METHOD FOR THE SYNTHESIS OF VITAMIN A

Description

[0001] The present invention relates to new transformation reactions of sesquiterpene compounds allowing a new route of access to vitamin A (C 20 H 30 O), its precursors and its derivatives.

[0002] The industrial-scale synthesis of vitamin A is carried out using various conventional methods. Among other preparations, vitamin A can be obtained via the C15 + C5 condensation route, such as the Julia reaction, which involves sulfone chemistry. In this reaction, vinyl-β-ionol is treated with a phenylsulfinate anion to yield a C15 sulfone, to which allyl bromide is added to obtain a C20 sulfone. This is then converted, by elimination, to vitamin A acetate, which is generally used as is, since vitamin A is very unstable, or saponified into vitamin A.

[0003] Other processes are also used. For example, vitamin A can be manufactured by a C15 + C5 coupling process via a Wittig reaction; however, this process uses intermediates with carcinogenic, mutagenic or reprotoxic (CMR) effects, such as C5 acetate, and requires a phosphine regeneration unit with phosgene, which is a highly toxic gas.

[0004] Thus, according to document FR2359822A1, we know a process for the synthesis of vitamin A acetate from vinyl-β-ionol consisting of reacting a salt of β-ionylidene-ethyl-triphenylphosphonium in aqueous solution with γ-acetoxy-glitic adehyde.

[0005] Another access route lies in a C6 + C14 coupling process through alkyne chemistry; it has the disadvantages of involving certain raw materials, such as acetylene, nButyl-Li, which present obvious HSE (Health - Safety - Environment) risks and of involving unstable and toxic epoxy intermediates.

[0006] These synthesis processes have not undergone any real evolution since their discovery, and to date, it is important to use new, safer and more economical industrial synthesis processes.

[0007] The invention provides a novel route for the synthesis of C15 sulfone from sesquiterpenes, particularly farnesene, or sesquiterpene derivatives, opening a new paradigm in vitamin A synthesis. The compounds used in this new route are found in nature; they are present in certain plant essences from which they can be extracted, and they are also biosynthesized by microorganisms, notably fungi. Since the reagent resource is therefore inexhaustible, the invention offers a sustainable solution to the cost problems of conventional processes and contributes to real progress in the production of vitamin A, as well as intermediates for other syntheses.

[0008] One of the objects of the invention is a method for preparing a compound of formula (I) in which R1 is chosen from H and alkyls, R2 is chosen from H, alkyls, OR' where R' is chosen from alkyls, silyls, CO-alkyl, R3 is chosen from acyl groups of the type CO(R") and the following groups CO(OR"), CO(NR"R‴), PO(OR"))(OR‴), PO(OR"))(R‴) where R" and R"', independently of each other, are chosen from H and alkyls; for example R3 is CO(CH3) or CO(CH2CH3), R represents a group C(R4)=C(R5)(R6) where R4, R5 and R6, independently of each other, are chosen from H, alkyls and alkenyls, linear or cyclic, aryls, alkylaryls, or R4 and R5 together form a ring, saturated or unsaturated, Substituted or unsubstituted; for example, R represents: the structural portion from carbon atom 1 to carbon atom 10 of a retinoid, illustrated below or the structural portion from carbon atom 1 to carbon atom 10 of a 7,8-dihydro-retinoid, illustrated below: or the structural portion from carbon atom 1 to carbon atom 6 of a retinoid, illustrated below: said compound of formula (I) being obtained by reaction of a compound of formula (II) in which R, R1, R2 and R3 have the above definition, in the presence of a strong base or in the presence of a metallic catalyst.

[0009] Another object of the invention, which constitutes a pivot of the invention, is a single-stage process for obtaining a compound (I) above, from a compound of formula (III) in which R, R1 and R2 have the above definition, said process comprising the formation of the compound of formula (II) in which R, R1, R2, and R3 have the above definition, from said compound (III) above, and the formation of compound (I) according to the isomerization process described above from compound (II). Advantageously, compound (II) is not isolated. This single-tope acylation / isomerization process represents a real advance in the synthesis of vitamin A, its precursors, and its derivatives.

