Method of cross-etherification of at least one alkylated ether phenyl compound under continuous-flow conditions

Abstract

The present invention deals with a method of cross-etherification of at least one alkylated phenyl alcohol compound in a solvent free continuous process in the presence of at least one heterogeneous acid catalyst, preferably at least one cationic exchange resin, for preparing at least one alkylated ether phenyl compound.

Description

[0001] DESCRIPTION

[0002] TITRE : Method of cross-etherification of at least one alkylated ether phenyl compound under continuous-flow conditions

[0003] The present invention deals with a method of cross-etherification of at least one alkylated phenyl alcohol, as defined hereafter, in a solvent free continuous process in the presence of at least one heterogeneous acid catalyst, preferably at least one cationic exchange resin, for preparing at least one alkylated ether phenyl compound as defined hereafter.

[0004] PRIOR ART AND BACKGROUND OF THE INVENTION

[0005] Alkyl ether compounds can be synthetized by numerous routes, such as by nucleophilic displacement of alkyl halides by at least one alkoxide under strongly basic conditions (this reaction being generally referred to as the Williamson ether synthesis) or by dehydration of alcohols at high temperature under strongly acidic conditions.

[0006] Even though the Williamson ether synthesis is commonly used to prepare symmetrical or unsymmetri cal alkyl ether compounds, thi s method exhibits the maj or drawbacks of involving the use of organic halide precursors prepared from the corresponding alcohols which is generally tedious to implement and not sufficiently environmentally friendly .

[0007] The Williamson ether synthesis further displays the disadvantage of being carried out under highly basic conditions in order to form the alkoxide from the parent alcohol, which requires the reaction medium to be neutralized and washed after the reaction occurred, sometimes even several times.

[0008] As regards the dehydration of alcohols, this synthesis is ordinarily catalysed by acids, for example sulfuric acid or hydrochloric acid, to protonate the hydroxyl functions of the alcohols involved. However, this method can be effective to generate symmetrical ethers, but often fails to form unsymmetrical ethers with good yields since all the hydroxyl functions of the alcohols can be protonated without chemoselectivity. Thus, this method often leads to the generation of a mixture of ethers compounds.

[0009] Furthermore, since the dehydration of alcohols is performed under highly acid conditions, the reaction medium requires to be neutralized and washed, resulting in one or more effluent washing operations at the reactor outlet to mitigate potential adverse effects caused to the environment. These operations generate additional energy and costs.

[0010] In addition, the use of an excess of acid to catalyse the dehydration of alcohols may also lead to the corrosion of the reactor, which may impede its lifetime and trigger additional costs.

[0011] In other words, even though the dehydration of alcohols may represent a more environmentally friendly alternative to the Williamson ether synthesi s, this reaction performed under highly acidic conditions still suffers from several pitfalls, especially when it comes to the synthesis of non-symmetrical ethers.

[0012] Several attempts related in the art have thus been developed to promote the formation of unsymmetrical alkyl ethers in a more eco- friendly manner during these etherification reactions.

[0013] However, selective etherifications or cross-etherifications of alcoholic -OH functionalities, especially of alkylated phenolic alcohols corresponding to the formula HO-(CeH4)-R-OH wherein R represents a divalent alkyl group, remain very difficult and cumbersome to be implemented, and often generate unsymmetrical ethers in very low yields.

[0014] In some cases, these selective etherifications may even be expensive as the reacti on medium is loaded with high content of transition-metal catalysts and is carried out under stringent conditions, for example in terms of pressure and / or temperature.

[0015] Moreover, these reactions are often carried out in batch conditions, for example in thick-walled glass batch reactors, to mitigate the generation of by-products, which can complicate their implementation on an industrial scale.

[0016] Especially, in the case of the cross-etherification of alkylated phenolic alcohols as previously described, the selective etherification of the alcoholic function linked to the alkyl divalent group without etherified the phenolic function, is particularly difficult to achieve in satisfactory yields.

[0017] Accordingly, it remains a real need to implement a method of cross-etherification, in particular for alkylated phenolic alcohols as described above, that achieves good chemoselectivity, in satisfactory, even high yields, and that i s sustainable on an industrial scale, while respecting the environment.

[0018] Furthermore, one of the purposes of the present invention is namely to devel op a method for selectively etherified bio-based alkylated phenyl alcohols, especially alkylated phenolic alcohol s, which may lead to alkylated ether phenyl compounds, preferably to alkylated ether phenolic alcohols, and enables the preparation of non-toxi c substances that can be used afterwards in an environmentally friendly manner in various applications.

[0019] OBJECT OF THE INVENTION

[0020] The inventors have shown that the implementation of a method of cross-etherification of at least one alkylated phenyl alcohol compound with at least one alkanol in a solvent free continuous process in the presence of at least one cationic exchange resin, as a heterogeneous acid catalyst, is able to achieve good chemoselectivity, in satisfactory, even high yields, while being sustainable on an industrial scale and respectful for the environment.

[0021] Therefore, the present invention relates to a method for preparing at least one alkylated ether phenyl compound having the following formula (I): Formula (I) wherein: p is an integer ranging from 1 to 5, preferably ranging from 1 to 2, specifically corresponding to 1 ,

[0022] Ri represents a hydroxy group, a halogen atom, a nitro group - NO2, or a linear or branched, saturated or unsaturated, C1-C4 alkyl group,

[0023] L represents a linear or branched, preferably linear, Ci-Ce alkyl group,

[0024] X denotes:

[0025] - a linear or branched, saturated or unsaturated, hydrocarbon group containing from 1 to 24 carbon atoms, optionally interrupted with one or more heteroatoms, especially one or more heteroatoms chosen among oxygen, nitrogen, sulfur and / or phosphorous atoms, or

[0026] - a saturated or unsaturated, aromatic or non-aromatic, cyclic or heterocyclic moiety; said method comprising reacting:

[0027] • at least one alkylated phenyl alcohol compound having the following formula

[0028] Formula (II) wherein : p, L and Ri have the same meaning as in formula (I),

[0029] • with at least one alkanol corresponding to the formula X-OH wherein X has the same meaning as in formula (I), by cross-etherification in a solvent free continuous process in the presence of at least one cationic exchange resin.

