound in which R8 is methoxyl. In another specific embodiment, the compound of formula (II) is a compound in which R’ is H. In another specific embodiment, in the compounds of formula (I) and formula (II), R1, R2, R4, R5, R6, R7, R9, and R 10is, independently, a process selected from the group consisting of H, hydroxy, amino, and methyl. In another specific embodiment, the process is a process in which in the compound of formula (I) and the compound of formula (II), R2, R4, R7, and R9 are H. In another specific embodiment, the compound of formula (II) is a compound in which R1, R5, R6, and R 10 is H.

[0060] Certain combinations of embodiments of the products between these are also embodiments of the products of compound (II) according to the present invention. In a specific embodiment, the compound of formula (II) is a compound in which R3 is tert-butyl and R8 is methoxyl. In another specific embodiment, the compound of formula (II) is a compound in which R’, R1, R2, R4, R5, R6, R7, R9, and R 10 is H.

[0061] Throughout this specification and the claims, the word "comprising" and variations of this word are not intended to exclude other technical features, additives, components, or steps. Further, the word "comprising" encompasses the case of "consisting of". Further objects, advantages, and features of the present invention may become apparent to those skilled in the art upon examination of this specification, or may be learned by practice of the present invention. The following examples are provided for illustration and are not intended to limit the present invention. Further, the present invention encompasses all possible combinations of the specific and preferred embodiments described herein.

[0062] Examples Example 1: Preparation of 2-bromo-1-(4-methoxyphenyl)ethan-1-ol (OBF) [Chemical formula]

[0063] CBF (100 g, 0.437 mol) was suspended in MeOH (370 mL) in a 2 L reactor equipped with mechanical stirring and a pressure-corrected dropping funnel under an inert atmosphere of N₂. This suspension was cooled to -5 °C and stirred for 15 minutes. A solution of NaBH₄ (16.55 g, 0.437 mol) and NaOH (80 mg) in MeOH (160 mL) at (-10)-(-3) °C was added to the reactor over 1.5 - 2.0 hours, and the temperature of the resulting mixture was maintained at -10 - -3 °C. After the addition was complete, the reaction mixture was further stirred at -10 - -3 °C for 5 - 10 minutes, and then the complete conversion of the starting material was confirmed by TLC. DCM (500 mL) was added to the reactor over 30 minutes while maintaining the temperature at -10 - -2 °C. The resulting mixture was stirred at -10 - -2 °C for 5 minutes. H₂O (400 mL) was added to the reactor over 45 minutes while maintaining the temperature at -5 - 0 °C. The resulting mixture was stirred at -5 - 0 °C for 10 minutes. This mixture was acidified from pH 11 - 12 to pH 1 - 2 by adding 85 mL of 6 M aqueous HCl solution to the reactor over 30 minutes while maintaining the temperature at -5 - -3 °C. The resulting mixture was stirred at -5 - -3 °C for 10 minutes. This stirring was stopped and the mixture was decanted for 15 minutes. The organic phase was washed with 3 × 250 mL of water while maintaining the temperature at 10 - 15 °C. The organic phase was dried over 20 g of MgSO₄ and the suspension was stirred at room temperature for 1 hour. This solution was filtered and concentrated under reduced pressure at 20 - 25 °C for about 6 hours until a constant weight was obtained to give 91.23 g (90% yield) of OBF as a light brown liquid (purity > 98% by HPLC).

[0064] Example 2: Preparation of 4-(tert-butyl)benzoyl chloride (ClBB) [Chemical formula]

[0065] ABB (4-(tert-butyl)benzoic acid, 600 g, 3.366 mol) was suspended in 1800 mL of toluene in a 5 L reactor equipped with mechanical stirring under an inert atmosphere of N2. This suspension was heated to 65 - 70 °C. Thionyl chloride (SOCl2, 800 g, 6.724 mol, 2 equivalents) was added to the reactor over 30 - 45 minutes, and the resulting mixture was maintained at 65 - 70 °C. The reaction mixture was heated to 80 - 90 °C for 20 minutes and stirred at this temperature for 3 hours until no gas evolution (SO2 and HCl) was observed. The remaining toluene and SOCl2 were distilled off under atmospheric pressure to obtain a clear bright yellow solution. Next, a vacuum was gradually applied (T B = 60 °C), and the two volatile substances were further removed. This product was purified by distillation through a fractionating column (T B main fraction at = 131 - 150 °C, T V = 110 - 112 °C and 4 - 5 mmHg) to obtain 551.3 g (83% yield) of ClBB as a colorless liquid.

