Process for the preparation of compounds comprising a 2,5-dihydrobenzoxepine structure by photochemical rearrangement

Abstract

The present invention relates to the field of the synthesis of chemical compounds having a dihydrobenzoxepine structure. In particular, the invention relates to a process for preparing chemical compounds comprising a 2,5-dihydro-1-benzoxepine structure by photochemical rearrangement from chemical compounds having a chromene structure.

Description

[0001] DESCRIPTION

[0002] PROCESS FOR THE PREPARATION OF COMPOUNDS COMPRISING A 2,5-DIHYDROBENZOXEPINE STRUCTURE BY PHOTOCHEMICAL REARRANGEMENT

[0003] The present invention applies to the field of synthesis of chemical compounds having a dihydrobenzoxepin structure. In particular, the invention relates to a process for preparing chemical compounds having a 2,5-dihydro-l-benzoxepin structure by photochemical rearrangement from chemical compounds having a chromene structure. This process is particularly applicable to the preparation of dihydrobenzoxepin derivatives having biological activity and in particular herbicidal activity, from the corresponding chromene derivatives.

[0004] Benzoxepin or benzooxepin is a bicyclic heterocyclic compound consisting of a benzene ring fused to that of oxepin. There are three isomers that can be represented by the following formulas:

[0005] [Chem 1]

[0006] 1 -benzoxepin 2-benzoxepin 3-benzoxepin

[0007] Chemical compounds with a dihydrobenzoxepin structure, also called dihydrobenzoxepin derivatives, are compounds in which a double bond in the oxepin ring is hydrogenated.

[0008] Benzoxepin derivatives often exhibit biological activity and therefore constitute a family of compounds of interest for various applications, particularly in the pharmaceutical field — this is the case, for example, of doxepin, which is an antidepressant — or in the phytopharmaceutical field — this is the case of radulanins A and H, which have herbicidal activity. In particular, bibenzyl derivatives with a 2,5-dihydro-l-benzoxepin nucleus have a structure of the following formula: [Chem 2]

[0009] 2,5-dihydro-1-benzoxepin

[0010] Natural dihydrobenzoxepines can be isolated from plant mosses called liverworts. These are allelopathic compounds known for their herbicidal activity. Among such compounds, we can particularly mention the benzoxepine derivatives described in the FR patent application.

[0011] 3,094,869 and among which are in particular radulanin A of the following formula:

[0012] [Chem 3]

[0013] Several synthetic routes leading to compounds with a 2,5-dihydrobenzoxepin structure have already been proposed in the literature.

[0014] A first synthetic route uses a cyclizing olefin metathesis reaction catalyzed by a ruthenium complex allowing the fusion of the double bond of the 2,5-dihydrooxepine ring (M. Yoshida et al., Tetrahedron, 2009, 65, 5702-5708), according to the following scheme: [Chem 4]

[0015] A second synthetic route uses a Mitsunobu reaction to form the cycloether bond (S. Yamaguchi et al., Tetrahedron Letters, 2000, 41, 4787-4790) according to the following scheme:

[0016] [Chem 5]:

[0017] A third synthetic route uses a retro-Claisen-type rearrangement reaction from a vinylcyclopropane precursor (W. Zhang et al., Chem. Eur. J., 2019, 25, 8643-8648), followed by aromatization, according to the following scheme:

[0018] [Chem 6]:

[0019] These synthetic routes are long to implement because obtaining the precursors of radulanine generally requires many steps involving reactions that are difficult to carry out, either due to the sensitivity of the reagents involved, or due to the use of expensive metals such as ruthenium used as a catalyst. None of these reactions therefore allows the synthesis of radulanine, and more generally of compounds containing a 2,5-dihydro-l-benzoxepin structure, in an efficient, short and economical manner.

[0020] There is therefore a need for a process which allows access economically, i.e. in a few steps and without using expensive metals, to chemical compounds having a 2,5-dihydrobenzoxepin structure.

[0021] Thus, the aim of the present invention is to overcome the drawbacks of the aforementioned prior art and to provide a process for the synthesis of chemical compounds having a 2,5-dihydrobenzoxepin structure.