[0030] The method according to the present invention displays the assets of achieving a high conversion rate of the alkylated phenyl alcohol responding to formula (II) and selectively etherifying the alcohol function present in the group L, while being respectful for the environment. Indeed, the method of the present invention enables to obtain alkylated ether phenyl compounds in satisfactory, even in very high yield, without implementing an organic solvent, which requires to be later removed from the reaction mixture, and without generating wastes that must be properly treated to mitigate potential adverse effects caused to the environment.

[0031] The method further exhibits the advantage of being highly sustainable on an industrial scale as said method is simple and effective to be implemented.

[0032] Especially, the method according to the present invention avoids the implementation of multiple steps that can be designed to neutralize and wash several times the reaction medium or that can be operated to separate the product from the organic solvent.

[0033] In other words, the method makes it possible to curb effluents leaving the reactor and to limit any washing operations to recover the alkylated ether phenyl compound.

[0034] Moreover, the method according to the present invention avoids the implementation of sequential steps as said method is carried out in continuous flow conditions.

[0035] It bespeaks therefore that the method makes it possible to obtain the alkylated ether phenyl compound in one step.

[0036] As a result, the implementation of the method according to the present invention makes it possible to achieve a reduction in energy expenditure compared to some traditional etherifications reactions.

[0037] Furthermore, the method pursuant to the invention avoids using a transition-metal catalyst whi ch mitigates its costs and is particularly advantageous on an industrial scale.

[0038] Parti cularly, the method allows the use of at least one cationic exchange resin, as a catalyst, which can be recycled, thus allowing the reduction of its carbon footprint.

[0039] In addition, the method is especially advantageous as the alkanol X-OH is a reagent that can be used either in equimolar quantities or in excess. When used in excess, said alkanol can advantageously be reused for further cycles. The method according to the present invention is therefore both highly sustainable and versatile as the alkylated phenyl alcohol responding to formula (II) can be highly converted, even completely converted, in one step, while the alkanol X-OH and the heterogeneous acid catalyst can be reused for the further cycl es.

[0040] In other words, the method maximises the use of the reagents and ensure their recyclability for further reactions.

[0041] The method thus guarantees an extended reagent life cycle and preserves the integrity of the reactor.

[0042] The method according to the present inventi on also has the advantage of being able to be implemented in simpler reaction systems, particularly in terms of size, structures and / or connectors.

[0043] It is worth noticing that when the alkylated phenyl alcohol compound responding to formula (II) is an alkylated phenolic alcohol (wherein Ri corresponds to a hydroxy group), this instant method displays the assets of achieving a high conversion rate of said alkylated phenolic alcohol and selectively etherifying the alcohol function linked to the group L, while being respectful for the environment

[0044] It is further worth noticing that the instant method is particularly designed to selectively etherified bio-based alkylated phenolic alcohols, such as 4-(2-hydroxyethyl)phenol (al so named tyrosol) which may lead to alkylated ether phenolic alcohol s, such as 4-(2-alkoxyethyl)phenol compounds (also named O-alkylated tyrosol).

[0045] Indeed, the method especially allows the preparation of nontoxic alkylated ether phenolic alcohols in an environmentally friendly manner.

[0046] Other obj ects, features, aspects and advantages of the invention will become more apparent upon reading the following description and examples.

[0047] In the following, and at least one other indication, the limits of a value range are included within this range, particularly in the expressions "between" and "ranging from ... to ... " .

[0048] Moreover, the expressions " at least one" and " at least" used in the present description are respectively equivalent to the expressions "one or more" and "more than or equal to" . Finally, in a manner known per se, Cncompound or group designates a compound or a group containing in its chemical structure n carbon atoms.

[0049] DETAILED DESCRIPTION

[0050] As previously defined, the method allows the preparation of at least one alkylated ether phenyl compound as defined in formula (I) compri sing a cross-etherification of at least one alkylated phenyl alcohol compound as defined in formula (II) with at least one alkanol X-OH, wherein X is as previously defined, in a solvent free continuous process in the presence of at least one cationic exchange resin.

[0051] The integer p ranges from 1 to 5, preferably from 1 to 4, more preferably ranges from 1 to 2, especially i s equal to 1 .

[0052] Ri represents : a hydroxy group -OH; a halogen atom, preferably a halogen atom chosen among the group constituted of a chlorine atom, a bromine atom and a fluorine atom; preferably a bromine or a fluorine atom; a nitro group - NO2, a linear or branched, saturated or unsaturated, C1-C4 alkyl group, preferably a C i alkyl .

[0053] Preferably, Ri represents a hydroxy group -OH or a halogen atom, such as a bromine atom or a fluorine atom, or a nitro group -NO2.

[0054] Advantageously, Ri represents a hydroxy group -OH or a halogen atom, such as a bromine atom or a fluorine atom.

[0055] Preferably, Ri represents a hydroxy group -OH.

[0056] L represents a linear or branched Ci-Ce alkyl group, preferably a linear or branched C1-C4 alkyl group, more preferably a C 1-C2 alkyl group, especially a C i or C2, in particular a C2 alkyl group.

[0057] L may represent a linear Ci-Ce alkyl group, preferably a linear C1-C4 alkyl group, more preferably a C 1-C2 alkyl group, even more preferably C i or C2 alkyl group, especially a C2 alkyl group.

[0058] Advantageously, L represents a linear C1-C4 alkyl group, preferably a C1-C2 alkyl group, especially a C2 alkyl group, and p is an integer ranging from 1 to 4, preferably from 1 to 3 , especially from 1 to 2, more preferably is equal to 1.

[0059] More advantageously, L represents a linear C1-C4 alkyl group, preferably a C1-C2 alkyl group, especially a C2 alkyl group, and p is equal to 1 or 2, especially to 1.

[0060] Even more advantageously, L represents a C1-C2 alkyl group, especially a C2 alkyl group, and p is equal to 1 or 2, especially to 1.

