Method for synthesising vitamin A

Abstract

A method for preparing a compound of formula (I) ##STR00001## in which 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 the acyl groups of the CO(R″) type, and the 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 (II) ##STR00002## or a compound of formula (III) ##STR00003## in which, R, R1, R2 and R3 have the above definition.

Claims

1. A method for preparing a compound of formula (I) ##STR00024## 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 the acyl groups of the CO(R″) type, and the 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) ##STR00025## 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.

2. A one-pot method for preparing a compound of formula (I) ##STR00026## 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 the acyl groups of the CO(R″) type, and the 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) ##STR00027## in which R, R1 and R2 have the above definition, said method comprising the following steps: acylating said compound of formula (III) in a compound of formula (II) ##STR00028## in which, R, R1, R2 and R3 have the above definition, and reacting said compound of formula (II), in the presence of a strong base or in the presence of a metal catalyst, to form compound (I).

3. The method according to claim 1, for the preparation of a compound of formula (IV) ##STR00029## 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) ##STR00030## in the presence of a strong base or in the presence of a metal catalyst, or by acylating a compound of formula (VI) ##STR00031## in said compound of formula (V), and reacting said compound of formula (V) in the presence of a strong base or in the presence of a metal catalyst, to form compound (IV).

4. The method according to claim 1, to obtain a compound of formula (I) selected from vitamin A acetate, dehydro-farnesyl acetate and dehydro-citral acetate, wherein the compound of formula (II) or (V) is selected from 11,12-dihydro-retinal enol acetate, dehydro-farnesyl enol acetate and dehydro-citral enol acetate, respectively.

5. The method according to claim 2, to obtain a compound of formula (I) or (IV) selected from vitamin A acetate, dehydro-farnesyl acetate and dehydro-citral acetate, wherein the compound of formula (III) is selected from 11,12-dihydroretinal or 7,8-dihydroretinal, farnesal and citral, respectively.

6. The method according to claim 1, wherein it is carried out in the presence of a strong base, and for example a strong base selected from phosphazenes, aminides, and alcoholates.

7. The method for preparing a compound of formula (VII) ##STR00032## 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 method for acylating said compound (II) into compound (I) according to claim 1, or from a compound of formula (III) comprising the one-pot isomerization/acylation method of said compound (III) into a compound of formula (I) according to claim 2.

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

9. A method for synthesizing vitamin A from farnesene, wherein it comprises at least one method according to claim 1.

10. An enol acetate of 11,12-dihydroretinal as an intermediate compound.

11. The method according to claim 3, to obtain a compound of formula (IV) selected from vitamin A acetate, dehydro-farnesyl acetate and dehydro-citral acetate, wherein the compound of formula (V) is selected from 11,12-dihydro-retinal enol acetate, dehydro-farnesyl enol acetate and dehydro-citral enol acetate, respectively.

12. The method according to claim 6, wherein it is carried out in the presence of a strong base, and for example a strong base selected from phosphazenes such as P.sub.2Et, aminides such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and alcoholates such as potassium tertbutoxide.

Description

EXAMPLE 1: PREPARATION OF VITAMIN A ACETATE FROM 11,12-DIHYDRORETINAL

(1) This preparation comprises two steps, a first step of obtaining the enol acetate of 11,12-dihydroretinal, which is a subject compound of the disclosure, from the 11,12-dihydroretinal, then a second step of involving the isomerization method of the disclosure of enol acetate of 11,12-dihydroretinal into vitamin A acetate.

(2) 1.1) Acetylation of 11,12-Dihydroretinal into Enol Acetate and Isomeric Forms

(3) ##STR00017##

(4) The operating conditions are as follows:

(5) The reagents are introduced under nitrogen in the following order: 11,12-dihydroretinal (DHR), 2 g (4.47 mmol) DMAP, 1 g (8.10 mmol) Pyridine, 10 g (126 mmol) Acetic anhydride, 10 g (96 mmol)

(6) The reaction medium is stirred in the absence of light, at 115° C., for 1 h. After cooling to 25° C., the reaction medium is poured into a mixture consisting of 100 mL of water, 100 mL of saturated aqueous solution of NaHCO.sub.3, and 100 mL of cyclohexane. After separation, the aqueous phase is re-extracted with 100 mL of cyclohexane, then the combined organic phases are washed with a saturated aqueous solution of NaCl (300 mL), dried over Na.sub.2SO.sub.4 and evaporated.