[0066] Example 3: Preparation of 2-bromo-1-(4-methoxyphenyl)ethyl 4-(tert-butyl)benzoate (BBBF): [Chemical formula]

[0067] OBF (90.0 g, 0.389 mol) was dissolved in 840 mL of dry DCM in a 2 L reactor equipped with mechanical stirring and a pressure-corrected dropping funnel under an inert atmosphere of N2. The mixture was cooled to 10 - 15 °C, and 99% DMAP (4-dimethylaminopyridine, 57.25 g, 0.468 mol, 1.2 equiv) was added while maintaining the temperature at 10 - 15 °C. The mixture was stirred at 20 - 25 °C for 15 minutes, and complete dissolution was observed. 98% ClBB (78.10 g, 0.389 mol) was added to the reactor over 1 hour, and the temperature of the resulting mixture was maintained at 20 - 30 °C. After the addition was complete, the mixture was stirred at 30 - 32 °C for 2 - 3 hours, and complete conversion of the starting material was observed by TLC. The mixture was cooled to 10 - 15 °C, and the organic phase was washed with 2 × 280 mL of H2O for 15 minutes. The organic phase was filtered and concentrated under reduced pressure at 20 - 25 °C for about 6 hours until a constant weight was obtained, and 156 g (quant. yield) of BBBF was obtained as a yellowish liquid (purity > 95% by HPLC).

[0068] Example 4: Preparation of 1-(4-methoxyphenyl)vinyl 4-(tert-butyl)benzoate (PREAVO-2) [Chemical formula]

[0069] BBBF (178 g, 0.454 mol) was dissolved in 534 mL of toluene in a 5 L reactor protected from light with mechanical stirring under an inert atmosphere of N2. This solution was heated to 70 - 75 °C. A solution of 478.4 mL of toluene containing DBU (207.4 g, 1.362 mol, 3.0 equivalents) was added to the reactor over 2.5 hours, and the temperature of the resulting mixture was maintained at 70 - 75 °C. After the addition was complete, the reaction mixture was stirred at 70 - 75 °C for 5 hours, and then the complete conversion of the starting material was observed by TLC. The mixture was cooled to 20 - 25 °C, and 2620 mL of H2O was added over 15 minutes while maintaining the temperature at 20 - 25 °C. This mixture was further stirred at this temperature for 15 minutes and then decanted for 15 minutes. The organic phase was washed twice with 2620 mL of 0.5 M HCl and twice with 2620 mL of H2O. Each of these four consecutive extractions was performed by adding the aqueous phase for 10 - 15 minutes at 20 - 25 °C and mixing the two phases at 20 - 25 °C for 15 minutes.

[0070] Example 5: Crystallization of Preavobenzone - 2: 1-(4 - Methoxyphenyl)vinyl 4-(tert - butyl)benzoate (PREAVO - 2) 560 mL of EtOH was added to the same reactor containing 140 g of crude preavobenzone - 2. This mixture was heated to 50 - 55 °C and complete dissolution was observed. When this solution was cooled to 45 °C, crystallization started. This suspension was further cooled to 5 - 10 °C for 1 hour and then maintained at 5 - 10 °C for 3 hours. The crystallized product was filtered and washed with 56 mL of cooled (0 °C) EtOH. This solid was dried in an oven at 40 °C under vacuum for about 15 hours until a constant weight was obtained, and 100.6 g (75% yield) of preavobenzone - 2 was obtained as white crystalline solids (purity > 99% by HPLC).

[0071] Citation List Patent Document International Patent Publication No. 2006 / 100225

[0072] Non - Patent Document A. Gallardo et al., A new strategy for photoprotection?”, Photochemical & Photobiological Sciences (2010), 9(4), 530-534 Noriko Okamoto et al, ,, Regio- and Stereoselective Multisubstituted Enol Ester Synthesis” JOC, 2011, vol. 76, pp. 9133-9138 Qi Xinxin et al.; “Palladium / aluminium-cocatalyzed carbonlylative synthesis of 2-chloroethyl benzoates from epoxides and aryl iodides”, Journal of Organometallic Chemistry, 2020, vol. 910, 121114

Claims

1. A process for preparing a compound of formula (I), a pharmaceutically or cosmetically acceptable salt thereof, or any stereoisomer or mixture thereof, wherein 【Chemical 1】 In the formula R' is H; (C １ -C ６ )-alkyl and (C ３ -C ６ )-cycloalkyl, and is selected from the group consisting of R １ 、R ２ 、R ４ 、R ５ 、R ６ 、R ７ 、R ９ 、and R １０ are, independently, radicals selected from the group consisting of H, hydroxy, amino, (C １ - C ６ )-alkyl, (C １ - C ６ )-alkoxy, (C １ - C ６ )-alkylamino, and (C １ - C ６ )-dialkylamino, R ３ and R ８ each independently is selected from the group consisting of (C １ -C ６ )-alkyl, (C １ )-alkoxy, hydroxy, amino, (C ６ )-alkylamino, and (C １ )-dialkylamino, ６ and １ ６ ​​ The process comprises reacting a compound of formula (II) or a suitable salt thereof with a strong non-nucleophilic base in the presence of a suitable solvent, 【Chemical 2】 In the formula R', R １ -R １０ is as defined by the compound of formula (I), and X is a halogen selected from the group consisting of Cl, Br, and I Process

2. The process according to claim 1, wherein the strong non-nucleophilic base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (IIIa) and 1,1,3,3-tetramethylguanidine (IIIb).