[0061] Preferably, L represents a linear C1-C4 alkyl group, preferably a C1-C2 alkyl group, especially a C2 alkyl group, p is equal to 1 or 2, Ri represents a hydroxy group or a halogen atom such as a bromine atom or a fluorine atom .

[0062] Preferably, L represents a C1-C2 alkyl group, especially a C2 alkyl group, p is equal to 1 or 2, and Ri represents a hydroxy group - OH and / or a halogen atom, such as a bromine atom or a fluorine atom and especially a bromine atom.

[0063] Preferably, L represents a C1-C2 alkyl group, especially a C2 alkyl group, p is equal to 1 and Ri represents a hydroxy group -OH.

[0064] X denotes: a saturated, linear or branched, hydrocarbon group containing from 1 to 24 carbon atoms, optionally interrupted with one or more heteroatoms, especially one or more heteroatoms chosen among oxygen, sulfur, nitrogen and / or phosphorous atoms, a saturated or unsaturated, aromatic or non-aromatic, cyclic or heterocyclic moiety.

[0065] According to the present invention, an aromatic or non-aromatic moiety may represent a mono- or polycyclic, fused or not fused compri sing 6- to 24-membered groups, especially comprising from 6 to 24 carbon atoms.

[0066] According to one embodiment of the present invention, the cyclic moiety i s aromatic and may represent a mono- or polycyclic, fused or not fused comprising from 6 to 24 carbon atoms, preferably from 6 to 12 carbon atoms.

[0067] Preferably, an aromatic cyclic moiety may be chosen among the group consisting of phenyl, biphenyl or naphthyl, indenyl, anthracenyl, preferably phenyl . According to one embodiment of the present invention, the cyclic moiety is non-aromatic and may represent a mono- or polycyclic, fused or not fused comprising from 6 to 24 carbon atoms, preferably from 6 to 12 carbon atoms, and may comprise one or more unsaturations.

[0068] According to the present invention, an aromatic or non-aromatic heterocyclic moiety may represent a mono- or polycyclic, fused or not fused, saturated or unsaturated, comprising 6- to 24-membered groups, including one or more heteroatoms chosen from nitrogen, oxygen, phosphorous and / or sulfur atoms, preferably chosen from oxygen and / or nitrogen atoms.

[0069] Preferably, the heterocyclic moiety is aromatic and may be chosen among the group consisting of morpholinyl, thiomoropholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, thioazepanyl; preferably pyrrolidinyl and morpholinyl .

[0070] According to one embodiment, X represents a linear or branched, saturated or unsaturated, hydrocarbon group containing from 1 to 24 carbon atoms optionally interrupted with one or more heteroatoms, in particular chosen from nitrogen, oxygen or sulfur atom, especially one or several oxygen atoms.

[0071] Preferably, X represents a linear or branched, saturated or unsaturated, hydrocarbon group containing from 1 to 24 carbon atoms.

[0072] Preferably, X represents a linear or branched, saturated or unsaturated, hydrocarbon group containing 2 to 14 carbon atoms, more preferably from 3 to 12 carbon atoms.

[0073] More preferably, X is a linear or branched saturated hydrocarbon group containing 2 to 14 carbon atoms, even more preferably from 3 to 12 carbon atoms.

[0074] Preferably, the at least one alkylated ether phenyl compound has the follo Formula (F ) wherein L, X and Ri have the same meaning as defined in formula (I).

[0075] Preferably, in formula (F ), L represents a linear C 1-C4 alkyl group, preferably a C1-C2 alkyl group, especially a C2 alkyl group, and Ri represents a hydroxy group -OH.

[0076] Preferably, in formula (F ), L represents a C1-C2 alkyl group, Ri represents a hydroxy group -OH and X represents a linear or branched, saturated or unsaturated, hydrocarbon group containing 2 to 14 carbon atoms, more preferably from 3 to 12 carbon atoms.

[0077] Preferably, in formula (F ), L represents a C1-C2 alkyl group, Ri represents a hydroxy group -OH and X represents a saturated, linear or branched, hydrocarbon group containing 2 to 14 carbon atoms, more preferably from 3 to 12 carbon atoms.

[0078] Hence, in other words, the instant method is advantageously aimed at a method for preparing at least one alkylated ether phenyl compound having the following formula (F ) :

[0079] CO

[0080] Formula (F ) wherein L, X and Ri have the same meaning as defined in formula (I), preferably L represents a linear C 1 -C4 alkyl group, more preferably a C1-C2 alkyl group, especially a C2 alkyl group, Ri represents a hydroxy group -OH and X represents a linear or branched, saturated or unsaturated, hydrocarbon group containing 2 to 14 carbon atoms, more preferably from 3 to 12 carbon atoms; said method comprising reacting:

[0081] • at least one alkylated phenyl alcohol compound having the following formula (IF ) : Formula (IF ) wherein:

[0082] L and Ri have the same meaning as in formula (I’ ),

[0083] • with at least one alkanol corresponding to the formula X-OH wherein X has the same meaning as in formula (I’ ), by cross-etherification in a solvent free continuous process in the presence of at least one cationic exchange resin.

[0084] Preferably, the at least one alkylated ether phenyl compound has the following formula (I”) :

[0085] Formula (I”) wherein X and Ri have the same meaning as defined in formula (I).

[0086] Preferably, in formula (I”), Ri represents a hydroxy group -OH and X represents a linear or branched, saturated or unsaturated, hydrocarbon group containing 2 to 14 carbon atoms, more preferably from 3 to 12 carbon atoms.

[0087] Preferably, in formula (I” ), Ri represents a hydroxy group -OH and X represents a saturated, linear or branched, hydrocarbon group containing 2 to 14 carbon atoms, more preferably from 3 to 12 carbon atoms.

[0088] Hence, in other words, the instant method is advantageously aimed at a method for preparing at least one alkylated ether phenyl compound having the following formula (I”) :

[0089] Formula (I”) wherein X and Ri have the same meaning as defined in formula (I), preferably Ri represents a hydroxy group -OH and X represents a linear or branched, saturated or unsaturated, hydrocarbon group containing 2 to 14 carbon atoms, more preferably from 3 to 12 carbon atoms, said method comprising reacting:

[0090] • at least one alkylated phenyl alcohol compound having the following formula (IF ) :

[0091] Formula (II”) wherein:

[0092] Ri has the same meaning as in formula (I”),

[0093] • with at least one alkanol corresponding to the formula X-OH wherein X has the same meaning as in formula (I”), by cross-etherification in a solvent free continuous process in the presence of at least one cationic exchange resin.

