Process for preparation of benzoate esters and intermediates thereof

Abstract

The present invention relates to a process for the preparation of a compound of formula (I), or a pharmaceutically or cosmetically acceptable salt thereof, or any one stereoisomer thereof, wherein: R'is selected from H, (C1 to C6)-alkyl and (C3 to C6)-cycloalkyl; r1, R2, R4, R5, R6, R7, R9 and R10 are radicals independently selected from the group consisting of H, hydroxyl, amino, (C1 to C6)-alkyl, (C1 to C6)-alkoxy, (C1 to C6)-alkylamino, and (C1 to C6)-dialkylamino; and R3 and R8 are independently selected from the group consisting of (C1 to C6)-alkyl, (C1 to C6)-alkoxy, hydroxyl, amino, (C1 to C6)-alkylamino, and (C1 to C6)-dialkylamino; the process comprises the beta-elimination reaction of the corresponding alkyl halide precursor in the presence of DBU and a suitable solvent. The invention also relates to intermediates useful in such a preparation process. # imgabs0 #

Description

[0001] This application claims the benefit of European patent application EP22382681 filed on July 15, 2022. Technical Field

[0002] The present invention relates to a method for preparing benzoate compounds and to some novel intermediates which can be used in the preparation method. Background Art

[0003] Several benzoates have been described as photochemical precursors of UV absorbers. Their photoprotective activity is due to their facile in situ photochemical conversion into sunscreen compounds with enhanced UV protection.

[0004] The compounds of formula (I) can be obtained by various methods disclosed in the art. Thus, WO2006 / 100225A1 discloses benzoate compounds and methods for their preparation based on the reaction of an acyl halide with an intermediate enol silyl ether according to the following scheme, wherein R1 to R21 and R' have defined values.

[0005]

[0006] Another method for preparing a specific benzoate 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 the method:

[0007]

[0008] Noriko et al., disclosed another method for preparing some benzoate compounds, which involves the synthesis of polysubstituted enol esters based on the reaction of alkynes with aromatic substituents with NXS and AcOH, wherein X is selected from Cl, Br and I, followed by a coupling reaction (see Noriko Okamoto et al., "Regio- and Stereoselective Multisubstituted Enol Ester Synthesis" JOC, 2011, vol. 76, pp. 9133-9138).

[0009] A method for preparing 2-chloroethyl benzoates has been disclosed in the art, which is based on a palladium / aluminium-cocatalyzed carbonlylative synthesis of 2-chloroethyl benzoates from epoxidesand aryl iodides (see Qi Xinxin et al.; "Palladium / aluminium-cocatalyzed carbonlylative synthesis of 2-chloroethyl benzoates from epoxidesand aryl iodides", Journal of Organometallic Chemistry, 2020, vol. 910,121114).

[0010] However, the search for new preparations of these benzoic acid esters with good yields and purity and which can be carried out on an industrial scale remains an active area, and therefore, it is highly desirable to provide new preparations of these compounds. Summary of the invention

[0011] The inventors have discovered a new process for preparing benzoic acid esters, which has good yield, good purity, and can be carried out on an industrial scale. Therefore, a first aspect of the present invention relates to a process for preparing a compound of formula (I), a pharmaceutically or cosmetically acceptable salt thereof, or any stereoisomer thereof or a mixture thereof;

[0012]

[0013] Wherein: R' is selected from H, (C1 to C6)-alkyl and (C3 to C6)-cycloalkyl; R1, R2, R4, R5, R6, R7, R9 and R 10 is a free radical independently selected from H, hydroxyl, amino, (C1 to C6)-alkyl, (C1 to C6)-alkoxy, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; and R3 and R8 are independently selected from (C1 to C6)-alkyl, (C1 to C6)-alkoxy, hydroxyl, amino, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; the method comprises the step of reacting a compound of formula (II) or a suitable salt thereof with a non-nucleophilic strong base in the presence of a suitable solvent, wherein: R', R1 to R 10 As defined in the compound of formula (I), and X is halogen.

[0014]

[0015] Another aspect of the present invention relates to a compound of formula (II) or a salt thereof, wherein: R' is H; R1, R2, R4, R5, R6, R7, R9 and R 10is a free radical independently selected from H, hydroxyl, amino, (C1 to C6)-alkyl, (C1 to C6)-alkoxy, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; R3 and R8 are independently selected from (C1 to C6)-alkyl, (C1 to C6)-alkoxy, hydroxyl, amino, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; and X is a halogen selected from Cl, Br and I. DETAILED DESCRIPTION

[0016] For the purpose of the present invention, any given range includes the lower and upper endpoints of the range. Unless otherwise specified, the given ranges, such as temperature, time, size, etc., should all be considered approximate.