(7) 2.01 g of a yellow-orange colored oil were obtained.

(8) TT.sub.DHR=100% (TLC)

(9) RR.sub.isolated=57% of a mixture of exo/endo isomers (80/20)

(10) Titer (HPLC)=41% (33% exo+8% endo).

(11) 1.2) Isomerization of Dihydroretinal Enol Acetate into Vitamin a Acetate

(12) ##STR00018##

(13) The general operating conditions are as follows:

(14) The reagents were introduced under nitrogen into a pillbox provided with magnetic stirring: enol acetates (mixture resulting from the reaction 1.2 above, 50 mg, 0.076 mmol), solvent (1.15 mL, except DMSO: 2.3 mL), base (tBuOK: 3.6 mg (added in solution in the case of DMSO, NMP, isopropanol, and THF); hydrotalcite: 25 mg; KOH: a piece of 30 mg, titer 85%; aqueous soda: 500 μL at 300 g/L). The reaction medium was stirred in the absence of light.

(15) For reaction monitoring, each sample (50 μL) of organic phase is hydrolyzed on a mixture of 0.5 mL of water, 0.5 mL of saturated aqueous solution of NaHCO.sub.3, and 0.5 mL of cyclohexane. An aliquot of the cyclohexane phase is deposited on a silica plate and eluted with a cyclohexane/ethyl acetate mixture (90/10).

(16) Different conditions were tested, the most representative are indicated in Table 1.

(17) TABLE-US-00001 TABLE 1 assayed RR .sub.«trans» Conditions (HPLC, %) P.sub.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

(18) This example is the «one-pot» alternative of Example 1 which comprises the acylation/isomerization method according to the disclosure.

(19) ##STR00019##

(20) The operating conditions are as follows:

(21) The reagents were introduced under nitrogen in the following order: Dihydroretinal, 3.62 g (12 mmol) Acetonitrile, 141.5 g (180 mL) Ac.sub.2O, 1.86 g (18 mmol) DBU, 9.23 g (60 mmol)

(22) The (homogeneous, dark yellow colored) reaction medium is stirred in the absence of light at 75° C. for 10 h. After cooling to 25° C., the (homogeneous, dark brown colored) reaction medium 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 (Na.sub.2SO.sub.4), and concentrated to obtain 3.97 g of a red-brown colored oil.

(23) The obtained crude reaction has the following characteristics:

(24) TT (DHR)=100% (TLC),

(25) RR.sub.isolated=77% of a mixture of (trans+13-cis+9-cis) isomers

(26) Titer (HPLC)=77% (trans+13-cis+9-cis)

(27) Isomeric distribution: trans/13-cis/9-cis=75/16/9.

(28) The above reaction crude was crystallized as follows.

(29) A solution of 3.91 g of the previous oil in 3.8 mL of n-heptane is cooled to −20° C. and seeded with crystals of trans vitamin A acetate (obtained during a previous crystallization in the n-heptane). After 4 h at −20° C., a massive crystallization takes place. The suspension is then cooled to 40° C. for 16 h, then filtered. 2.41 g of orange crystals (after drying) and 4.3 ml (3.37 g) of red-brown mother liquors are obtained.

(30) Characterization of the Crystals:

(31) Crystallization yield of the trans isomer=88%

(32) Trans titer (HPLC)=81%

(33) Titer (trans+13-cis+9-cis, HPLC)=90%

(34) Isomeric distribution: trans/13-cis/9-cis=90/8/2

(35) Characterization of Mother Liquors:

(36) Titer (trans+13-cis+9-cis, HPLC)=23%

(37) 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 DISCLOSURE

(38) This example is another «one-pot» alternative for manufacturing vitamin A acetate which comprises the acylation/isomerization method according to the disclosure.

(39) ##STR00020##

(40) The operating conditions are as follows:

(41) 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.sub.2O, 0.097 g (0.943 mmol) DBU, 0.483 g (3.142 mmol)

(42) The (homogeneous, dark yellow colored) reaction medium is stirred in the absence of light, at 80° C. Samples are taken during the reaction for 24 hours.