[0094] Advantageously, the at least one alkylated ether phenyl compound can be selected among the 4-(2-alkoxyethyl)phenol compounds (also named O-alkylated tyrosol), having the following formula (III) : wherein X denotes : a linear or branched, saturated or unsaturated, hydrocarbon group containing from 1 to 24 carbon atoms, optionally interrupted with one or more heteroatoms, especially one or more heteroatoms chosen among oxygen, nitrogen, sulfur and / or phosphorous atoms, or a saturated or unsaturated, aromatic or non-aromatic, cyclic or heterocyclic moiety, preferably a saturated or unsaturated, aromatic or non-aromatic, 6- to 24-membered heterocyclic or cyclic moiety.

[0095] Preferably, in formula (III), X represents a linear or branched, saturated or unsaturated, hydrocarbon group containing from 1 to 24 carbon atoms.

[0096] Preferably, in formula (III), X represents a linear or branched, saturated or unsaturated, hydrocarbon group containing 2 to 14 carbon atoms, more preferably from 3 to 12 carbon atoms.

[0097] Even more preferably, in formula (III), X represents a saturated, linear or branched, hydrocarbon group containing 2 to 14 carbon atoms, more preferably from 3 to 12 carbon atoms.

[0098] Advantageously, the at least one alkylated ether phenyl compound according to formula (I) is selected among the group consisted of the compounds corresponding to formula (F ), (I” ) or (HE ) as previously defined.

[0099] Advantageously, the at least one alkylated ether phenyl compound according to formula (I) is selected among the group constituted of the following compounds:

[0100] and mixtures thereof.

[0101] Advantageously, the at least one alkylated ether phenyl compound according to formula (I), (F ), (I” ) or (III) is selected among the group constituted of the following compounds: and mixtures thereof.

[0102] As previously defined, the cross-etherification is carried out in a solvent free continuous process in the presence of at least one cationic exchange resin. The at least one cationic exchange i s namely a heterogeneous acid catalyst.

[0103] The at least one cationic exchange is preferably a solid acid catalyst. The at least one cationic exchange resin is namely selected among resins comprising several carboxylic and / or sulfonic groups, preferably several sulfonic groups.

[0104] The at least one cationic exchange resin is preferably a resin compri sing several sulfonic groups (-SO3H) and / or sulfonate groups (- SO3 ), more preferably several sulfonate groups (-SO3 ).

[0105] The at least one cationic exchange resin is preferably a solid acid resin, preferably a sulfonic acid resin, such as the catalysts sold under the commercial names Amberlyst®- 15, Amberly st-35, Purolite® C-275 and Dowex® 50, preferably Amberlyst®- 15.

[0106] The alkanol as previously defined may be used in the method according to the present invention in an equimolar amount to the alkylated phenolic alcohol compound of formula (II) or in excess, preferably in excess.

[0107] The reaction may occur at a temperature ranging from 20°C to 200°C, preferably from 80°C to 150°C, more preferably from 100°C to 140°C, especially occurs at 120°C.

[0108] The time reaction may range from 1 hour to 56 hours, preferably from 20 hours to 50 hours, more preferably from 30 hours to 50 hours especially lasts 48 hours.

[0109] In a preferred embodiment, the reaction occurs from 30 hours to 50 hours at a temperature ranging from 100°C to 140°C .

[0110] The reaction may occur at a pressure ranging from 100 to 1500 kPa, preferably ranging from 100 to 500 kPa, especially occurs at 400 to 500 kPa.

[0111] The retention time for achieving a complete conversion from at least one alkylated phenolic alcohol compound as defined in formula (II) to at least one alkylated ether phenolic compound as defined in formula (I) may range from 1 to 1000 minutes, preferably range 1 to 70 minutes, especially ranging from 10 to 40 minutes.

[0112] The method of the present invention i s namely implemented at a flow rate ranging from 0.1 to 50 ml / min, preferably from 0.1 to 10 ml / min, especially ranging from 0. 10 to 0.30 ml / min.

[0113] The completion of the reaction is preferably monitored by a thin layer chromatography. Advantageously, one the at least one alkylated ether phenyl compound as defined in formula (I), preferably as defined in formula (I’) or (I” ) or (III), is obtained, said compound may be washed with the alkanol X-OH involved as a reagent in the method of the present invention.

[0114] The one alkylated ether phenyl compound may be purified by column chromatography.

[0115] The example hereafter only aims at illustrating the present invention and shall not be interpreted so as to limit its scope.

[0116] EXAMPLES

[0117] Example 1 : Synthesis of 4-(2-butoxyethyl)phenol (also named O-butylated tyrosol) :

[0118] Synthesis via a batch-process:

[0119] 4-(2-butoxyethyl)phenol ( l a) (al so named O-butylated tyrosol) was prepared by reacting 4-(2-hydroxyethyl)phenol, as a tyrosol starting material ( 1 ) (50g, 0.36 mol) with n-butanol (200 mL) in a solvent free batch process in the presence of Amberlyst®- 15 as catalyst at a temperature of 120°C for 48 hours.

[0120] The completion of the reaction was monitored by a thin layer chromatography.

[0121] The obtained product was then repeatedly washed with w-butanol (50 mL) over the Buckner funnel . The filtrate was evaporated under reduced pressure to remove n- butanol which afforded the crude 4-(2-butoxyethyl)phenol and recovered w-butanol was used for the reaction.

[0122] The crude product was purified by column chromatography by using silica-gel (60- 120 mesh) and EA / hexane (9 %) to afford pure product in 69% yield (48.50 gm). The purified compound was characterized byJH NMR,13C NMR, and HRMS.