[0022] The present invention thus relates to a process for synthesizing a compound of the following formula (I):

[0023] [Chem 7] in which:

[0024] - R. 1 represents a hydrogen atom or a C1-C6 alkyl radical,

[0025] - R 2 , R 3 and R 4 , represent, independently of each other, a hydrogen atom, a halogen atom, a C1 to C8 alkyl or cycloalkyl radical, or a group chosen from -OH, -COOH, -COOR 6 , -GOLD 6 and -SO2R 6 , with R 6being a C 1 to C 8 alkyl or cycloalkyl radical, said C 1 to C 8 alkyl or cycloalkyl radical possibly being substituted by one or more substituents chosen from a halogen atom and a hydroxyl group;

[0026] - R 5 represents a hydrogen atom, a halogen atom, a C1 to C8 alkyl or cycloalkyl radical, or a group chosen from -OH, -COOH, -COOR 6 , -GOLD 6 and -SO2R 6 , with R 6 being a C 1 to C 8 alkyl or cycloalkyl radical, said C 1 to C 8 alkyl or cycloalkyl radical possibly being substituted by one or more substituents chosen from a halogen atom and a hydroxyl group, or R 5 represents a -LA group in which:

[0027] * L represents a linker arm chosen from linear and branched alkylene chains having at least one carbon atom, said linear or branched alkylene chains being able to be interrupted and / or terminated by one or more heteroatoms chosen from an oxygen, sulfur, and substituted nitrogen atom, and

[0028] * A represents an aromatic group selected from phenyl, naphthyl, furyl, thiophenyl, pyrrolyl, pyridinyl, indolyl, isoindolyl, benzofuryl, benzothiophenyl, quinolyl, isoquinolyl, imidazolyl, oxazolyl, thiazolyl, pyrimidyl, pyridazyl, pyrazyl, pyrrazolyl, and triazolyl groups, said aromatic group A possibly being substituted by one or more substituents selected from a halogen atom, a C1-C8 alkyl or cycloalkyl radical, an -OH group, a -COOH group, a -COOR group. 7 , an -OR group 7 , and a -SO2R group 7 , with R 7being a C 1 to C 8 alkyl or cycloalkyl radical, said C 1 to C 8 alkyl or cycloalkyl radical possibly being substituted by one or more substituents chosen from a halogen atom and a hydroxyl group or one of its organic and inorganic salts, and in which

[0029] - at least R groups 2 , R 3 , R 4 and R 5 represents an -OH group, characterized in that said method comprises a step of irradiation with ultraviolet radiation of a solution in a solvent of a compound of the following formula (II):

[0030] [Chem 8] in which R 1 , R 2 , R 3 , R 4 , and R 5have the same meaning as indicated above for the compounds of formula (I). The process according to the present invention thus implements a ring extension reaction of a compound comprising a 2-methylchromene structure, preferably 2-alkyl-2-methylchromene, and most preferably 2,2-dimethylchromene, said reaction being carried out under photochemical conditions. The chromene precursors can be synthesized in a few steps from o,p-unsaturated phenols and aldehydes using acid catalysis.

[0031] In formulas (I) and (II) above, the alkyl radical indicated for R 1 may be linear or branched. It is preferably chosen from the group comprising a methyl radical, an ethyl radical and a t-butyl radical, the methyl radical being particularly preferred.

[0032] Examples of inorganic salts of the compound of formula (I) include the alkali and alkaline earth salts of the compound of formula (I).

[0033] Examples of organic salts of the compound of formula (I) include ammonium salts of the compound of formula (I).

[0034] In the present invention the C 1 -C 8 alkyl or cycloalkyl radical may be linear or branched, and is preferably linear.

[0035] For the purposes of the present invention, a halogen is chosen from F, Cl, Br and I, and preferably from F and Cl.

[0036] Definition of R 2 , R 3 , R 4 and R 5

[0037] The alkyl or cycloalkyl radical as the R group 2 , R 3 , R 4 or R 5is preferably an alkyl radical, particularly preferably a linear alkyl radical, and more particularly preferably a linear C1 to C3 alkyl radical.

[0038] The alkyl or cycloalkyl radical as the R group 6 is preferably an alkyl radical, particularly preferably a linear alkyl radical, and more particularly preferably a linear C1 to C3 alkyl radical.

[0039] Said alkyl or cycloalkyl radical as group R 2 , R 3 , R 4 or R 5 may be substituted by one or more substituents chosen from a halogen atom and a hydroxyl group. According to a particularly preferred embodiment of the invention, at least one of the groups R 2 , R 3 , R 4 and R 5 represents an -OH group. In this case, said at least one hydroxyl group is preferably in position 6.