(43) TT (7,8-DHR)=100% (HPLC)

(44) Assayed RR.sub.vitamin A acetate=4% of a mixture of (trans+13-cis+9-cis) isomers after 4 h.

(45) 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 DISCLOSURE

(46) ##STR00021##

(47) The operating conditions are as follows:

(48) The reagents were introduced under nitrogen in the following order: Citral, 7.7 g (48 mmol) Acetonitrile, 72 mL Ac.sub.2O, 7.47 g (72 mmol) DBU, 36.5 g (240 mmol)

(49) The (homogeneous) reaction medium is stirred in the absence of light at 82° C. for 24 h. After cooling to 25° C., the (homogeneous) reaction medium is poured into a stirred mixture of [cyclohexane (300 mL)+saturated aqueous solution of ammonium chloride (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 (Na.sub.2SO.sub.4), and concentrated to obtain 9.34 g of a brown colored oil.

(50) TT (DHR)=100% (TLC)

(51) RR.sub.isolated=80%

(52) Titer (.sup.1H NMR)=80%

EXAMPLE 5: PREPARATION OF DEHYDROFARNESYL ACETATE FROM FARNESAL ACCORDING TO THE «ONE-POT» ALTERNATIVE OF THE DISCLOSURE

(53) ##STR00022##

(54) The operating conditions are as follows:

(55) Ac.sub.2O is added to a solution of farnesal in CH.sub.3CN in a 500 mL three-necked flask equipped with a magnetic stirrer bar and a thermometer, under a nitrogen atmosphere. The medium is stirred at 25° C. for 5 minutes then the DBU is stirred in the reaction medium. The change in the composition of the reaction medium is followed by TLC. After 6 p.m., the conversion of the farnesal is complete. The reaction medium is washed with NH.sub.4Cl (2×50 mL), dried over Na.sub.2SO.sub.4, filtered, then concentrated under reduced pressure (40° C., 10 mbar). The purification by chromatography (SiOH, 120 g, cyclohexane.fwdarw.cyclohexane/AcOEt=98:2) allowed isolating 4.5 g of an orange oil from dehydrofarnesal acetate.

(56) TT Farnesal=100% (GC)

(57) Assayed RR.sub.dehydrofarnesal acetate=89% (GC)

(58) Isolated RR.sub.dehydrofarnesal acetate=75% (chromatography)

(59) Dehydrofarnesal acetate titer=90% (.sup.1H NMR estimate)

EXAMPLE 6: PREPARATION OF DEHYDRO-FARNESYISULFONE FROM DEHYDROFARNESYLACETATE OBTAINED IN EXAMPLE 5

(60) ##STR00023##

(61) The operating conditions are as follows:

(62) In a Schott tube equipped with a magnetic stirring bar, under a nitrogen atmosphere, is added a solution of Pd(p-allylCl).sub.2 (0.028 g, 0.075 mmoles) and 1,1′-Ferrocenediyl-bis(diphenylphosphine (dppf) (0.126 g, 0.21 mmol) contained in CH.sub.2Cl.sub.2 (4.4 mL) degassed (N.sub.2) is added to a solution of PhSO.sub.2Na (1.1 g, 7.57 mmol) and Me.sub.4NBr (0.15 g, 0.038 mmol) in H.sub.2O (12.4 mL) and dehydrofaresyl acetate (1.1 g, 3.79 mmol) contained in CH.sub.2Cl.sub.2 (8.8 mL). The evolution of the composition of the reaction medium is followed by TLC of the organic phase. After 5 h at 25° C., the conversion of the dehydrofarnesyl acetate is complete. The reaction medium is extracted with CH.sub.2Cl.sub.2 (2×20 mL), dried over Na.sub.2SO.sub.4, filtered, then concentrated under reduced pressure (40° C., 10 mbar). The purification by chromatography (SiOH, 40 g, cyclohexane.fwdarw.cyclohexane/AcoEt=95:5) allowed isolating 1 g of a light yellow oil of dehydro-farnesylsulfone.

(63) TT.sub.dehydrofaresyl acetate=100% (GC)

(64) Assayed RR.sub.dehydro-farnesylsulfone=76% (GC)

(65) Isolated RR.sub.dehydro-farnesylsulfone=68% (chromatography) Dehydro-farnesylsulfone titer=90% (.sup.1H NMR estimate)