[0123] XH NMR (CDCh, 400 MHz) d = 7.04 (d, J = 8.4 Hz, 2H), 6.73 - 6.71 (m, 2H), 3.62 (t, J = 7.3 Hz, 2H), 3.47 (t, J = 6.8 Hz, 2H), 2.81 (t, J = 7.3 Hz, 2H), 1.59 - 1.55 (m, 2H), 1.34 (dd, J = 15.1 , 7.5 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H) ppm;

[0124] 13C NMR (CDCh, 101 MHz) S = 157.9, 130.2, 129.9, 1 14.7, 67.7, 63.8, 38.3 , 31.4, 30.9, 19.3, 13.9 ppm;

[0125] HRMS (ESI) Calculated for C12H18O2 (M+H)+: 195.1385; found: 195.1350.

[0126] Synthesis via a continuous flow process:

[0127] 0.1 M solution of 4-(2-hydroxyethyl)phenol, as a tyrosol starting material (1 ) (5g, 0.0362 mol), in w-butanol (362 mL) was flown five times through the packed bed reactor (Omnift column: 10mm width xl 50 mm height) loaded with a heterogeneous catalyst, i .e Amberlyst®- 15, up to 7 cm (3.5 g), swollen up to 10 cm at 120 °C with residence time 36.7 min and flow rate 0.3 mL / min (4.5 bar pressure).

[0128] The completion of the reaction was monitored by thin-layer chromatography. The reaction mixture was evaporated by vacuum.

[0129] Finally, the crude product was purified by column chromatography by using silica-gel (60-120 mesh) and EA / hexane (9%) to afford pure 4-(2-butoxyethyl)phenol (l a) in 73% yield (5.13g).

[0130] The purified compound was characterized byXH NMR,13C NMR, and HRMS.

[0131] XH NMR (CDCh, 400 MHz) d = 7.04 (d, J = 8.4 Hz, 2H), 6.73 - 6.71 (m, 2H), 3.62 (t, J = 7.3 Hz, 2H), 3.47 (t, J = 6.8 Hz, 2H), 2.81 (t, J = 7.3 Hz, 2H), 1.59 - 1.55 (m, 2H), 1.34 (dd, J = 15.1 , 7.5 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H) ppm;13C NMR (CDC13, 101 MHz) d = 157.9, 130.2, 129.9, 1 14.7, 67.7, 63.8, 38.3 , 31.4, 30.9, 19.3, 13.9 ppm;

[0132] HRMS (ESI) Calculated for C12H18O2 (M+H)+: 195.1385; found: 195.1350.

[0133] Comparative results display that the yield of 4-(2- butoxyethyl)phenol obtained by the continuous flow process of the present invention is therefore higher (73% yield) than that obtained by the batch process (69% yield).

[0134] Example 2: Synthesis of 4-(2-isobutoxyethyl)phenol (also ending to O-isobutvlated tvrosol):

[0135] Synthesis via a batch-process:

[0136] 4-(2-isobutoxyethyl)phenol (also named O-isobutylated tyrosol) was prepared by reacting 4-(2-hydroxyethyl)phenol, as a tyrosol starting material (1) (50g, 0.36 mol) with isobutanol in a solvent free batch cross-etherification process in the presence of Amberlyst®-15 as catalyst according to the method previously detailed for the preparation of 4-(2-butoxyethyl)phenol.

[0137] The product 4-(2-isobutoxyethyl)phenol was obtained in 54% yield (38.3g).

[0138] The purified compound was characterized byXH NMR,13C NMR, and HRMS.

[0139] XH NMR (CDCh, 400 MHz) <5 = 7.07 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 6.22 (s, 1H), 3.63 (t, J = 7.3 Hz, 2H), 3.25 (d, J = 7.5 Hz, 2H), 2.83 (t, J = 7.3 Hz, 2H), 1.89 (dp, J = 13.4, 6.7 Hz, 1H), 0.90 (d, J = 6.7 Hz, 6H) ppm;13C NMR (CDCh, 101 MHz) 3 = 154.3, 130.7, 130.0, 1 15.4, 78.0, 72.3, 35.3 , 28.3, 19.4 ppm;

[0140] HRMS (ESI) Calculated for C12H18O2 (M+H)+: 195.1385; found: 195.1357.

[0141] Synthesis via a continuous flow process:

[0142] 4-(2-isobutoxyethyl)phenol was prepared in continuous flow by 0.1 molar solution of starting material 4-(2-hydroxyethyl)phenol (1) (1 g, 0.0072 mol) in isobutanol (72 mL) was passed four times through a heterogeneous catalyst i.e Amberlyst®- 15 column bed of 7 cm (3.5 g) in Omnifit column (10mm width xl 50 mm height), which is swollen up to 10 cm at 120°C with residence time 36.7 min and flow rate 0.3 mL / min (4.5 bar pressure).

[0143] The completion of the reaction was monitored by thin-layer chromatography. The reaction mixture was evaporated by vacuum, the crude product was purified by column chromatography by using silica- gel (60- 120 mesh) and EA / hexane (9%) to afford pure 4-(2- isobutoxyethyl)phenol in 82% yield (1.16g).

[0144] The purified compound was characterized byXH NMR,13C NMR, and HRMS.

[0145] 3H NMR (CDCh, 400 MHz) 3 = 7.07 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 6.22 (s, 1H), 3.63 (t, J = 7.3 Hz, 2H), 3.25 (d, J = 7.5 Hz, 2H), 2.83 (t, J = 7.3 Hz, 2H), 1.89 (dp, J = 13.4, 6.7 Hz, 1H), 0.90 (d, J = 6.7 Hz, 6H) ppm;

[0146] 13C NMR (CDCh, 101 MHz) 3 = 154.3, 130.7, 130.0, 1 15.4, 78.0, 72.3, 35.3 , 28.3, 19.4 ppm;

[0147] HRMS (ESI) Calculated for C12H18O2 (M+H)+: 195.1385; found: 195.1357.

