Method for synthesising vitamin A

Abstract

A method for preparing dehydro-cyclofarnesal from dehydro-farnesal by cyclization in the presence of an acid may include the dehydro-farnesal being obtained from the farnesal by dehydrogenation and may further includes the cyclization being carried out in the presence of an acid selected from Lewis acids, Bronstedt acids, and zeolites. The synthesis of vitamin A using this method further includes the conversion of dehydro-cyclofarnesal into vitamin A.

Claims

1. A method for preparing dehydro-cyclofarnesal from dehydro-farnesal by cyclization in the presence of an acid.

2. The method according to claim 1, wherein the cyclization is carried out in the presence of an acid selected from Lewis acids, Bronstedt acids, and zeolites.

3. The method according to claim 2, wherein the acid is selected from chlorosulfonic acid, boron trifluoride and its etherates, and tin chloride.

4. The method according to claim 1, wherein the dehydro-farnesal is obtained from farnesal by dehydrogenation.

5. The method according to claim 4, wherein the dehydrogenation of the farnesal is carried out in the presence of at least one palladium (II) salt.

6. The method according to claim 4, wherein the farnesal is obtained from farnesene, farnesol, ethyl farnesoate, nerolidol, or dehydro-nerolidol.

7. The method according to claim 4, wherein the dehydro-farnesal is obtained from farnesene, and in that the method further includes the following steps: oxidation of farnesene into farnesal, then dehydrogenation of farnesal into dehydro-farnesal.

8. The method according to claim 7, wherein the oxidation of farnesene is carried out under catalytic conditions of the Wacker type in the presence of at least one precious metal such as palladium.

9. A method for synthesising vitamin A from farnesene, wherein it comprises at least one method according to claim 7, then the conversion of dehydro-cyclofarnesal into vitamin A.

10. The method for synthesising vitamin A according to claim 9, wherein the dehydro-cyclofarnesal is converted into vitamin A by reaction with a silyl enol ether of prenal.

Description

DETAILED DESCRIPTION OF THE DISCLOSURE

(1) The disclosure thus concerns the cyclization of dehydro-farnesal to dehydro-cyclofarnesal carried out in the presence of an acid. Advantageously, the acid is selected from Lewis acids, Bronstedt acids and zeolites, and any combination thereof. By way of example, it can be chlorosulfonic acid, boron trifluoride or an etherate thereof, or even tin chloride.

(2) The disclosure also concerns the manufacture of dehydro-farnesal from farnesal by catalytic dehydrogenation. Under preferred conditions, this dehydrogenation is carried out in the presence of one or more palladium (II) salts. Use will advantageously be made of salts of Pd(OAc).sub.2 type, a base and an oxidizing agent.

(3) Typically, the conditions for this reaction are as follows: Pd(OAc).sub.2, a base selected from Na.sub.2CO.sub.3 and K.sub.2CO.sub.3, and in the presence of oxygen. The use of protic polar type solvents is more particularly indicated with, for example, the use of dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) or dimethylol-ethylene urea (DMEU). These conditions can be supplemented by the presence of ligands selected in particular from aromatic compounds such as hydroquinone, catechol or diazafluorenone, or precursor additives of pi-allyl such as allyl diethylphosphate.

(4) The disclosure also provides a method for oxidizing farnesene into farnesal. This reaction is carried out under the catalytic conditions of a Wacker-type method in the presence of at least one precious metal, mainly palladium. Advantageously, the reaction medium comprises palladium (II) salts such as PdCl.sub.2, copper salts and an oxidizing agent. For example, the reaction is carried out in the presence of PdCl.sub.2(CH2CH2), CuCl.sub.2—LiMoO.sub.4.

(5) The disclosure also concerns the manufacture of dehydro-farnesal from farnesene, according to a method implementing the aforementioned steps, namely: oxidation of farnesene to farnesal, then dehydrogenation of farnesal to dehydro-farnesal, these two steps being carried out under the conditions of the disclosure described above.

(6) Another of the advantages of the disclosure is a method for synthesising vitamin A from farnesene, which comprises at least one of the steps described above, namely: cyclization of dehydro-farnesal into dehydro-farnesal; oxidation of farnesene into farnesal; dehydrogenation of farnesal into dehydro-farnesal.