[0010] Before discussing the invention in more detail, the definitions of terms used in this text are given below.

[0011] Any reference to an unsaturated compound extends to the isomers of that compound, in particular its regioisomers and stereoisomers.

[0012] As an example, the term farnesene includes the alpha and beta regioisomers of farnesene, as well as the stereoisomers of each of them, as illustrated below: α-Farnesene (3,7,11-trimethyl-1,3,6,10-dodecatetraene) has the following formula which can exist in the form of the following 4 isomers (3E, 6E), (3E, 6Z), (3Z, 6Z) and (3Z, 6E), and β-farnesene (7,11-dimethyl-3-methylene-1,6,10-dodecatriene) having the following formula which can exist in the form of the following 2 isomers (6E) and (6Z).

[0013] This definition applies in particular to farnesal, dehydrofarnesal, farnesol, retinal, dihydroretinal, their acetates and their enol acetates, whose names cover all their respective isomers.

[0014] According to the invention, an alkyl group is defined as a saturated, monovalent, linear, cyclic, and / or branched hydrocarbon chain comprising from 1 to 20 carbon atoms, preferably from 1 to 6 carbon atoms, representative elements of which are, for example, the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, and hexyl groups. A cyclic hydrocarbon chain alkyl group is defined as a saturated, monovalent hydrocarbon chain comprising from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms, and one or more rings. Representative elements are, for example, the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and norbornyl groups.

[0015] An alkenyl group is understood to be a monovalent, linear, cyclic and / or branched, mono- or polyunsaturated hydrocarbon chain comprising 2 to 20 carbon atoms.

[0016] A silyl group is a group consisting of a Si atom substituted by 3 substituents, identical or different, chosen from H and alkyls, such as trimethylsilyl.

[0017] An aryl group according to the invention is understood to be a monofunctional, monocyclic or polycyclic aromatic hydrocarbon chain comprising from 6 to 20 carbon atoms. Examples include benzyl, naphthyl and biphenyl groups.

[0018] The terms 'alkyl' and 'aryl' as defined above retain the same definition when they incorporate the name of a group, for example in the groups -CO-alkyl, alkylaryls.

[0019] According to a variant of either of the two above processes, the invention relates to the preparation of a compound of formula (IV) in which R is such as defined previously for formula (I), by reaction of a compound of formula (V) or by reaction of a compound of formula (VI) via formula (V). Advantageously, compound (V) is not isolated.

[0020] Thus, any one of the following compounds of formula (I) or (IV): vitamin A acetate, dehydro-β-farnesyl acetate, and dehydro-citral acetate, can be obtained: according to the acylation step of the invention, from a compound of formula (II) or (V) selected from 11,12-dihydroretinal enol acetate, dehydro-β-farnesyl enol acetate and dehydro-citral enol acetate, respectively, or preferably according to the one-pot acylation / isomerization process according to the invention, from a compound of formula (III) or (VI) selected from 11,12-dihydroretinal, farnesal and citral, respectively, without isolating the corresponding acetate intermediate.

[0021] The feasibility of the one-pot acylation / isomerization process of the invention for obtaining vitamin A acetate from 7,8-dihydroretinal was also observed. According to the invention, it can be obtained from dehydrocyclofarnesyl acetate enol, but preferably in a one-pot process from cyclofarnesal without isolating the dehydrocyclofarnesyl acetate enol.

[0022] In an advantageous embodiment of the invention, the isomerization of compound (II) or (V) into compound (I) or (IV) is carried out in the presence of a strong base, and for example a strong base chosen from phosphazenes such as P2Et, aminides such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and alkoxides such as potassium terbutylate.

[0023] The acetylation of compound (III) or (VI) into compound (II) or (V) respectively, is classically carried out under conditions known to those skilled in the art, for example in the presence of acetic anhydride and pyridine.