[0017] As disclosed herein, the term "room temperature" refers to the temperature of an unheated or uncooled environment, and it is typically 20°C to 25°C.

[0018] Throughout the description and throughout the claims, the terms (C1 to C6)-alkyl, (C1 to C6)-alkoxy, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino are to be understood as straight-chain or branched.

[0019] As mentioned above, part of the present invention is a process for preparing a compound of formula (I), a pharmaceutically or cosmetically acceptable salt thereof, or any stereoisomer thereof or a mixture thereof, wherein: R' is selected from H, (C1 to C6)-alkyl and (C3 to C6)-cycloalkyl; R1, R2, R4, R5, R6, R7, R9 and R 10 is a free radical independently selected from H, hydroxyl, amino, (C1 to C6)-alkyl, (C1 to C6)-alkoxy, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; and R3 and R8 are independently selected from (C1 to C6)-alkyl, (C1 to C6)-alkoxy, hydroxyl, amino, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; the method comprises the step of reacting a compound of formula (II) with a non-nucleophilic strong base in the presence of a suitable solvent, wherein: R', R1 to R 10 as defined in the compound of formula (I), and X is halogen as defined above.

[0020] When R' is different from H, the compound of formula (I) exhibits cis-trans isomerism. The process according to the invention for preparing any one of the isomers of the compound of formula (I) as defined above or a mixture thereof forms part of the present invention. Usually, a mixture of isomers is obtained. When necessary, the isomers can be separated by conventional methods of purification.

[0021] In certain embodiments, the method is wherein in the compound of formula (I), R' is H.

[0022] In another specific embodiment, the method is that in the compound of formula (I) and the compound of formula (II), R1, R2, R4, R5, R6, R7, R9 and R 10 is a free radical independently selected from H, hydroxyl, amino and methyl.

[0023] In another specific embodiment, the method is wherein in the compound of formula (I) and the compound of formula (II), R2, R4, R7 and R9 are H.

[0024] In another specific embodiment, the method is that in the compound of formula (II), X is bromine. In another specific embodiment, the method is that in the compound of formula (I) and the compound of formula (II), R', R1, R2, R4, R5, R6, R7, R9 and R 10 is H; R3 is tert-butyl and R8 is methoxy. Preferred compounds produced by the process of the present invention are as follows: 1-phenylvinyl 4-methoxybenzoate; 1-(4-methoxyphenyl)-vinyl 4-tert-butylbenzoate; 1-(4-tert-butylphenyl)vinyl 4-methoxybenzoate; and 1-phenylvinyl 4-tert-butylbenzoate.

[0025] As used herein, a non-nucleophilic strong base refers to an organic base with steric hindrance, which is a weak nucleophile. Typical non-nucleophilic strong bases are large in size, which allows protons to attach to the basic center, but inhibits alkylation and complexation. 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)non-5-ene (DBN), lithium diisopropylamide; silylamides, such as sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide (NaHMDS and KHMDS, respectively), lithium tetramethylpiperidinium (LiTMP). Other non-nucleophilic strong bases can be inorganic bases, such as sodium hydride and potassium hydride.

[0026] In a particular embodiment, the strong non-nucleophilic base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, IIIa) and 1,1,3,3-tetramethylguanidine (TMG, IIIb).

[0027]

[0028] Typically, the amount of the non-nucleophilic strong base comprises 1 to 3 equivalents per equivalent of compound (II).

[0029] Suitable solvents for the reaction are, for example, (C6 to C8)-aromatic hydrocarbons, such as toluene or xylene, or (C1-C3)-chlorinated solvents, such as dichloromethane or dichloroethane.

[0030] Typically, the reaction is carried out at a temperature comprised between 20°C and 90°C. In a particular embodiment, the reaction is carried out at a temperature comprised between 60°C and 80°C. In another particular embodiment, the reaction is carried out at a temperature comprised between 70°C and 75°C.

[0031] The term "suitable salts" refers to non-toxic salts. Since some of the compounds of formula (I) are basic compounds, salts can be prepared with pharmaceutically or cosmetically acceptable non-toxic acids.

