Process for preparing 2,7-dimethyl-2,4,6-octatrienal...

Details Process for preparing 2,7-dimethyl-2,4,6-octatrienal... Process for preparing 2,7-dimethyl-2,4,6-octatrienal...

2002-03-12

2003-08-26

Keys, Rosalynd (Department: 1621)

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

Organic compounds

Oxygen containing

C568S596000, C568S600000, C549S369000, C549S374000, C549S375000, C549S376000, C549S430000, C549S454000, C560S183000, C560S186000, C560S187000

Reexamination Certificate

active

06610892

ABSTRACT:

The invention relates to a novel process for preparing 2,7-dimethyl-2,4,6-octatrienal monoacetals (also referred to hereinafter as C
10
-dialdehyde monoacetals) of the general formula I,
in which the substituents R
1
and R
2
may, independently of one another, be C
1
-C
8
-alkyl or, together with the oxygen atoms and the carbon atoms to which they are bonded, form a 1,3-dioxolane or 1,3-dioxane ring of the following structures.
Monoacetals of this structure are required according to Helv. Chim. Acta 1981, 64 (7), 2469 for the selective synthesis of C
40
-carotenoids with a nonsymmetrical structure.
Protection of one of the two carbonyl groups in the central C
10
building block (9) in the following reaction scheme makes it possible to carry out the Wittig reactions with the two C
15
phosphonium salts (2) and (5) very selectively in succession and thus obtain a carotenoid (6) which is free of the products (7) and (8) with symmetrical structures, whose formation is unavoidable on use of an unprotected C
10
-dialdehyde (9).
Of particular interest from the group of carotenoids which have a nonsymmetrical structure with different end groups A and B are lutein (10) and meso-zeaxanthin (11) because these carotenoids protect inter alia the human eye from blindness resulting from age-related macular degeneration [Exp. Eye Res. 1997, 64 (2), 211-218; GB 2301775 (1996)].
In order to obtain meso-zeaxanthin (11) which is free of R,R-zeaxanthin (12) and S,S-zeaxanthin (13) it is necessary, for example, for the two Wittig reactions of the central C
10
building block with the R—C
15
phosphonium salt (14) to give a C
25
intermediate (15), and its reaction with the S—C
15
phosphonium salt (16) to take place completely selectively in succession.
These requirements also apply analogously to the synthesis of lutein.
The selectivity of the two Wittig reactions which is necessary for synthesizing a pure product is ensured only if a C
10
-dialdehyde in which one carbonyl group is in protected form as acetal is employed.
Various syntheses of C
10
-dialdehyde monoacetals have been described in the literature:
Thus, for example, the dimethyl acetal (17) can be obtained by p-toluenesulfonic acid-catalyzed acetalyzation of the dialdehyde (9) [Helv. Chim. Acta 1981, 64 (7), 2469]. The process includes a complicated low-temperature crystallization, and the product can be obtained only in inadequate yield.
Another synthetic process relates to the formation of the aldehyde function by reduction of the corresponding nitrile (18) [Pure & Appl. Chem. 1994, 66 (5), 963; Recl. Trav. Chim. Pays-Bas 1994, 113, 552]. This reduction is effected with diisobutylaluminum hydride at −70° C. The complete synthesis, which is described only on the mmol scale, has the aim of introducing
13
C isotopes and has no industrial significance.
The synthesis described in the literature of the C
10
-dialdehyde mononeopentyl glycolacetal (19) is based on the selective cleavage of the corresponding bisneopentyl glycolacetal (20) to the monoacetal by brief contact with HCl. This synthesis is likewise described only on the mmol scale. Because the selectivity is poor it was possible to isolate pure monoacetal (19) in a yield of only 37% only after elaborate purification by crystallization twice (Helv. Chim. Acta 1981, 64 (7), 2471) This synthesis is also unsuitable for industrial implementation.
It is an object of the present invention to provide a process for preparing C
10
-dialdehyde monoacetals which can be implemented on the industrial scale and has maximum flexibility in relation of the protective group.
We have found that this object is achieved by a process for preparing 2,7-dimethyl-2,4,6-octatrienal monoacetals of the general formula I,
in which the substituents R
1
and R
2
may, independently of one another, be C
1
-C
8
-alkyl or, together with the oxygen atoms and the carbon atoms to which they are bonded, form a 1,3-dioxolane or 1,3-dioxane ring of the following structures
in which R
3
and R
4
, and R
5
may each, independently of one another, be hydrogen or C
1
-C
4
-alkyl,
which comprises
a) condensing an ester phosphonium salt of the general formula II or an ester phosphonate of the general formula III,
in which the substituents have, independently of one another, the following meaning:
R
6
C
1
-C
8
-alkyl;
R
7
aryl;
X
−
an anion equivalent of an inorganic or organic acid;
R
8
and R
9
C
1
-C
8
-alkyl;
with an aldehyde of the formula IV
in a Wittig or Wittig-Horner reaction to give an acetal ester of the general formula V,
in which the substituents R
1
, R
2
and R
6
in the compounds IV and V have the abovementioned meaning,
b) reducing the ester of the formula V to an acetal alcohol of the general formula VI,
and
c) oxidizing the alcohol to 2,7-dimethyl-2,4,6-octatrienal monoacetals of the general formula I.
It was surprisingly possible to achieve this object in a simple manner, starting from C
5
building blocks which have a fixed place in polyene synthesis and are easily obtainable on the industrial scale (cf. Carotenoids, Vol. 2, “Synthesis”, pp. 115 ff.; Birkhauser Verlag 1996).
In the case of open-chain acetals, alkyl radicals which may be mentioned for R
1
and R
2
are linear or branched C
1
-C
8
-alkyl chains, 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.
Alkyl radicals which may be mentioned for R
3
to R
5
are linear or branched C
1
-C
4
-alkyl chains, 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.
Alkyl radicals which may be mentioned for R
6
, R
8
and R
9
are linear or branched C
1
-C
8
-alkyl chains, 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
6
, R
8
and R
9
are methyl, ethyl, n-propyl and 1-methylethyl, particularly preferably methyl and ethyl, very particularly preferably ethyl.
The term aryl for R
7
refers to conventional aryl radicals occurring in phosphines and phosphonium salts, such as phenyl, tolyl, naphthyl, optionally substituted in each case, preferably phenyl.
The radical X
−
represents one anion equivalent of an inorganic or organic acid, preferably a strong inorganic or organic acid.
The term strong acid encompasses hydrohalic acids (especially hydrochloric acid and hydrobromic acid), sulfuric acid, phosphoric acid, sulfonic acids and other inorganic or organic acids with a comparable degree of dissociation. Strong organic acids also mean in this connection C
1
-C
6
-alkanoic acids such as formic acid, acetic acid, propionic acid, butyric acid and caproic acid.
Particularly preferred anions which should be mentioned are acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid and sulfonic acids, very particularly preferred Cl
−

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