[0024] Farnesal is a readily available reagent. It can be produced synthetically from farnesene, farnesol, ethyl farnesoate, nerolidol, or dehydronerolidol using methods known to those skilled in the art (Tetrahedron Letters 2016, 57, 40, 4496-4499; New Journal of Chemistry 2001, 25, 7, 917-929; Catal. Comm. 2014, 44, 40-45), but it can also be isolated from essential oils, such as lemongrass. According to an original variant, farnesal can be produced by the oxidation of farnesene under the catalytic conditions of a Wacker-type process in the presence of at least one precious metal, primarily palladium. Advantageously, the reaction medium comprises palladium(II) salts such as PdCl₂, copper salts, and an oxidizing agent. For example, the reaction is carried out in the presence of PdCl₂ (CH₂CH₂), CuCl₂, and LiMoO₄.

[0025] One of the major interests of the invention concerned the preparation of a compound of formula (VII) in which R and R1 have the definition previously given for formula (I) and R'2 is chosen from H and alkyls.

[0026] This process is also an object of the invention, and it consists of: to prepare the sulfone of formula (VII), from a compound of formula (II) described above, comprising the process of acylation of said compound (II) into compound (I), or to prepare the sulfone of formula (VII), from a compound of formula (III) comprising the one-pot isomerization / acylation process of said compound into compound of formula (I), said compounds (I), (II) and (III) being as defined above.

[0027] In one embodiment of the invention, dehydro farnesyl sulfone is prepared from farnesal enol acetate.

[0028] One of the objectives is to produce vitamin A from farnesene or its derivatives, and this is another object of the invention, this synthesis comprising at least one of the processes described above. The various objects of the invention and their applications are illustrated in the following examples.

[0029] In the examples, the abbreviations used are defined below: TT defines the transformation rate; RR defines a yield on reactant; RR isolated defines a yield on reactant after isolation; RR titrated defines a yield on titrated reactant in a reaction medium. Example 1: Preparation of vitamin A acetate from 11,12-dihydroretinal

[0030] This preparation comprises two steps, a first of obtaining the enol acetate of 11,12-dihydroretinal, which is a compound of the invention, from 11,12-dihydroretinal, then a second step involving the isomerization process of the invention of the enol acetate of 11,12-dihydroretinal into vitamin A acetate. 1.1) Acetylation of 11,12-dihydroretinal to enol acetate and isomeric forms

[0031]

[0032] The operating conditions are as follows: The reactants are introduced under nitrogen in the following order: 11,12-Dihydroretinal (DHR), 2 g (4.47 mmols) DMAP, 1 g (8.10 mmols) Pyridine, 10 g (126 mmols) Acetic anhydride, 10 g (96 mmols)

[0033] The reaction mixture is stirred in the dark at 115°C for 1 h. After cooling to 25°C, the reaction mixture is poured into a solution of 100 mL of water, 100 mL of saturated aqueous NaHCO3 solution, and 100 mL of cyclohexane. After separation, the aqueous phase is re-extracted with 100 mL of cyclohexane, and the combined organic phases are washed with 300 mL of saturated aqueous NaCl solution, dried over Na2SO4, and evaporated. 2.01 g of a yellow-orange oil were obtained. TT DHR = 100% (TLC) Sole RRi = 57% of a mixture of exo / endo isomers (80 / 20) Titer (HPLC) = 41% (33% exo + 8% endo). 1.2) Isomerization of dihydroretinal enol acetate to vitamin A acetate

[0034]

[0035] The general operating conditions were as follows: The reagents were introduced under nitrogen into a pillbox equipped with a magnetic stirrer: enol acetates (mixture from reaction 1.2 above, 50 mg, 0.076 mmols), solvent (1.15 mL, except for DMSO: 2.3 mL), base (tBuO₄K: 3.6 mg (added in solution in the case of DMSO, NMP, isopropanol, and THF); hydrotalcite: 25 mg; KOH: a 30 mg piece, 85% concentration; aqueous sodium hydroxide: 500 µL at 300 g / L). The reaction mixture was stirred in the absence of light.

[0036] For reaction monitoring, each 50 µL sample of the organic phase is hydrolyzed over a mixture of 0.5 mL of water, 0.5 mL of saturated aqueous NaHCO3 solution, and 0.5 mL of cyclohexane. An aliquot of the cyclohexane phase is loaded onto a silica plate and eluted with a 90 / 10 cyclohexane / ethyl acetate mixture.