[0148] Comparative results display that the yield of 4-(2- isobutoxyethyl)phenol obtained by the continuous flow process of the present invention is therefore higher (82% yield) than that obtained by the batch process (54% yield). Example 3 : Synthesis of 4-(2-((2-ethylhexyDoxy)ethyl)phenol

[0149] Synthesis via a batch-process:

[0150] The starting material 4-(2-hydroxyethyl)phenol ( 1 ) (50g, 0.362 mol) reacted with 2-ethyl hexanol (200 mL) by using a heterogeneous catalyst (50g, w / w) i . e Amberlyst®- 15 at a temperature of 1 10 °C for 48 hrs. The completion of the reaction was monitored by thin-layer chromatography.

[0151] After that, the reaction mixture was filtered out with a Buchner funnel by repeatedly washing with 2-ethyl hexanol (50mL) and ethyl acetate.

[0152] Then, the filtrate was evaporated under reduced pressure to remove ethyl acetate to afford the crude 4-(2-((2- ethylhexyl)oxy)ethyl)phenol (3h) along with 2-ethyl hexanol . But still, 2-ethyl hexanol was not removed by rotary evaporator, so we used a fractional or vacuum distillation process for the removal of 2-ethyl hexanol and recovered 2-ethyl hexanol was used for the reaction.

[0153] Then, the crude product (3h) was purified by column chromatography by using silica-gel (60- 120 mesh) and EA / hexane (15%) to afford pure product (3h) in 50.4% (45.6g) yield as a colorless liquid.

[0154] The purified compound was characterized byJH NMR,13C NMR and HRMS .

[0155] XH NMR (CDC13, 400 MHz) 8 = 7.05 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 3.56 - 3.54 (m, 4H), 3.3 1 (d, J = 6.1 Hz, 2H), 2.81 - 2.77 (m, 1H), 1.41 - 1.25 (m, 8H), 0.90-0.83 (m, 6H) ppm;13C NMR (CDCh, 101 MHz) <5 = 154.6, 130.5, 129.9, 1 15.3 , 74.0, 72.4, 65.3 , 41.9, 30.1 , 29.2, 23.3 , 23.0, 14. 1 , 1 1.0 ppm; HRMS (ESI) Calculated for C16H26O2 (M+H)+: 251.201 1 found: 251.2021 . Synthesis via a continuous flow process:

[0156] A 0. 1 molar solution of starting material 4-(2- hydroxyethyl)phenol ( 1 ) ( 1 g, 00072 mol) and 2-ethyl hexanol (72 mL) was passed eight times through a heterogeneous catalyst i . e Amberlyst®- 15 column bed of 7 cm (3.5 g) at a temperature of 120°C with residence time 36.7 min and flow rate 0.3 mL / min (4.6 bar pressure).

[0157] The completion of the reaction was monitored by thin layer chromatography. Then, the reaction mixture was evaporated by vacuum distillation method to remove 2-ethyl hexanol and got the crude 2-ethyl hexyl ether (3h).

[0158] Then the crude product (3h) was purified through column chromatography by using silica-gel (60- 120 mesh) and EA / hexane (15%) to afford pure product (3 h) in 88% yield (1 .54 g) as a colorless liquid.

[0159] The purified compound was characterized byJH NMR,13C NMR and HRMS .

[0160] XH NMR (CDC13, 400 MHz) S = 7.05 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 3.56 - 3.54 (m, 4H), 3.3 1 (d, J = 6.1 Hz, 2H), 2.81 - 2.77 (m, 1H), 1.41 - 1.25 (m, 8H), 0.90-0.83 (m, 6H) ppm;13C NMR (CDCh, 101 MHz) <5 = 154.6, 130.5, 129.9, 1 15.3 , 74.0, 72.4, 65.3 , 41.9, 30.1 , 29.2, 23.3 , 23.0, 14. 1 , 1 1 .0 ppm; HRMS (ESI) Calculated for C16H26O2 (M+H)+: 251.201 1 , found: 251.2021.

[0161] Conclusion:

[0162] Comparative results display that the yield of 4-(2-((2- ethylhexyl)oxy)ethyl)phenol obtained by the continuous flow process of the present invention is therefore higher (88% yield) than that obtained by the batch process (50.4% yield).

[0163] Example 4 : Synthesis of 4-(2-(dodecyloxy)ethyl)phenol under continuous

[0164] A 0.1 M solution of the 4-(2-hydroxyethyl)phenol (1) (1g. 0.0072mmol in 72 mL of w-dodecanol) was flown through the packed bed reactor (Omnifit, 10.0 mm i.d. x 150.0 mm length) loaded with Amberlyst®-15 up to 7 cm (3.5g, swollen up to 10 cm after passing solvent) of bed heated at 120 °C temperature at 4.5 to 4.6 bar pressure.

[0165] The organic layer was concentrated under reduced pressure, and the residue was subj ected to column chromatography (EtOAc: n-hexane =4%) purification affording corresponding 4-(2- (dodecyloxy)ethyl)phenol and w-dodecanol in 71% yield 1.6 g) as a mixture in 2:1 ration.

[0166] The purified compound was characterized byJH NMR,13C NMR and HRMS.

[0167] XH NMR (CDC13, 400 MHz) <5 = 7.06 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 5.87 (s, 1H), 3.66 (t, J = 6.7 Hz, 1H), 3.60 (t, J = 7.4 Hz, 2H), 3.45 (t, J = 6.8 Hz, 2H), 2.81 (t, J = 7.3 Hz, 2H), 1.62 - 1.53 (m, 3H), 1.28 (d, J = 17.7 Hz, 27H), 0.88 (t, J = 6.8 Hz, 4H) ppm;

[0168] 13C NMR (CDCh, 101 MHz) <5 = 153.3, 129.6, 128.9, 1 14.2, 71.0, 70.1 , 62.1 , 34.3, 31.6, 30.9, 28.6, 28.5, 28.4, 28.3 , 28.3, 25.1 , 24.6, 21.6, 13.1 ppm;

[0169] HRMS (ESI) Calculated for C20H34O2 (M+H)+: 307.2637 found: 307.2095. Example 5 : Synthesis of 4-(2-isopropoxyethyDphenol

[0170] Synthesis via a continuous flow process:

[0171] 0. 1 molar solution of starting material 4-(2-hydroxyethyl)phenol (1 ) ( 1 g, 0.0072 mol) and isopropanol (72 mL)in was prepared and was flown through a 10 * 150 mm Omnifit packed bed reactor (3.5g of Amberlyst®- 15, 14 cm bed height) (Vapourtec R-series) at a temperature of 120°C with residence time 36.7 min and flow rate 0.3 mL / min (4.5 bar pressure). The reaction was performed 10 cycles in continuous flow.