[0040] In this embodiment, two of the other R groups 2 , R 3 , or R 2 and R 4 or R 3 and R 4 represent a hydrogen atom and R 5 represents a -LA group.

[0041] Definition of L

[0042] L preferably represents a linear or branched alkylene chain having from 1 to 6 carbon atoms, particularly preferably a linear alkylene chain having from 2 to 3 carbon atoms, and more particularly preferably a linear alkylene chain having 2 carbon atoms.

[0043] The linear or branched alkylene chain as linker arm L may be interrupted and / or terminated by one or more heteroatoms selected from oxygen, sulfur, and substituted nitrogen, and preferably by one or more oxygen atoms.

[0044] Nitrogen may be substituted by a C1-C8, preferably C1-C3, alkyl group, said alkyl radical preferably being a linear alkyl radical.

[0045] Definition of A

[0046] The alkyl or cycloalkyl radical as a substituent of group A is preferably an alkyl radical, particularly preferably a linear alkyl radical, and more particularly preferably a linear C1-C3 alkyl radical.

[0047] The alkyl or cycloalkyl radical as the R group 7 is preferably an alkyl radical, particularly preferably a linear alkyl radical, and more particularly preferably a linear C1 to C3 alkyl radical.

[0048] Said alkyl or cycloalkyl radical as a substituent of group A or group R 7may be substituted by one or more substituents selected from a halogen atom and a hydroxyl group. A preferably represents an aromatic group selected from phenyl, naphthyl, and pyridinyl groups, and particularly preferably is a phenyl group.

[0049] The method of the invention can be carried out in static mode or in continuous flow.

[0050] According to a first embodiment, the process is carried out in static mode. This first embodiment makes it possible to obtain conversion rates of the compound of formula (II) of 90 to 100%, with yields of compound of formula (I) of the order of 10 to 50%.

[0051] According to this first embodiment, the method according to the invention is carried out in an immersion well equipped with a tube transparent to UV radiation, for example made of Pyrex, immersed and cooled with iced water and containing a UV lamp.

[0052] According to a second embodiment, the process is carried out in continuous flow. This second embodiment makes it possible to improve the reaction speed, the reproducibility and the yields of compounds comprising a structure of formula (I). In this case, the conversion rate of the starting compound of formula (II) can vary from 90 to 100% and the yield of compound comprising a structure of formula (I) is of the order of approximately 30 to 50%. This second embodiment is preferred.

[0053] According to this second embodiment, the method is carried out in a continuous flow reactor consisting of a tube transparent to UV radiation, for example made of a thermoplastic material such as a perfluoroalkoxy alkane (PFA). This tube is wrapped around a UV lamp equipped with a Pyrex-type filter. A degassed solution of the compound of formula (II) is injected into this reactor, in a continuous flow at a flow rate which can vary in particular from 0.5 to 2 mb / min.

[0054] The solvent of the solution may be chosen from aromatic hydrocarbons such as, for example, benzene and toluene, acetonitrile and ethyl acetate. Among such solvents, acetonitrile and ethyl acetate are preferred, with acetonitrile being particularly preferred. The duration of the irradiation step is generally from about 5 minutes to 5 hours.

[0055] According to the first embodiment of the invention, the method is carried out in static mode and the duration of the irradiation step is 1 to 5 hours, preferably 1 to 2 hours.

[0056] According to the second embodiment of the invention, the method is carried out in continuous flow and the duration of the irradiation step is 5 to 20 minutes, preferably 8 to 12 minutes.

[0057] According to the invention, ultraviolet radiation means any invisible radiation which emits in the wavelength range of 100 to 400 nanometers (nm).

[0058] According to a preferred embodiment of the invention, the irradiation step is carried out at a length of approximately 200 to 400 nm, and even more preferably of approximately 250 to 350 nm.

[0059] UV radiation may, conventionally, be generated by a lamp emitting in the ultraviolet (UV) range. According to the invention, a medium-pressure mercury UV lamp having a power of approximately 100 to 400 W, preferably of the order of approximately 150 W, is preferably used.

[0060] According to the invention, and by definition, "medium pressure" means a pressure of the order of 1.10 5 at 1.10 6 Pascal.