3. The process according to any one of claims 1 to 2, wherein in the compound of formula (II), X is bromine.

4. In the compound of formula (I) and the compound of formula (II), R', R １ , R ２ , R ４ , R ５ , R ６ , R ７ , R ９ , and R １０ are H, R ３ is tert-butyl, and R ８ is methoxyl, the process according to any one of claims 1 to 3.

5. The solvent is selected from the group consisting of solvents containing (C ６ -C ８ ) aromatic hydrocarbons and (C １ -C ３ )-chlorine, the process according to any one of claims 1 to 4.

6. The process according to any one of claims 1 to 5, comprising reacting a compound of formula (IV) with a compound of formula (V) or a stereoisomer or mixture thereof in the presence of a suitable solvent to obtain a compound of formula (II), [Chemical 3] In the formula R', R １ -R １０ is as defined by the compound of formula (I), and X is a halogen selected from the group consisting of Cl, Br, and I Process

7. The process according to claim 6, which is carried out in the presence of a coupling agent capable of intervening in the conversion of an acyl halide to an ester.

8. The preparation process according to any one of claims 6 to 7, further comprising a previous step of reacting a compound of formula (VI) with a halogenating agent in the presence of a suitable solvent to obtain a compound of formula (IV), 【Chemical Formula 4】 In the formula R １ 、 R ２ 、 R ４ 、 and R ５ are, independently, radicals selected from the group consisting of H, hydroxy, amino, (C １ -C ６ )-alkyl, (C １ -C ６ )-alkoxy, (C １ -C ６ )-alkylamino, and (C １ -C ６ )-dialkylamino, R ３ is selected from the group consisting of (C １ -C ６ )-alkyl, (C １ -C ６ )-alkoxy, hydroxy, amino, (C １ -C ６ )-alkylamino, and (C １ -C ６ )-dialkylamino; Preparation process

9. wherein the halogenating agent is SO ２ Cl ２ , SOCl ２ , PBr ３ , and PBr ５ The process according to claim 7, selected from the group consisting of.

10. The process according to any one of claims 6 to 7, further comprising a previous step of reacting a compound of formula (VII) with a reducing agent in the presence of a solvent to obtain a compound of formula (V), 【Chemical Formula 5】 In the formula R' is H, R ６ 、 R ７ 、 R ９ 、 and R １０ are, independently, H, hydroxy, amino, (C １ -C ６ ), -alkyl, (C １ -C ６ ), -alkoxy, (C １ -C ６ ), -alkylamino, and (C １ -C ６ ), -dialkylamino radicals selected from the group consisting of, R ８ is independently selected from the group consisting of (C １ -C ６ )-alkyl, (C １ )-alkoxy, hydroxy, amino, (C ６ )-alkylamino, and (C １ )-dialkylamino, ６ wherein the alkylamino and dialkylamino each have an alkyl group having 1 to 6 carbon atoms, １ and is selected from the group consisting of ６ ​ X is a halogen selected from the group consisting of Cl, Br, and I, Process

11. The process according to claim 10, wherein the reducing agent is selected from sodium borohydride and lithium aluminum hydride.

12. A compound of formula (II) or a suitable salt thereof, wherein 【Chemical Formula 6】 In the formula R' is selected from the group consisting of H, (C １ -C ６ )-alkyl, and (C ３ -C ６ )-cycloalkyl, R １ 、R ２ 、R ４ 、R ５ 、R ６ 、R ７ 、R ９ 、およびR １０ are, independently, radicals selected from the group consisting of H, hydroxy, amino, (C １ -C ６ )-alkyl, (C １ -C ６ )-alkoxy, (C １ -C ６ )-alkylamino, and (C １ -C ６ )-dialkylamino, R ３ and R ８ each independently is selected from the group consisting of (C １ -C ６ )-alkyl, (C １ -C ６ )-alkoxy, hydroxy, amino, (C １ -C ６ )-alkylamino, and (C １ -C ６ )-dialkylamino; X is a halogen selected from the group consisting of Cl, Br, and I, A compound of formula (II) or a suitable salt thereof.

13. The compound of formula (II) according to claim 12, wherein X is bromine.

14. R ３ is tert-butyl and R ８ is methoxyl, a compound of formula (II) according to any one of claims 12 to 13.

15. R', R １ , R ２ , R ４ , R ５ , R ６ , R ６ , R ７ , R ９ , and R １０ is H, a compound of formula (II) according to any one of claims 12 to 14.

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