[0032] The compounds of formula (II) may also be in the form of non-toxic salts. In certain embodiments, the salts of the compounds of formula (I) are pharmaceutically or cosmetically acceptable salts.

[0033] For any of Compound (I) and Compound (II), the term "pharmaceutically or cosmetically acceptable salt" as used herein includes any salt formed from organic acids 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-naphthalene disulfonic acid, oxalic acid, pivalic acid, propionic acid, p-toluenesulfonic acid, succinic acid, tartaric acid, and the like.

[0034] The preparation of pharmaceutically or cosmetically acceptable salts of compounds of formula (I) or compounds of formula (II) can be implemented by methods known in the art. For example, it can be prepared from parent compounds containing alkaline moieties by conventional chemical methods. Usually, for example, these salts are prepared by reacting these compounds in free alkali form with a suitable pharmaceutically or cosmetically acceptable acid of a stoichiometric amount in water or in an organic solvent or in a mixture thereof.

[0035] When a non-toxic salt of a compound of formula (II) is used to prepare a compound of formula (I), it may be converted in advance in a free base by reaction with an appropriate base, if necessary, or it may be used in the reaction in the form of a salt.

[0036] The compounds of formula (I) may be in crystalline form either as free solvated compounds or as solvates (eg hydrates) and it is intended that both forms are within the scope of the present invention.Methods of solvation are well known in the art.

[0037] The term "solvate" refers to a molecular complex comprising 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 the one or more solvent molecules forming part of the molecular complex are water, the solvate is a hydrate.

[0038] The compound of formula (I) or its salt can be further purified, for example, by crystallization in a suitable solvent. The example of a suitable solvent is (C2 to C6)-alcohol, for example ethanol or 2-propanol. The compound of formula (I) having a purity greater than or equal to 99% can be obtained by HPLC. In a specific embodiment, the compound of formula (I) having a purity greater than or equal to 99.5% is obtained. Other suitable solvents for purification steps can be (C6 to C8)-aromatic hydrocarbons, such as toluene or xylene, (C1 to C3)-chlorinated solvents, such as methylene chloride, ethylene dichloride, or a mixture of (C6 to C8)-aromatic hydrocarbons and (C2 to C6)-alcohol. In a specific embodiment, the solvent mixture is 2-propanol / toluene.

[0039] Compound (II) can be prepared by reacting a compound of formula (IV) with a compound of formula (V) or a stereoisomer thereof or a mixture thereof in the presence of a suitable solvent, wherein R', R1 to R 10 As defined in the compound of formula (I), and X is a halogen selected from Cl, Br and I.

[0040]

[0041] Therefore, when R' is different from H, the compounds of formula (V) also exhibit cis-trans isomerism. The process according to the invention for preparing the compounds of formula (II) from any one of the isomers of the compounds of formula (V) as defined above or a mixture thereof forms part of the present invention. For compounds of formula (I), usually, a mixture of isomers is obtained. When necessary, the isomers can be separated by conventional methods of purification.

[0042] In a specific embodiment, the method for preparing a compound of formula (II) is carried out in the presence of a coupling agent capable of participating in the conversion of an acyl halide into an ester. In a specific embodiment, the coupling agent is selected from 4-dimethylaminopyridine (DMAP), pyridine, 4-pyrrolidinylpyridine (PPY), collidine isomers, i.e., trimethyl derivatives of pyridine, such as 3,4,5-trimethylpyridine, 2,3,4-trimethylpyridine, 2,3,5-trimethylpyridine, 2,3,6-trimethylpyridine, 2,4,5-trimethylpyridine, 2,4,6-trimethylpyridine, and 3,4,5-trimethylpyridine, and N-methylimidazole. In another specific embodiment, the coupling agent is N,N-dimethylaminopyridine (DMAP).

[0043] Typically, a coupling agent is used in an amount comprising 1 to 1.5 equivalents. In a specific embodiment, this step is carried out in the presence of an amount comprising 1.2 to 1.5 equivalents per equivalent of the compound of formula (IV). Optionally, a tertiary amine may also be present, which may help the catalyst to be regenerated in situ. In a specific embodiment, DMAP is used in an amount of 1 equivalent, and a tertiary amine is also present. An example of a suitable tertiary amine is triethylamine. When a tertiary amine is used, a substoichiometric amount such as 0.2 equivalents of DMAP may be used.