[0037] Different conditions were tested; the most representative are shown in Table 1. Table 1 Terms RR measured "trans" (HPLC, %) P 2 -ET (0.2 eq.), 25°C, 30 min 33 DBU (1.1 eq.), 75°C, 120 min 59 tBuOK (0.4 eq.), 75°C, 30 min 19 Example 2: Preparation of vitamin A acetate from 11,12-dihydroretinal

[0038] This example is the "one-pot" alternative to example 1 which includes the acylation / isomerization process according to the invention.

[0039] The operating conditions are as follows: The reagents were introduced under nitrogen in the following order: Dihydroretinal, 3.62 g (12 mmol) Acetonitrile, 141.5 g (180 mL) Ac 2 O, 1.86 g (18 mmol) DBU, 9.23 g (60 mmol)

[0040] The reaction mixture (homogeneous, dark yellow) is stirred in the dark at 75°C for 10 h. After cooling to 25°C, the reaction mixture (homogeneous, dark brown) is poured into a stirred mixture of [cyclohexane (600 mL) + saturated aqueous sodium bicarbonate solution (600 mL) + water (600 mL)]. The aqueous phase (pH 9) is re-extracted with 100 mL of cyclohexane, then the cyclohexane phases are combined, washed with water (100 mL), dried (Na₂SO₄), and concentrated to obtain 3.97 g of a reddish-brown oil.

[0041] The crude reaction product obtained has the following characteristics: TT DHR = 100 % CCM , RR isolé = 77 % d ′ un mélange d ′ isomères trans + 13 − cis + 9 − cis Titre HPLC = 77 % trans + 13 − cis + 9 − cis

[0042] Isomeric distribution: trans / 13 − cis / 9 − cis = 75 / 16 / 9 .

[0043] The above reaction crude was crystallized as follows.

[0044] A solution of 3.91 g of the previous oil in 3.8 mL of n-heptane is cooled to -20°C and inoculated with trans vitamin A acetate crystals (obtained from a previous crystallization in n-heptane). After 4 h at -20°C, massive crystallization occurs. The suspension is then cooled to 40°C for 16 h and filtered. This yields 2.41 g of orange crystals (after drying) and 4.3 mL (3.37 g) of reddish-brown mother liquor.

[0045] Crystal characterization: Crystallization yield of the trans isomer = 88% Titre en trans HPLC = 81 % Titre trans + 13 − cis + 9 − cis , HPLC = 90 %

[0046] Isomeric distribution: trans / 13 − cis / 9 − cis = 90 / 8 / 2

[0047] Characterization of mother liquors: Titre trans + 13 − cis + 9 − cis , HPLC = 23 %

[0048] Isomeric distribution: trans / 13 − cis / 9 − cis = 37 / 37 / 26 Example 3: Preparation of vitamin A acetate from 7,8-dihydroretinal according to the "one pot" alternative of the invention

[0049] This example is another "one-pot" alternative for manufacturing vitamin A acetate which includes the acylation / isomerization process according to the invention.

[0050] The operating conditions are as follows: The reagents were introduced under nitrogen at 25°C in the following order: 7,8-dihydroretinal, 0.2 g (0.628 mmol) Acetonitrile, 0.42 mL Ac 2 O, 0.097 g (0.943 mmol) DBU, 0.483 g (3.142 mmol)

[0051] The reaction medium (homogeneous, dark yellow in color) is stirred in the absence of light, at 80°C. Samples are taken during the reaction for 24 hours. TT 7 , 8 − DHR = 100 % HPLC RR dosé Acétate de Vitamine A = 4 % d ′ un mélange d ′ isomères trans + 13 − cis + 9 − cis after 4 a.m.