[0172] After the reaction, Amberlyst®- 15 was filtered out from the reaction mixture. The desired product was purified through column chromatography (8% EtOAc in hexane). The yield of the desired product (3k) was 0.3 1 g (24%) as a colorless liquid.

[0173] The purified compound was characterized byJH NMR,13C NMR and HRMS .

[0174] XH NMR (CDC13, 400 MHz) 5 = 7.08 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 5.01 (s, 1H), 3.63 - 3.53 (m, 3H), 2.80 (t, J = 7.4 Hz, 2H), 1 .15 (d, J = 6. 1 Hz, 6H) ppm;13C NMR (CDCI3, 101 MHz) <5 = 154.0, 13 1. 1 , 130.0, 1 15.2, 71.7, 69.5, 35.9, 22.1 ppm; HRMS (ESI) Calculated for C nHi6O2(M+H)+: 181. 1229 181.0880

[0175] Example 5 - Synthesis of compounds (6) under continuous flow conditions : Compounds (6) were synthesized according to the following general protocol :

[0176] Protocol :

[0177] 0. 1 molar solution of tyrosol (1 ) in alcohol (2), corresponding to formula X-OH, was prepared and was flown through a 10 x 150 mm Omnifit packed bed reactor (3.5g of Amberlyst®- 15, 7 cm bed height) (Vapourtec R-series) at a temperature of 120°C or at room temperature (depending on the obtained product) with residence time 36.7 min and flow rate 0.3 mL / min (between 4. 5-4.8 bar pressure). The reaction was performed several cycles in continuous flow depending on the obtained product.

[0178] The completion of the reaction was monitored by thin layer chromatography. After the reaction, Amberlyst®- 15 was filtered out from the reaction mixture.

[0179] The crude product was purified by column chromatography by using EA / hexane (5%) to afford pure product.

[0180] The obtained products are given in the table 3 below with their respective isolated yield, reacting temperature and their characterization byXH NMR,13C NMR and HRMS .

[0181] Table 3 :

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188] (a) The reaction was performed 2 cycles in continuous flow

[0189] (b) The reaction was performed 4 cycles in continuous flow

[0190] (c) The reaction was performed 3 cycles in continuous flow

[0191] Example 6 - Synthesis of 1 -bromo-2-(butoxymethyl)benzene (8c) :

[0192] Compound (8c) was synthesized according to the respective following protocol :

[0193] Synthesis via a batch process:

[0194] 1 mmol of (2-bromophenyl)methanol and a heterogeneous catalyst (Amberlyst®' 15) were taken in a resealable reaction vial followed by 2 mL of w-butanol which was added to the same vial and heated at 120°C for 48 hours.

[0195] After completion of the reaction, the catalyst was filtered out from the reaction mixture. The desired product was purified through column chromatography (5% EtOAc in hexane).

[0196] The yield of the desired product (8a) was (177.5mg) 74% as a colorless liquid.

[0197] The purified compound was characterized byJH NMR

[0198] XH NMR (CDC13, 400 MHz) ; 57.47 - 7.39 (m, 2H), 7.23 (td, J= 7.6, 1.1 Hz, 1H), 7.05 (td, J= 7.9, 1.7 Hz, 1H), 4.48 (s, 2H), 3.48 (t, J= 6.6 Hz, 2H), 1.59 - 1.52 (m, 2H), 1.39 - 1.32 (m, 2H), 0.86 (t, J= 7.4 Hz, 3H) ppm. Synthesis via a continuous flow process:

[0199] A 0. 1 molar solution of (2-bromophenyl)methanol in butanol was prepared and was flown through a 10 * 150 mm Omnifit prepacked bed reactor (3.5 g of Amberlyst®- 15, 14 cm bed height) (Vapourtec R-series) at 120 °C with residence time 36.7 minutes and flow rate 0.3 mL / min (4.5 bar pressure). After the reaction, Amberlyst®- 15 was filtered out from the reaction mixture. The completion of the reaction was monitored by thin layer chromatography.

[0200] The crude product was purified by column chromatography EA / hexane (5%) to afford pure product in 94% yield (228 mg) as a colorless liquid.

[0201] The purified compound was characterized byJH NMR and13C NMR.

[0202] XH NMR (CDC13, 400 MHz) ; 57.47 - 7.39 (m, 2H), 7.23 (td, J= 7.6, 1.1 Hz, 1H), 7.05 (td, J= 7.9, 1.7 Hz, 1H), 4.48 (s, 2H), 3.48 (t, J= 6.6 Hz, 2H), 1.59 - 1.52 (m, 2H), 1.39 - 1.32 (m, 2H), 0.86 (t, J= 7.4 Hz, 3H) ppm.

[0203] Conclusion:

[0204] Comparative results display that the yield of compound (8c) obtained by the continuous flow process of the present invention is therefore higher (94% yield) than that obtained by the batch process (74% yield).

[0205] Example 7 - Synthesis of l -methyl-4-(propoxymethyl)benzene (8a) :

[0206] Compound (8a) was synthesized according to the general following protocol : Synthesis via a batch process :

[0207] A 1 mmol of para-tolylmethanol was taken in a resealable reaction vial followed by 2 mL of ^-propanol which was added to the same vial and heated at 120°C for 24 hours in the presence of a heterogeneous catalyst (Amberlyst®- 15).

[0208] The complete conversion of para-tolylmethanol was monitored by TLC. After completion of the reaction, the catalyst was filtered out from the reaction mixture. The desired product was purified through column chromatography (5% EtOAc in w-hexane). The yield of the desired product (2d) was (144mg) 47%.

[0209] The purified compound was characterized byJH NMR.