[0044] Suitable solvents for the reaction are (C6 to C8)-aromatic hydrocarbons, such as toluene or xylene, and (C1 to C3)-chlorinated solvents, such as dichloromethane or dichloroethane.

[0045] Typically, the reaction is carried out at a temperature comprised between 0°C and 50°C. In a particular embodiment, the reaction is carried out at a temperature comprised between 10°C and 40°C. In another particular embodiment, the reaction is carried out at a temperature comprised between 25°C and 40°C.

[0046] The compound of formula (IV) can be obtained by reacting a compound of formula (VI) with a halogenating agent in the presence of a suitable solvent, wherein R1, R2, R3, R4 and R5 are as defined in the compound of formula (I).

[0047]

[0048] The halogenating agent may be selected from SO2Cl2, SOCl2, PBr3 and PBr5 to produce a compound of formula (IV), wherein X is Cl or Br. In a particular embodiment, the halogenating agent is SOCl2.

[0049] Acid chlorides can be reacted with HF to give 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 reacting acetyl iodide with a monocarboxylic acid.

[0050] Suitable solvents are, for example, (C6 to C8)-aromatic hydrocarbons, such as toluene or xylene, or (C1-C3)-chlorinated solvents, such as dichloromethane or dichloroethane.

[0051] The reaction of the compound of formula (VI) with the halogenating agent is generally carried out at a temperature of 50° C. to 120° C., inclusive. In a specific embodiment, the reaction is carried out at a temperature of 60° C. to 90° C., inclusive. In another specific embodiment, the reaction is carried out at a temperature of 70° C. to 90° C., inclusive.

[0052] Once the reaction has stopped, for example, the excess halogenating agent can be separated by continuous cycles of adding toluene and subsequent distillation thereof. The product can also be purified, for example, by distillation.

[0053] Any isomeric form of the compound of formula (V) or a mixture thereof can be prepared by reacting a compound of formula (VII) with a reducing agent in the presence of a solvent to produce a compound of formula (V), wherein: R', R6, R7, R8, R9 and R 10 As defined in any embodiment of the compound of formula (I), and X is halogen.

[0054]

[0055] Suitable solvents are, for example, protic solvents such as (C1 to C6)-alcohols. In a particular embodiment, the solvent is methanol. In another particular embodiment, the reducing agent used in the process for preparing compound (V) is sodium borohydride or lithium aluminum hydride.

[0056] The reaction of the compound of formula (VII) with the reducing agent is generally carried out at a temperature of -10°C to 15°C, inclusive. In a particular embodiment, the reaction is carried out at a temperature of -10°C to 0°C, inclusive. In a particular embodiment, the reaction is carried out at a temperature of -10°C to -5°C, inclusive.

[0057] The product can be isolated by extraction using a solvent such as toluene followed by evaporation to dryness. Alternatively, the organic solution can be used directly in the next step, preferably removing any water that may be present in the solution, for example by evaporation.

[0058] The process may comprise carrying out the preparation steps for preparing compound (VII) and other steps for converting it into compound (II) without isolating the compound of formula (VII).

[0059] In addition to the compound of formula (II), some intermediates (IV) to intermediates (VII) used to prepare the compound of formula (I) may also be in the form of non-toxic salts. The salts may be those disclosed above. In a specific embodiment, the intermediates (IV) to intermediates (VII) used are in the form of free alkalis.

[0060] The preparation of the salts of these intermediates involved in the method of the present invention can be implemented by methods known in the art. For example, it can be prepared by conventional chemical methods from a parent compound containing a basic moiety. Typically, these salts are prepared, for example, by reacting these compounds in free alkali form with a suitable nontoxic acid in a stoichiometric amount in a suitable solvent.

[0061] Regarding the specific conditions for implementing the steps of the method of the present invention, a skilled person will know how to adjust the parameters of each of the above steps according to the description and embodiments of the present invention.

[0062] Part of the present invention is to provide a single reaction step for preparing compound (I) from compound (II) of the overall process of the present invention, as well as a combination of two or more consecutive steps of the overall process comprising the step of converting compound (II) to compound (I).

[0063] Scheme I illustrates a general method for preparing specific compounds of formula (I) wherein R', R1, R2, R4, R5, R6, R7, R9 and R 10 is H; R3 is tert-butyl and R8 is methoxy.