[0052] Isomeric distribution: trans / 13 − cis / 9 − cis = 86 / 10 / 4 Example 4: Preparation of triene-ol acetate from citral according to the "one pot" alternative of the invention

[0053]

[0054] The operating conditions are as follows: The reagents were introduced under nitrogen in the following order: Citral, 7.7 g (48 mmol) Acetonitrile, 72 mL Ac 2 O, 7.47 g (72 mmol) DBU, 36.5 g (240 mmol)

[0055] The homogeneous reaction mixture is stirred in the dark at 82°C for 24 h. After cooling to 25°C, the homogeneous reaction mixture is poured into a stirred mixture of [cyclohexane (300 mL) + saturated aqueous ammonium chloride solution (300 mL) + water (300 mL)]. The aqueous phase (pH 5) is re-extracted with 100 mL of cyclohexane, then the cyclohexane phases are combined, dried (Na₂SO₄), and concentrated to obtain 9.34 g of a brown oil. TT DHR = 100 % CCM RR isolé = 80 % Titre RMN H <mprescripts / > <none / > 1 = 80 % Example 5: Preparation of dehydrofarnesyl acetate from farnesal according to the "one pot" alternative of the invention

[0056]

[0057] The operating conditions were as follows: In a 500 mL three-necked flask equipped with a magnetic stir bar and a thermometer, under a nitrogen atmosphere, Ac₂O was added to a solution of farnesal in CH₃CN. The mixture was stirred at 25°C for 5 minutes, and then the DBU (dehydrofarnesal acetate) was stirred into the reaction mixture. The evolution of the reaction mixture's composition was monitored by TLC. After 18 hours, the conversion of farnesal was complete. The reaction mixture was washed with NH₄Cl (2 x 50 mL), dried over Na₂SO₄, filtered, and then concentrated under reduced pressure (40°C, 10 mbar). Purification by chromatography (SiOH, 120 g, cyclohexane → cyclohexane / AcOEt = 98:2) allowed the isolation of 4.5 g of an orange oil of dehydrofarnesal acetate. TT farnésal = 100 % GC RR dosé déhydrofarnésal acétate = 89 % GC RR isolé déhydrofarnésal acétate = 75 % chromatographie Titre déhydrofarnésal acétate = 90 % estimation RMN H <mprescripts / > <none / > 1 Example 6: Preparation of dehydrofarnesylsulfone from dehydrofarnesyl acetate obtained in Example 5

[0058]

[0059] The operating conditions are as follows: In a Schott tube equipped with a magnetic stir bar, under a nitrogen atmosphere, a solution of Pd(p-allylCl)₂ (0.028 g, 0.075 mmols) and 1,1'-Ferrocenediyl-bis(diphenylphosphine (dppf)) (0.126 g, 0.21 mmols) contained in degassed CH₂Cl₂ (4.4 mL) is added to a solution of Na₂PhSO₂ (1.1 g, 7.57 mmols) and Me₄NBr (0.15 g, 0.038 mmols) in H₂O (12.4 mL) and dehydrofarnesyl acetate (1.1 g, 3.79 mmols) contained in CH₂Cl₂ (8.8 mL). The evolution of the reaction mixture's composition is monitored by TLC. the organic phase. After 5 hours at 25°C, the conversion of dehydrofarnesyl acetate is complete. The reaction mixture is extracted with CH₂Cl₂ (2 x 20 mL), dried over Na₂SO₄, filtered, and then concentrated under reduced pressure (40°C, 10 mbar). Purification by chromatography (SiOH, 40 g, cyclohexane → cyclohexane / AcoEt = 95:5) allowed the isolation of 1 g of a light yellow oil from the dehydro-farnesylsulfone. TT déhydrofarnésyl acétate = 100 % GC RR dosé déhydro − farnésylsulfone = 76 % GC RR isolé déhydro − farnésylsulfone = 68 % chromatographie Titre déhydro − farnésylsulfone = 90 % estimation RMN H <mprescripts / > <none / > 1