[0061] According to a particularly preferred embodiment of the invention, the process is carried out for the preparation of a compound of the following formula (Ia):

[0062] [Chem 9] in which R 1 , R 2 , R 3 , R 4, A and L have the same meaning as indicated above for compounds of formula (I). In this case, said compound of formula (II) subjected to said irradiation step corresponds to the following formula (Ha):

[0063] [Chem 10] in which R. 1 , R 2 , R 3 , R 4 , A and L have the same meaning as indicated below for compounds of formula (I).

[0064] Preferably, in the compounds of formula (Ia), at least one of the groups R 2 , R 3 and R 4 represents an -OH group. In this case, said at least one hydroxyl group is preferably in position 6. Also particularly preferably, the -LA group is in position 8, L represents an ethylene chain and A is a phenyl ring.

[0065] According to a particularly preferred embodiment of the invention, the process is carried out for the preparation of radulanin A of the following formula (Ia-1):

[0066] [Chem 11]

[0067] (la-l)

[0068] Radulanine A thus corresponds to a compound of formula (Ia) in which R 1 represents a methyl radical, one of the R groups 2 , R 3 and R 4 represents an OH group in position 6, the other two R groups 2 and R 3 , respectively R 3 and R 4 , represent a hydrogen atom and R 5 is a -LA group is in position 8, and A is a phenyl ring.

[0069] Several synthetic methods can be used to access chromenes of formula (II). Such methods are particularly described by R. Pratap et al., Chem. Rev., 2014, 114, 10476-10526.

[0070] In particular, when the process is carried out for the preparation of a compound of formula (I) in which R 1 and R 5 are as defined in formula (I), one of the groups R 2 , R 3 and R 4 represents an OH group in position 6, the other two R groups 2 and R 3 , respectively R 3 and R 4 represent a hydrogen atom (compounds of formula (I'), then the corresponding chromenes of formula (II) (chromenes of formula (II') are preferably obtained by condensation of a diphenol of formula (III) in which R 5 has the same meaning as in formula (I) and an o,£-unsaturated aldehyde of formula (IV) in which R 1 has the same meaning as in formula (I), according to the following reaction scheme:

[0071] [Chem 12] in the presence of an acid catalyst such as ethylenediammonium diacetate (EDDA) according to the method described by Lee et al. (Tetrahedron Lett. 2005, 46, 7539-7543), or a Lewis acid such as Yb(0Tf)3, ZnCh, or a Bronsted acid such as ammonium acetate (NhUOAc), trifluoroacetic acid (TFA), or acetic acid (AcOH); a solvent, in a closed reactor (e.g. sealed tube), at reflux, and under an inert atmosphere.

[0072] When the precursors of formula (III) and (IV) are not commercially available, they can be synthesized according to conventional methods. For example, unsaturated aldehydes can be obtained by a Horner-Wadsworth-Emmons type olefination reaction on a carbonyl derivative with triethyl phosphonoacetate, followed by reduction of the ester function to aldehyde. Phenolic derivatives can be obtained by various electrophilic aromatic substitution methods well known to those skilled in the art, or by cross-coupling of activated derivatives, or by functionalization of a group already present on the aromatic system.

[0073] The reaction solvent may be chosen from toluene, xylene, benzene, dichloromethane, and acetic acid.

[0074] Other characteristics, variants and advantages of the method according to the invention will become more apparent upon reading the following exemplary embodiments, given for illustrative and non-limiting purposes of the invention.

[0075] EXAMPLES

[0076] Toluene, acetonitrile, and benzene were distilled over calcium hydride before use and, if necessary, degassed by bubbling nitrogen gas through.

[0077] Analytical thin-layer chromatographies (TLC) were performed on silica gel-on-aluminum plates (silica gel 60, F254, Merck) and visualized by exposure to ultraviolet light and / or exposure to basic potassium permanganate solution or p-anisaldehyde staining solution followed by heating.

[0078] Flash column chromatographies were performed on silica 60 (40-63 pm).