[0064]

[0065] The process of the present invention can be carried out in successive steps of isolating the intermediates obtained, or some steps of the present invention can be carried out in a one-pot process.

[0066] The intermediate compounds of formula (II) or their salts as described above are novel. Therefore, the provision of novel compounds of formula (II) or their salts as intermediates useful for preparing the benzoic acid esters according to the invention also forms part of the present invention.

[0067] The use of compounds of formula (II) as intermediates to prepare compounds of formula (I) or salts thereof is considered part of the present invention. The intermediate compounds of formula (II) as products are themselves also part of the present invention. In formula (II): R' is selected from H, (C1 to C6)-alkyl and (C3 to C6)-cycloalkyl; R1, R2, R4, R5, R6, R7, R9 and R 10 is a free radical independently selected from H, hydroxyl, amino, (C1 to C6)-alkyl, (C1 to C6)-alkoxy, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; R3 and R8 are independently selected from (C1 to C6)-alkyl, (C1 to C6)-alkoxy, hydroxyl, amino, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; and X is a halogen selected from Cl, Br and I.

[0068]

[0069] The term halogen refers to any one of Cl, Br and I. In a specific embodiment, the compound of formula (II) is wherein X is bromine. In another specific embodiment, the compound of formula (II) is wherein R3 is tert-butyl. In another specific embodiment, the compound of formula (II) is wherein R8 is methoxy. In another specific embodiment, the compound of formula (II) is wherein R' is H. In another specific embodiment, the method is wherein in the compound of formula (I) and the compound of formula (II), R1, R2, R4, R5, R6, R7, R9 and R10 is a free radical independently selected from H, hydroxyl, amino and methyl. In another specific embodiment, the method is that 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 wherein R1, R5, R6 and R 10 For H.

[0070] The combination of the specific embodiments of the product between them is also an embodiment of the product of the compound (II) according to the present invention. In a specific embodiment, the compound of formula (II) is wherein R3 is tert-butyl and R8 is methoxy. In another specific embodiment, the compound of formula (II) is wherein R', R1, R2, R4, R5, R6, R7, R9 and R 10 For H.

[0071] Throughout the specification and the claims, the words "comprise" or "include" and their variations are not intended to exclude other technical features, additives, components or steps. In addition, the word "comprising" also includes the situation of "consisting of ..." Other objects, advantages and features of the present invention will become obvious to those skilled in the art after reviewing the specification, or can be learned through the practice of the present invention. The following examples are provided by way of illustration and are not intended to limit the present invention. In addition, the present invention covers all possible combinations of the specific and preferred embodiments described herein.

[0072] Example

[0073] Example 1: Preparation of 2-bromo-1-(4-methoxyphenyl)ethan-1-ol (OBF)

[0074]

[0075] In a 2L reactor equipped with mechanical stirring and a dropping funnel with pressure compensation, CBF (100 g, 0.437 mole) was suspended in MeOH (370 mL) under an inert atmosphere of N2. The suspension was cooled to -5°C and stirred for 15 minutes. A solution of NaBH4 (16.55 g, 0.437 mole) and NaOH (80 mg) in MeOH (160 mL) at a temperature of -10°C to -3°C was added to the reactor over 1.5 to 2.0 hours, keeping the temperature of the resulting mixture at -10°C to -3°C. Once the addition was complete, the reaction mixture was further stirred at -10°C to -3°C for 5 to 10 minutes, after which complete conversion of the starting material was observed by TLC. DCM (500 mL) was added to the reactor over 30 minutes, keeping the temperature at -10°C to -2°C. The resulting mixture was stirred at -10°C to -2°C for 5 minutes. H2O (400 mL) was added to the reactor over 45 minutes, maintaining the temperature at −5°C to 0°C. The resulting mixture was stirred at −5°C to 0°C for 10 minutes. The mixture was acidified from pH 11 to 12 to pH 1 to 2 by adding 85 mL of 6M HCl aqueous solution to the reactor over 30 minutes, maintaining the temperature at −5°C to −3°C. The resulting mixture was stirred at −5°C to −3°C for 10 minutes. The stirring was stopped and the mixture was decanted for 15 minutes. The organic phase was washed with 3×250 mL of water, maintaining the temperature at 10°C to 15°C. The organic phase was dried over 20 g of MgSO4 and the suspension was stirred at room temperature for 1 hour. The solution was filtered and concentrated under reduced pressure at 20°C to 25°C for about 6 hours until constant weight, obtaining 91.23 g (90% yield) of OBF as a brown liquid (HPLC purity >98%).

