Process for the preparation of meso-zeaxanthin

Details Process for the preparation of meso-zeaxanthin Process for the preparation of meso-zeaxanthin

2002-09-10

2004-06-01

Shippen, Michael L. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

Reexamination Certificate

active

06743954

ABSTRACT:

Process for the preparation of meso-zeaxanthin
The present invention relates to a novel process for the preparation of meso-zeaxanthin. Meso-zeaxanthin is of great importance, inter alia, for the therapy and prophylaxis of age-related macular degeneration (AMD).
Blindness in old age as a result of age-related macular degeneration is an important problem from the epidemiological point of view. More recent investigations show that certain carotenoids can protect the eye effectively from AMD and thus from blindness. The carotenoids which exert this protection function are lutein and zeaxanthin.
Lutein and zeaxanthin can be employed both for prophylaxis and for the treatment of advanced AMD. The administration of meso-zeaxanthin and lutein was described as particularly efficacious (U.S. Pat. No. 6,218,436). meso-Zeaxanthin has to be made available for this therapeutic task. Since isolation from natural sources is excluded, only partial syntheses (isomerization of Lutein) or totally synthetic processes are suitable.
There has been no lack of attempts to convert lutein into meso-zeaxanthin by base-catalyzed isomerization (EP-A-0 834 536; WO 96/02594; U.S. Pat. No. 5,523,434). The processes described here for the isomerization of lutein always lead to mixtures of lutein and meso-zeaxanthin. A uniform product, which is desired for therapeutic purposes, can be obtained from such mixtures only by extremely complicated separation operations, associated with high yield losses.
A multistage total synthesis of meso-zeaxanthin, starting from Safranal, is described in Pure Appl. Chem. 51, 535 f. (1979), Pure Appl. Chem. 51, 565 f. (1979), Helv. Chim. Acta 63, 6, 1377, (1980) and Helv. Chim. Acta 63, 6, 1465, (1980).
The yields of meso-zeaxanthin achieved here are too low for industrial implementation of the synthesis. In order to obtain a uniform final product, on account of the low selectivities of many reaction steps it is necessary to laboriously purify many of the intermediates obtained.
It is therefore an object of the present invention to make available a process for the preparation of meso-zeaxanthin using which the abovementioned disadvantages of the prior art are avoided.
We have found that this object is achieved by a process for the preparation of meso-zeaxanthin,
which comprises
a) resolving a racemic mixture of the acetylenediols R-I and S-I
into its antipodes,
b) converting the separated antipodes R-I and S-I in each case into the C
15
-phosphonium salts R-II and S-II respectively
in which Ph is aryl and X is an anion equivalent of an inorganic or organic acid,
c) reacting the phosphonium salts R-II or S-II with a C
10
-dial monoacetal of the general formula III,
in which the substituents R
1
and R
2
independently of one another are C
1
-C
8
-alkyl or, together with the oxygen atoms and the carbon atom to which they are bonded, can form a 1,3-dioxolane or 1,3-dioxane ring of the following structures
in which R
3
and R
4
and also R
5
in each case independently of one another can be hydrogen or C
1
-C
4
-alkyl, in a Wittig reaction to give the C
25
-acetals R-IV or S-IV,
d) converting the C
25
-acetals R-IV or S-IV into the C
25
-aldehydes R-V or S-V
e) and reacting the C
25
-aldehyde R-V with the C
15
-phosphonium salt S-II or the C
25
-aldehyde S-V with the C
15
-phosphonium salt R-II in a Wittig reaction to give sterically uniform meso-Zeaxanthin.
In the case of the C
10
-dial monoacetal III used in process step c), possible open-chain acetals as alkyl radicals R
1
and R
2
are linear or branched C
1
-C
8
-alkyl radicals, e.g. methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl and n-octyl.
Preferred alkyl radicals for R
1
and R
2
are methyl, ethyl, n-propyl and 1-methylethyl, particularly preferably methyl and ethyl.
For cyclic acetals, possible alkyl radicals for R
3
to R
5
are linear or branched C
1
-C
4
-alkyl radicals, e.g. methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl.
Preferred radicals for R
3
to R
5
are hydrogen and methyl.
The radical Ph of the C
15
-phosphonium salts R-II and S-II designates customary aryl radicals occurring in phosphines and phosphonium salts, such as phenyl, toluene, naphthyl, if appropriate in each case substituted, preferably phenyl.
The radical X
−
is an anion equivalent of an inorganic or organic acid, preferably strong inorganic or organic acid.
The expression strong acid includes hydrohalic acids (in particular hydrochloric acid and hydrobromic acid), sulfuric acid, phosphoric acid, sulfonic acids and other inorganic or organic acids having a comparable degree of dissociation. Strong organic acids are to be understood in this connection as also meaning C
1
-C
6
-alkanoic acids such as formic acid, acetic acid, propionic acid, butyric acid and caproic acid.
Particularly preferred anions are those of acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid and sulfonic acid, very particularly preferably Cl
−
, Br
−
, C
n
H
2n+
—SO
3
−
(where n=1−4), Ph-SO
3
−
, p-Tol-SO
3
−
or CF
3
—SO
3
−
.
For the preparation of the racemic mixture of the acetylenediols R-I and S-I, oxoisophorone VIII is used as a starting material and is converted into X in a manner known per se by catalytic hydrogenation, for example using Raney nickel in methanol. Racemic IX, which, however, does not have to be isolated, is passed through as an intermediate here. X is obtained as a trans/cis diastereomer mixture, trans-X being the predominant main product. trans-X and cis-X are in each case present as the racemate. The separation of the diastereomers can be carried out according to one of the methods discussed in EP-A-0 775 685, preferably by distillative processes. The racemic cis-X obtained here as a by-product can be equilibrated by base-catalyzed epimerization of C
6
to give a mixture of racemic cis-X and racemic trans-x and fed back into the distillative separation of diastereomers. The pure racemic trans-X is converted into the racemic mixture R-I/S-I in 3 stages according to the synthesis indicated in Helv. Chim. Acta. 73 (4), 868, (1990).
The process according to the invention is thus also one wherein the mixture employed in stage a) is a diastereomerically pure racemate of the acetylenediols R-I and S-I.
The resolution of the racemic mixture in process step a) can be carried out according to methods known per se, for example by enzymatically catalyzed separation of enantiomers, by chromatography on a chiral column or by separation of diastereomers.
A preferred variant of the process according to the invention comprises converting a racemic mixture of the acetylenediols R-I and S-I in stage a) into a mixture of diastereomers using an optically active auxiliary reagent, separating the diastereomers and subsequently eliminating the auxiliary reagent again.
Thus it has now surprisingly been found that the racemic mixture of the acetylenediols R-I and S-I can be resolved into its antipodes in a particularly simple manner after derivatization using optically active auxiliary reagents to give the diastereomeric intermediates R-VI and S-VI,
in which the substituent R
6
is preferably an optically active urethane, carbonate, sulfonate or acyl radical.
The derivatization takes place completely selectively on the secondary OH group. The acetylenediols R-I and S-I surprisingly prove stable both chemically and also in terms of configuration to the conditions which are ne

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