[0079] Nuclear magnetic resonance (NMR) spectra X H and NMR 13 C) were recorded at 25°C with a Bruker Avance 400 spectrometer (400 MHz, X H at 400 MHz, NMR 13 C at 100 MHz) using CDCl3 as solvent referenced to residual CHCl3 (SH = 7.26 ppm, SC = 77.1 ppm). Chemical shifts are given in ppm and coupling constants (J) in Hertz. Data for NMR spectra X H are reported as follows: chemical shift ppm (br s = broad singlet, s = singlet, d = doublet, t = triplet, q = quadruplet, dd = doublet of doublets, td = triplet of doublets, ddd = doublet of doublets of doublets, m = multiplet, coupling constants, integration). Infrared spectra were recorded on a PerkinElmer FTIR spectrometer using the attenuated total reflectance (ATR) technique. The absorption maxima (v max) are reported in wavenumbers (cm ). High-resolution mass spectra (HRMS) were obtained on a JEOL JMS-GCmate II spectrometer and reported in m / z.

[0080] Static batch photochemical experiments were performed in a 500 mL immersion well or 10 mL sealed Pyrex tubes irradiated with a 150 W Heraeus medium-pressure Hg lamp. Flow photochemical experiments were performed on a Vapourtec E-series system equipped with a UV-150 photoreactor with a medium-pressure Hg lamp (75-150 W) used in combination with a Pyrex filter.

[0081] EXAMPLE 1: Synthesis of radulanin A (compound of formula Ia-1) according to the process according to the present invention Radulanin A was prepared according to a process according to the present invention implementing a continuous flow photochemical rearrangement step according to the steps illustrated in the following scheme:

[0082] [Chem 13]

[0083] 1.1 First step: Preparation of (E)-3,5-dimethoxystilbene (compound

[0084] 3) The first step is a Horner-Wadsworth-Emmons reaction. To a flame-dried 500 mL flask equipped with a magnetic stir bar, under an inert atmosphere, were added potassium tert-butoxide (t-BuOK) (10.8 g, 96.3 mmol) and anhydrous tetrahydrofuran (THF) (120 mL). The mixture was cooled in an ice bath, and then diethyl benzylphosphonate (compound 1) (20.6 mL, 90.3 mmol) was added dropwise over 30 min, followed by the portionwise addition of 3,5-dimethoxybenzaldehyde (compound 2) (10.0 g, 60.2 mmol). The mixture was allowed to warm to room temperature and then stirred for 2 h. The THF was removed in vacuo, and then a mixture of water and methanol (HzCL MeOH) (2:1, approximately 60 mL) was added until the product precipitated. Filtration and drying in vacuo gave (E)-3,5-dimethoxystilbene (compound 3) as a white solid (13.5 g, 56.0 mmol, 93% yield).

[0085] The second step is a catalytic hydrogenation reaction of the double bond using ammonium formate. This avoids the use of hydrogen gas. To a flame-dried 500 mL flask, (E)-3,5-dimethoxystilbene as prepared in the previous step (14.0 g, 58.2 mmol) and 10% Pd / C (1.40 g, 10% by weight) were added, followed by ethyl acetate (243 mL, 0.245 M). Ammonium formate (18.4 g, 291 mmol) was then added, and the mixture was allowed to stir overnight at room temperature. The reaction mixture was then filtered through a pad of celite and evaporated in vacuo. The remaining ammonium formate was precipitated by the addition of dichloromethane and the mixture was filtered again and evaporated in vacuo to give the expected 1,3-dimethoxy-5-phenethylbenzene (compound 4) as a light yellow oil (12.7 g, 52.4 mmol, 90% yield).

[0086] NMR XH (400 MHz, CDCI3): 5 = 7.32 - 7.25 (m, 2H), 7.23 - 7.17 (m, 3H), 6.36 - 6.30 (m, 3H), 3.76 (s, 6H), 2.95 - 2.82 (m, 4H).

[0087] 1.3. Third step: Preparation of dihydropinosylvin (compound 5)

[0088] The third step is a demethylation of phenols in acidic aqueous medium. To a 250 mL flask equipped with a magnetic stir bar, 1,3-dimethoxy-5-phenethylbenzene as prepared in the previous step (2.03 g, 8.38 mmol) was added, followed by hydrobromic acid (HBr) (24.6 mL, 48% by weight in water) and glacial acetic acid (24.6 mL, HBr:AcOH 1:1 v / v, final concentration of 0.15 M). The reaction mixture was then heated at reflux for 4 h and allowed to cool to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with diethyl ether (EtzO) (3 x 50 mL). The organic phase was treated with activated carbon, filtered and reduced in vacuo to give dihydropinosylvin as a white solid (1.68 g, 7.86 mmol, 94%). 7.33 - 7.25 (m, 2H), 7.24 - 7.15 (m, 3H), 6.31 - 6.18 (m, 3H), 4.71 (br s, 2H), 2.93 - 2.75 (m, 4H).