[0076] Example 2: Preparation of 4-(tert-butyl)benzoyl chloride (CIBB)

[0077]

[0078] In a 5L reactor equipped with mechanical stirring, under an inert atmosphere of N2, ABB (4-(tert-butyl)benzoic acid, 600g, 3.366 moles) was suspended in 1800mL toluene. The suspension was heated to 65°C to 70°C. Thionyl chloride (SOCl2, 800g, 6.724 moles, 2 equivalents) was added to the reactor in 30 to 45 minutes, keeping the temperature of the resulting mixture at 65°C to 70°C. The reaction mixture was heated to 80°C to 90°C in 20 minutes, and then stirred at this temperature for 3 hours until no gas (SO2 and HCl) was observed to be released. The residue of toluene and SOCl2 was distilled at normal pressure to obtain a transparent bright yellow solution. Subsequently, vacuum (T B = 60 ° C) to further remove the two volatiles. B=131℃ to 150℃, T V =110°C to 112°C and 4mmHg to 5mmHg as the main fraction) to obtain 551.3g (83% yield) of CIBB as a colorless liquid.

[0079] Example 3: Preparation of 2-bromo-1-(4-methoxyphenyl)ethyl 4-(tert-butyl)benzoate (BBBF):

[0080]

[0081] In a 2L reactor equipped with a mechanical stirring and a dropping funnel with pressure compensation, under an inert atmosphere of N2, OBF (90.0 g, 0.389 mole) was dissolved in 840 mL of dry DCM. The mixture was cooled to 10°C to 15°C, and DMAP 99% (4-dimethylaminopyridine, 57.25 g, 0.468 mole, 1.2 equivalents) was added while maintaining the mixture at a temperature of 10°C to 15°C. The mixture was stirred for 15 minutes at 20°C to 25°C, and complete dissolution was observed. CIBB 98% (78.10 g, 0.389 mole) was added to the reactor within 1 hour, maintaining the temperature of the resulting mixture at 20°C to 30°C. Once the addition was completed, the mixture was stirred at 30°C to 32°C for 2 to 3 hours, and the complete conversion of the raw material was observed by TLC afterwards. The mixture was cooled to 10°C to 15°C, and then 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° C. to 25° C. for about 6 hours until constant weight was obtained to obtain 156 g (quantitative yield) of BBBF (HPLC purity>95%) as a light yellow liquid.

[0082] Example 4: Preparation of 1-(4-methoxyphenyl)vinyl 4-(tert-butyl)benzoate (PREAVO-2)

[0083]

[0084] In a 5L reactor equipped with mechanical stirring and protected from light, under an inert atmosphere of N2, BBBF (178g, 0.454 mole) was dissolved in 534mL toluene. The solution was heated to 70°C to 75°C. A solution of DBU (207.4g, 1.362 moles, 3.0 equivalents) in 478.4mL toluene was added to the reactor within 2.5 hours, keeping the temperature of the resulting mixture at 70°C to 75°C. Once the addition was completed, the reaction mixture was stirred at 70°C to 75°C for 5 hours, after which the complete conversion of the raw material was observed by TLC. The mixture was cooled to 20°C to 25°C, and 2620mL H2O was added within 15 minutes to keep the temperature at 20°C to 25°C. The mixture was further stirred for 15 minutes at this temperature, and decanted for 15 minutes. The organic phase was washed with 2×2620mL of 0.5M HCl and 2×2620mL of H2O. Each of these four consecutive extractions was performed by adding the aqueous phase at 20°C to 25°C over 10 to 15 minutes and mixing the two phases at 20°C to 25°C for 15 minutes.

[0085] Example 5: Preavobenzone-2: 1-(4-methoxyphenyl)vinyl 4-(tert-butyl Crystallization of benzoate (PREAVO-2)

[0086] 560 mL of EtOH was added to the same reactor containing 140 g of crude pre-avobenzone-2. The mixture was heated to 50°C to 55°C and complete dissolution was observed. The solution was cooled to 45°C and crystallization began. The suspension was further cooled to 5°C to 10°C within 1 hour and then stored at 5°C to 10°C for 3 hours. The crystalline product was filtered and washed with 56 mL of cold (0°C) EtOH. The solid was dried in an oven under vacuum at 40°C for about 15 hours until constant weight to obtain 100.6 g (75% yield) of pre-avobenzone as a white crystalline solid. Avobenzone-2 (HPLC purity>99%).