Claims

1. A process for preparing a compound of formula (I) wherein R1 is selected from H and alkyls, R2 is selected from H, alkyls, OR' where R' is selected from alkyls, silyls, CO-alkyl, R3 is selected from acyl groups of the type CO(R"), and CO(OR"), CO(NR"R‴), PO(OR")(OR‴), PO(OR")(R‴) groups where R" and R‴, independently of each other, are selected from H and alkyls, R represents a C(R4)=C(R5)(R6) group where R4, R5 and R6, independently of each other, are selected from H, linear or cyclic alkyls and alkenyls, aryls, alkylaryls, or R4 and R5 together form a saturated or unsaturated, substituted or unsubstituted ring, by reacting a compound of formula (II) wherein R, R1, R2 and R3 have the above definition, in the presence of a strong base or in the presence of a metal catalyst; in the above formulas, an alkyl group represents a saturated, monovalent, linear, cyclic and / or branched hydrocarbon chain comprising 1 to 20 carbon atoms, an alkenyl group represents a monovalent, linear, cyclic and / or branched, mono- or polyunsaturated hydrocarbon chain comprising 2 to 20 carbon atoms, an aryl group represents a monofunctional, monocyclic or polycyclic aromatic hydrocarbon chain comprising 6 to 20 carbon atoms and includes a benzyl and biphenyl group.

2. A one-pot process for preparing a compound of formula (I) wherein R1 is selected from H and alkyls, R2 is selected from H, alkyls, OR' where R' is selected from alkyls, silyls, CO-alkyl, R3 is selected from acyl groups of the type CO(R"), and CO(OR"), CO(NR"R‴), PO(OR")(OR‴), PO(OR")(R‴) groups where R" and R‴, independently of each other, are selected from H and alkyls, R represents a C(R4)=C(R5)(R6) group where R4, R5 and R6, independently of each other, are selected from H, linear or cyclic alkyls and alkenyls, aryls, alkylaryls, or R4 and R5 together form a saturated or unsaturated, substituted or unsubstituted ring, from a compound of formula (III) wherein R, R1 and R2 have the above definition. said process comprising the formation of the compound of formula (II) wherein R, R1, R2 and R3 have the above definition, and the formation of the compound (II) to a compound (I) according to the process of claim 1.

3. The process according to claim 1 or 2, for the preparation of a compound of formula (IV) wherein R represents a C(R4)=C(R5)(R6) group where R4, R5 and R6, independently of each other, are selected from H, linear or cyclic alkyls and alkenyls, aryls, alkylaryls, or R4 and R5 together form a saturated or unsaturated, substituted or unsubstituted ring, by reacting a compound of formula (V) or by reacting a compound of formula (VI) via the intermediate of formula (V).

4. The process according to claim 1 or 3, for obtaining a compound of formula (I) or (IV) selected from vitamin A acetate, dehydro-farnesyl acetate and dehydro-citral acetate, characterized in that the compound of formula (II) or (V) is 11,12-dihydroretinal enol acetate, dehydro-farnesyl enol acetate and dehydro-citral enol acetate, respectively.

5. The process according to claim 2 or 3, for obtaining a compound of formula (I) or (IV) selected from vitamin A acetate, dehydro-farnesyl acetate and dehydro-citral acetate, characterized in that the compound of formula (III) is selected from 11,12-dihydroretinal or 7,8-dihydroretinal, farnesal and citral, respectively.

6. The process according to any one of claims 1, 3 and 4, characterized in that it is carried out in the presence of a strong base, and for example a strong base selected from phosphazenes such as P2Et, amidines such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and alkoxides such as potassium tertbutoxide.

7. A process for preparing a compound of formula (VII) wherein R1 is selected from H and alkyls, R'2 is selected from H and alkyls, R represents a C(R4)=C(R5)(R6) group where R4, R5 and R6, independently of each other, are selected from H, linear or cyclic alkyls and alkenyls, aryls, alkylaryls, or R4 and R5 together form a saturated or unsaturated, substituted or unsubstituted ring from a compound of formula (II), comprising the process for acylating said compound (II) to a compound (I) according to claim 1, or from a compound of formula (III) comprising the process of one-pot isomerization / acylation of said compound (III) to a compound of formula (I) according to claim 2.

8. The process according to claim 7 for the preparation of dehydro-farnesyl sulfone from farnesal enol acetate.

9. A process for synthesizing vitamin A from farnesene, characterized in that it comprises at least one process according to any one of claims 1 to 8.

10. 11,12-Dihydroretinal enol acetate as an intermediate compound.