[0089] 1.4 Fourth step: Preparation of 2,2-dimethyl-7-phenethyl-2H-chromen 5-ol (compound 6)

[0090] To a sealed, flame-dried tube equipped with a magnetic stir bar under an inert atmosphere, dihydropinosylvin obtained in the previous step (4.00 g, 18.7 mmol - 1 equiv.) was added, followed by anhydrous toluene (0.1 M) and 3-methyl-2-butenal (prenal) (1.5 equiv.). Ethylenediammonium diacetate (EDDA, ​​5 mol%) was then added. The container was sealed and heated to 115°C for 1 h. This procedure (EDDA addition and heating) was repeated 3 times (totaling an addition of 15 mol% EDDA), then after returning to room temperature a small amount of silica was added and the solvent was removed under vacuum. The crude mixture was purified by flash silica column chromatography (dry loading), eluting with hexane / ethyl acetate to give the expected 2,2-dimethyl-7-phenethyl-2H-chromen-5-ol (compound 6) as a viscous brown liquid (4.28 g, 15.3 mmol, 82% yield). 7.31 - 7.24 (m, 2H), 7.22 - 7.15 (m, 3H), 6.58 (d, J = 10.0, 1H), 6.32 - 6.29 (m, 1H), 6.14 - 6.10 (m, 1H), 5.55 (d, J = 10.0, 1H), 4.59 (br s, 1H), 2.92 - 2.83 (m, 2H), 2.80 - 2.73 (m, 2H), 1.42 (s, 6H).

[0091] 1.5. Fifth step: Preparation of radulanin A (compound (Ia-1)) by continuous flow photochemical rearrangement

[0092] In a 1 L flame-dried flask under nitrogen atmosphere, a solution of compound 6 (200 mg, 0.713 mmol) as obtained in the previous step in nitrogen-degassed anhydrous acetonitrile (713 mL, 0.001 M) was prepared. The continuous flow system was first rinsed with degassed anhydrous acetonitrile, and then the solution of compound 6 was injected into the photochemical reactor equipped with a Pyrex filter at 100% lamp power (150 W), at a flow rate of 1.2 mL.min-1 (8.44 min residence time in the reactor), a pressure of 300 KPa and a reactor temperature of 30 °C. The collected solution was evaporated in vacuo and the crude mixture purified by flash column chromatography, eluting at 2-10% EtOAc:hexane to give radulanin A (compound of formula (Ia-1) as a brown oil (52.2 mg, 0.186 mmol, 26%).

[0093] The NMR analysis of radulanin A is given below: NMR (400 MHz, CDCl3): 5 = 7.32 - 7.24 and 7.22 - 7.14 (m, 5H), 6.53 (d, J = 1.5 Hz, 1H), 6.37 (d, J = 1.5 Hz, 1H), 5.64 - 5.57 (m, 1H), 4.84 (br s, 1H), 4.44 - 4.37 (m, 2H), 3.44 - 3.34 (m, 2H), 2.91 - 2.83 and 2.83 - 2.75 (m, 4H), 1.57 - 1.50 (m, 3H).

[0094] EXAMPLE 2: Synthesis of radulanin A (compound of formula Ia-1) according to the process according to the invention in static mode

[0095] Radulanin A was prepared using the same steps as illustrated in the synthesis scheme presented above in Example 1, but implementing a fifth step of photochemical rearrangement in static mode.

[0096] To a sealed 10 mL flame-dried Pyrex tube equipped with a magnetic stir bar under an inert atmosphere, compound 5 (2.70 mg, 0.00963 mmol) as prepared above in step 4 of Example 1 and degassed dry benzene (9.00 mL, 0.001 M) were added. The tube was directly attached to the cooling sheath of a 150 W medium-pressure mercury lamp. The reaction mixture was irradiated for 1 hour with stirring. The solvent was evaporated in vacuo and the crude reaction mixture was subjected to NMR analysis. X H, to reveal a complete conversion of compound 5 to radulanin A.