[0087] Reference List

[0088] Patent Literature

[0089] WO2006 / 100225A1

[0090] Non-patent literature

[0091] A. Gallardo et al., "A new strategy for photoprotection?", Photochemical& Photobiological Sciences (2010), 9(4), 530-534.

[0092] Noriko Okamot et al., "Regio- and Stereoselective Multisubstituted EnolEster Synthesis", JOC, 2011, vol. 76, pp. 9133-9138.

[0093] 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 method for preparing a compound of formula (I), a pharmaceutically or cosmetically acceptable salt thereof, or any stereoisomer thereof or a mixture thereof, in: R' is selected from H; (C1 to C6)-alkyl and (C3 to C6)-cycloalkyl; R1, R2, R4, R5, R6, R7, R9 and R 10 is a free radical independently selected from H, hydroxyl, amino, (C1 to C6)-alkyl, (C1 to C6)-alkoxy, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; and R3 and R8 are independently selected from (C1 to C6)-alkyl, (C1 to C6)-alkoxy, hydroxy, amino, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; The method comprises the steps of reacting a compound of formula (II) or a suitable salt thereof with a non-nucleophilic strong base in the presence of a suitable solvent, Among them: R', R1 to R 10 As defined in the compound of formula (I); and X is a halogen selected from Cl, Br and I.

2. The method according to claim 1, wherein the 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. The method according to any one of claims 1 to 3, wherein in the compound of formula (I) and the compound of formula (II), R', R1, R2, R4, R5, R6, R7, R9 and R 10 is H; R3 is tert-butyl and R8 is methoxy.

5. The process according to any one of claims 1 to 4, wherein the solvent is selected from (C6 to C8)-aromatic hydrocarbons and (C1 to C3)-chlorinated solvents.

6. The method according to any one of claims 1 to 5, wherein the method comprises reacting a compound of formula (IV) with a compound of formula (V) or a stereoisomer thereof or a mixture thereof in advance in the presence of a suitable solvent to produce a compound of formula (II), in: R', R1 to R 10 As defined in the compound of formula (I), and X is a halogen selected from Cl, Br and I.

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

8. The preparation method according to any one of claims 6 to 7, wherein the method further comprises a preliminary step comprising reacting a compound of formula (VI) with a halogenating agent in the presence of a suitable solvent to generate a compound of formula (IV), R1, R2, R4 and R5 are free radicals independently selected from H, hydroxyl, amino, (C1 to C6)-alkyl, (C1 to C6)-alkoxy, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; and R3 is selected from the group consisting of (C1 to C6)-alkyl, (C1 to C6)-alkoxy, hydroxy, amino, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino.

9. The method of claim 7, wherein the halogenating agent is selected from the group consisting of SO2Cl2, SOCl2, PBr3 and PBr5.

10. The method according to any one of claims 6 to 7, wherein the method further comprises a preliminary step comprising reacting a compound of formula (VII) with a reducing agent in the presence of a solvent to produce a compound of formula (V), in: R' is H; R6, R7, R9 and R 10 is a free radical independently selected from H, hydroxyl, amino, (C1 to C6)-alkyl, (C1 to C6)-alkoxy, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; R8 is independently selected from (C1 to C6)-alkyl, (C1 to C6)-alkoxy, hydroxy, amino, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; and X is a halogen selected from Cl, Br and I.

11. The method of 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: in: R' is selected from H, (C1 to C6)-alkyl and (C3 to C6)-cycloalkyl; R1, R2, R4, R5, R6, R7, R9 and R 10 is a free radical independently selected from H, hydroxyl, amino, (C1 to C6)-alkyl, (C1 to C6)-alkoxy, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; R3 and R8 are independently selected from (C1 to C6)-alkyl, (C1 to C6)-alkoxy, hydroxy, amino, (C1 to C6)-alkylamino and (C1 to C6)-dialkylamino; and X is a halogen selected from Cl, Br and I.

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

14. A compound of formula (II) according to any one of claims 12 to 13, wherein R3 is tert-butyl and R8 is methoxy.

15. A compound of formula (II) according to any one of claims 12 to 14, wherein R', R1, R2, R4, R5, R6, R7, R9 and R 10 For H.

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