[0210] XH NMR (CDCh, 400 MHz) 5 = 7.27 (d, J = 7.8 Hz, 2H), 7. 18 (d, J = 7.9 Hz, 2H), 4.50 (s, 2H), 3.49 - 3.40 (m, 2H), 2.38 (s, 3H), 1.75 - 1.60 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H) ppm.

[0211] 13C NMR (CDCh, 101 MHz) S = 137.1, 135.7, 129.1, 127.8, 72.7, 72.0, 23.0, 21.2, 10.7 ppm;

[0212] Synthesis via a continuous flow process:

[0213] A 0.1 molar solution of para-tolylmethanol in propanol was prepared and was flown through a 10 * 150 mm Omnifit packed bed reactor (3.5 g of Amberlyst®- 15, 10 cm bed height) (Vapourtec R-series) at 120 °C with residence time 36.7 minutes and flow rate 0.3 mL / min (3.3 bar pressure). After the reaction, Amberlyst®- 15 was filtered out from the reaction mixture. The completion of the reaction was monitored by thin layer chromatography.

[0214] The crude product was purified by column chromatography EA / hexane (5%) to afford pure product in 93% yield as a colorless liquid.

[0215] The purified compound was characterized byXH NMR and13C NMR.

[0216] XH NMR (CDCh, 400 MHz) 5 = 7.27 (d, J = 7.8 Hz, 2H), 7. 18 (d, J = 7.9 Hz, 2H), 4.50 (s, 2H), 3.49 - 3.40 (m, 2H), 2.38 (s, 3H), 1.75 - 1.60 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H) ppm.

[0217] 13C NMR (CDCh, 101 MHz) d = 137.1, 135.7, 129.1, 127.8, 72.7, 72.0, 23.0, 21.2, 10.7 ppm; Conclusion:

[0218] Comparative results display that the yield of compound (8a) obtained by the continuous flow process of the present invention is therefore higher (93% yield) than that obtained by the batch process (47% yield).

Claims

CLAIMS1. Method for preparing at least one alkylated ether phenolic compound having the following formula (I):Formula (I) wherein: p is an integer ranging from 1 to 5, preferably ranging from 1 to2, specifically corresponds to 1 ,Ri represents a hydroxy group, a halogen atom, a nitro group - NO2, or a linear or branched, saturated or unsaturated, C1-C4 alkyl group,L represents a linear or branched, preferably linear, Ci-Ce alkyl group,X denotes :- a linear or branched, saturated or unsaturated, hydrocarbon group containing from 1 to 24 carbon atoms, optionally interrupted with one or more heteroatoms, especially one or more heteroatoms chosen among oxygen, sulfur, nitrogen and / or phosphorous atoms, or- a saturated or unsaturated, aromatic or non-aromatic, 6- to 24- membered cyclic or heterocyclic moiety, said method comprising reacting:• at least one alkylated phenolic alcohol compound having the following formulaFormula (II) wherein :p, L and Ri have the same meaning as in formula (I),• with at least one alkanol corresponding to the formula X-OH wherein X has the same meaning as in formula (I), by cross-etherification in a solvent free continuous process in the presence of at least one cationic exchange resin.

2. Method according to Claim 1 , wherein Ri represents a hydroxy group -OH or a halogen atom, such as a bromine atom or a fluorine atom, or a nitro group -NO2, more preferably a hydroxy group -OH.

3. Method according to Claim 1 or Claim 2, wherein L represents a linear C 1-C4 alkyl group, preferably a C1-C2 alkyl group, even more preferably C i or C2 alkyl group, especially a C2 alkyl group.

4. Method according to any of the preceding claims, wherein p is an integer ranging from 1 to 4, preferably from 1 to 2, more preferably is equal to 1 .

5. Method according to any of preceding claims, wherein L represents a linear C 1-C4 alkyl group, preferably a C1-C2 alkyl group, especially a C2 alkyl group, and p is equal to 1 or 2, especially to 1.

6. Method according to any of the preceding claims, wherein X represents a linear or branched, saturated or unsaturated, hydrocarbon group containing 2 to 14 carbon atoms, more preferably from 3 to 12 carbon atoms, even more preferably a linear or branched saturated hydrocarbon group containing 2 to 14 carbon atoms, and more specifically from 3 to 12 carbon atoms.

7. Method according to any of the preceding claims, wherein L represents a linear C 1-C4 alkyl group, preferably a C1-C2 alkyl group, especially a C2 alkyl group, p is equal to 1 or 2, and Ri represents a hydroxy group or a halogen atom such as a bromine atom or a fluorine atom .

8. Method according to any of the preceding claims, wherein the at least one alkylated ether phenolic compound can be selected among the 4-(2-alkoxyethyl)phenol compounds, having the following formula (HI) :wherein X has the same meaning as defined either in Claim 1 or Claim 6.

9. Method according to any of the preceding claims, wherein the at least one alkylated ether phenyl compound according to formula (I) i s selected among the group constituted of the following compounds :and mixtures thereof, preferably chosen from the compounds (3 a), (3b), (3 c), (3 d), (3 e), (3 f), (3g), (3h), (3i), (3j ), (3k) and mixtures thereof.

10. Method according to any of the preceding claims, wherein the cationic exchange resin is chosen among the resins comprising several carboxylic and / or sulfonic groups, preferably several sulfonic groups.1 1. Method according to any of the preceding claims, wherein the cationic exchange resin is a sulfonic resin, preferably comprising several sulfonate groups (-SO3 ).

12. Method according to any of the preceding claims, wherein the reaction occurs at a temperature ranging from 20°C to 200°C, preferably from 80°C to 150°C, more preferably from 100°C to 140°C, especially occurs at 120°C .

13. Method according to any of the preceding claims, wherein the time reaction ranges from 1 hour to 56 hours, preferably from 20 hours to 50 hours, more preferably from 30 hours to 50 hours, especially lasts 48 hours.

14. Method according to any of the preceding claims, wherein the reaction occurs at a pressure ranging from 100 to 1500 kPa, preferably ranging from 100 to 500 kPa, especially occurs at 400 to 500 kPa.

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