[0097] NMR XH (400 MHz, CDCI3): 5 = 7.32 - 7.24 and 7.22 - 7.14 (m, 5H), 6.53 (d, J = 1.5 Hz, 1H), 6.37 (d, J = 1.5 Hz, 1H), 5.64 - 5.57 (m, 1H), 4.84 (br s, 1H), 4.44 - 4.37 (m, 2H), 3.44 - 3.34 (m, 2H), 2.91 - 2.83 and 2.83 - 2.75 (m, 4H), 1.57 - 1.50 (m, 3H). EXAMPLE 3: Synthesis of 3,8-dimethyl-2,5-dihydrobenzoxepin-6-ol (compound of formula 1-1) according to the process according to the invention in static mode

[0098] 3,8-Dimethyl-2,5-dihydrobenzoxepin-6-ol was prepared according to a process in accordance with the present invention implementing a continuous flow photochemical rearrangement step according to the steps illustrated in the following scheme:

[0099] [Chem 14]

[0100] 3.1 First step: Preparation of 2,2,7-trimethyl-2H-chromen-5-ol (compound 7)

[0101] To a sealed, flame-dried tube equipped with a magnetic stir bar under an inert atmosphere was added orcinol (1 equiv.) followed by anhydrous toluene (0.1 M) and prenal (1.5 equiv.). Ethylenediammonium diacetate (EDDA, ​​5 mol%) was then added. The container was sealed and heated to 115 °C for 1 h. This procedure (addition of EDDA and heating) was repeated 3 times (totaling an addition of 15 mol% EDDA), then after returning to room temperature a small amount of silica was added and the solvent removed under vacuum. The crude mixture was purified by flash silica column chromatography (dry loading), eluting with hexane / EtOAc to give the expected 2,2,7-trimethyl-2H-chromen-5-ol (compound 7). 6.57 (d, J = 10.0, 1H), 6.26 - 6.24 (m, 1H), 6.14 - 6.11 (m, 1H), 5.53 (d, J = 10.0 Hz, 1H), 4.60 (br s, 1H), 2.22 - 2.20 (m, 3H), 1.41 (s, 6H).

[0102] 3.2. Second step: Preparation of 3,8-dimethyl-2,5-dihydrobenzoxeoin-6-ol (compound of formula 1-1)

[0103] In a 500 mL immersion well equipped with a 150 W mercury lamp, a water cooling jacket, and a magnetic stir bar, under an inert atmosphere, compound 7 obtained above in the previous step (75 mg, 0.394 mmol) and anhydrous benzene degassed by bubbling nitrogen (250 mL, 0.00158 M) were introduced. The reaction mixture was stirred and irradiated for 30 minutes and then cooled. This procedure was repeated 10 times until the mixture had been irradiated for a total of 5 hours. The reaction mixture was then evaporated in a flask under vacuum, and the crude mixture was purified by flash column chromatography, eluting with hexane:CH2Cl2 1:1, to provide the expected compound of formula (Ia-1) in the form of a yellow oil (35.3 mg, 0.185 mmol, 47%).

[0104] Rf = 0.19 (hexane / CH2Cl2 1:1)

[0105] RMN X H (400 MHz, CDCI3) : 5 = 6.50 - 6.52 (m, 1H), 6.39 - 6.36 (m, 1H), 5.65 - 5.57 (m, 1H), 4.80 (br s, 1H), 4.44 - 4.37 (m, 2H), 3.43 - 3.36 (m, 2H), 2.25 - 2.23 (m, 3H), 1.56 - 1.51 (m, 3H).

[0106] RMN 13 C (101 MHz, CDCI3) : 5 = 159.7, 152.0, 137.4, 134.0, 120.7, 120.1, 114.5, 112.2, 74.3, 21.6, 21.0, 20.1.

[0107] IR (ATR) : 3350, 2931, 1715, 1619, 1583, 1450, 1378, 1311, 1207, 1068, 986, 836, 753.

[0108] HRMS (EI+) : Calculé pour C12H15Û2+ : 191.1067; obtenu : 191.1064.