(7) Advantageously, the method for synthesising vitamin A comprises at least two, or even all of these steps, and is followed by a conversion of dehydro-cyclofarnesal into vitamin A, according to a method within the reach of one skilled in the art having an average level of knowledge. According to an advantageous variant of the disclosure, vitamin A is obtained by reacting dehydro-cyclofarnesal with a silyl enol ether of prenal, for example a trimethylsilyl enol ether, resulting in retinal.

(8) The disclosure is hereinafter illustrated in examples carried out under reaction conditions which support the practice of the disclosure but to which it is certainly not restricted.

(9) In the examples, the used abbreviations are defined below:

(10) TT defines the conversion rate;

(11) RR defines a yield on reagent;

(12) Assayed RR defines a yield on reagent assayed in a reaction medium.

Example 1: Cyclization of Dehydro-Farnesal into Dehydro-β-Cyclofarnesal

(13) The cyclization of dehydro-farnesal to dehydro-β-cyclofarnesal is carried out according to the scheme hereinbelow:

(14) ##STR00005##

(15) The operating conditions are as follows:

(16) Dehydro-farnesal (0.115 mmol), the solvent (0.46 mL) and finally the source of acid, added at the indicated temperature, are introduced into a 4 mL vial fitted with a magnetic bar and placed under a nitrogen atmosphere. The reaction medium is then stirred with magnetic stirring at the specified temperature. The times indicated in the table correspond to the best obtained yields. The samples (200 μL) are analyzed by gas chromatography (GC). Different conditions were tested, the most representative are indicated in Table 1.

(17) TABLE-US-00001 TABLE 1 assayed TT.sub.dehydrofarnesal RR.sub.dehydro-β-cyclofarnesal Conditions (GC, %) (GC, %) ClSO.sub.3H, CH.sub.2Cl.sub.2, −78° C.,  94 22 30 min. SnCl.sub.4 (2 éq.), toluene, 0° C., 100 35 30 min. BF.sub.3 .Math. Et.sub.2O (2 eq.), toluene, 100 14 30° C.

Example 2: Oxidation of β-Farnesene into Farnesal

(18) The oxidation of β-farnesene in farnesal is carried out according to the scheme below:

(19) ##STR00006##

(20) The operating conditions are as follows:

(21) PdCl.sub.2(CH.sub.3CN).sub.2 (0.25 mmol), Li.sub.2MoO.sub.4 (1.7 mmol), CUCl.sub.2 (0.3 mmol), the solvent (2 mL), H.sub.2O (0.2 mL) and alkene (1.0 mmol) are introduced into a 4 mL vial fitted with a magnetic bar, and placed under a nitrogen atmosphere. The reaction medium is then stirred with magnetic stirring at 90° C. The times indicated in the table below correspond to the best obtained yields. The samples (200 μL) are analyzed by GC.

(22) TABLE-US-00002 TABLE 2 Assayed TT.sub.farnesene RR.sub.farnesal Conditions Solvent (GC, %) (GC, %) β-farnesene, NMP 73 17 24 h, 90° C. DMEU 75 13 DMSO 57  6

Example 3: Dehydrogenation of Farnesal into Dehydro-Farnesal

(23) The dehydrogenation of the farnesal into dehydro-farnesal is carried out according to the scheme below:

(24) ##STR00007##

(25) The operating conditions are as follows:

(26) Pd(OAc).sub.2 (0.03 mmol), K.sub.2CO.sub.3 (0.05 mmol), 4,5-diazafluorenone (DAF) (0.045 mmol), the solvent (0.46 mL) and the farnesal (0.5 mmol) are introduced into an open 4 mL vial fitted with a magnetic bar, and placed under a nitrogen atmosphere. The reaction medium is then stirred with magnetic stirring at 30° C. The samples (approximately 200 μL) are taken after 1 h, 3 h, 5 h, 7 h, 24 h and then analyzed by GC.

(27) These conditions lead to a TT.sub.farnesal (GC,%) of 92% and an assayed RR.sub.dehydrofarnesal (GC,%) of 60%.

Example 4: Preparation of Retinal from Dehydro-Cyclofarnesal

(28) The retinal is prepared according to the scheme below:

(29) ##STR00008##

(30) In detail, this transformation takes place under the following conditions, passing through non-isolated intermediates:

(31) ##STR00009##

(32) These conditions lead to a TT.sub.dehydro-β-cyclofarnesal (TLC) of 100% and an assayed RR.sub.retinal of 40%.