Claims

DEMANDS 1. Synthesis process for a compound with the following formula (I): [Chem 15] in which: - R. 1 represents a hydrogen atom or an alkyl radical in Ci-C, - R 2 , R 3 and R 4 , represent, independently of each other, a hydrogen atom, a halogen atom, an alkyl or cycloalkyl radical in C1 to C1, or a group chosen from -OH, -COOH, -COOR 6 , -GOLD 6 and -SO2R 6 , with R 6 being an alkyl or cycloalkyl radical in Ci to Cs, said alkyl or cycloalkyl radical in Ci to Cs being able to be substituted by one or more substituents chosen from a halogen atom and a hydroxyl group; - R 5 represents a hydrogen atom, a halogen atom, an alkyl or cycloalkyl radical in C1 to C1, or a group chosen from -OH, -COOH, -COOR 6 , -GOLD 6 and -SO2R 6, with R 6 being an alkyl or cycloalkyl radical in C1 to C1, said alkyl or cycloalkyl radical in C1 to C1 being able to be substituted by one or more substituents selected from a halogen atom and a hydroxyl group, or R 5 represents a grouping -LA in which: * L represents a linking arm chosen from linear and branched alkylene chains having at least one carbon atom, said linear or branched alkylene chains being able to be interrupted and / or terminated by one or more heteroatoms chosen from an oxygen, sulfur, and substituted nitrogen atom, and * A represents an aromatic group selected from the following groups: phenyl, naphthyl, furyl, thiophenyl, pyrrolyl, pyridinyl, indolyl, isoindolyl, benzofuryl, benzothiophenyl, quinolyl, isoquinolyl, imidazolyl, oxazolyl, thiazolyl, pyrimidyl, pyridazyl, pyrazyl, pyrrazolyl, and triazolyl, said aromatic group A which can be substituted by one or more substituents chosen from a halogen atom, an alkyl or cycloalkyl radical in Ci to Cs, an -OH group, a -COOH group, a -COOR group. 7 , a group -OR 7 and a group -SO2R 7 , with R 7 being an alkyl or cycloalkyl radical in C1 to C1, said alkyl or cycloalkyl radical in C1 to C1 being able to be substituted by one or more substituents selected from a halogen atom and a hydroxyl group or one of its organic and inorganic salts, and in which - at least some R groups 2 , R 3 , R 4 and R 5 represents a -OH group, characterized in that said process comprises a step of irradiation by ultraviolet radiation of a solution in a solvent of a compound of the following formula (II): [Chem 16] in which R 1 , R 2 , R 3 , R 4 , and R5 have the same meaning as that indicated below for compounds of formula (I).

2. A process according to claim 1, characterized in that the solvent of the solution is selected from aromatic hydrocarbons, acetonitrile and ethyl acetate.

3. A method according to any one of claims 1 to 3, characterized in that it is carried out in static mode and the duration of the irradiation step is from 1 to 5 hours.

4. A method according to any one of claims 1 to 3, characterized in that it is carried out in continuous flow.

5. Method according to claim 4, characterized in that the duration of the irradiation step is from 5 to 20 minutes.

6. A method according to any one of the preceding claims, characterized in that the irradiation step is carried out at a wavelength of 250 to 350 nm.

7. A method according to any one of the preceding claims, characterized in that said at least one hydroxyl group is in position 6.

8. A method according to any one of the preceding claims, characterized in that two of the other groups R 2 , R 3 , or R 2 and R 4 or R 3 and R 4 represent a hydrogen atom and R 5 represents a group - LA.

9. A method according to any one of the preceding claims, characterized in that L represents a linear alkylene chain having 2 to 3 carbon atoms.

10. A method according to any one of the preceding claims, characterized in that A represents an aromatic group selected from the phenyl, thiophenyl, and pyridinyl groups.

11. A process according to any one of the preceding claims, characterized in that said process is implemented for the preparation of a compound of the following formula: [Chem 17] in which R 1 , R 2 , R 3 R 4 , A and L have the same meaning as that indicated for compounds of formula (I), and in that said compound of formula (II) subjected to said irradiation step corresponds to the following formula (Ha): [Chem 18] in which R. 1 , R 2 , R 3 , R 4 , A and L have the same meaning as that indicated for compounds of formula (I).

12. Method according to claim 11, characterized in that the group LA is in position 8, L represents an ethylene chain and A is a phenyl ring.

13. A process according to claim 11 or 12, characterized in that it is implemented for the preparation of radulanine A of the following formula (Ia-1): [Chem 19]

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