Diallylic sulfides and processes for preparing the same

Details Diallylic sulfides and processes for preparing the same Diallylic sulfides and processes for preparing the same

2001-06-04

2001-12-04

Padmanabhan, Sreeni (Department: 1621)

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

Organic compounds

Sulfur containing

C568S041000, C568S045000, C568S046000, C568S055000, C568S056000, C568S448000, C568S459000, C568S863000, C568S029000, C570S258000

Reexamination Certificate

active

06326519

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds having a polyene chain structure, and processes for preparing the same. More specifically, it relates to intermediate compounds, which can be effectively used in the synthesis of &bgr;-carotene, processes for preparing the same, processes for preparing &bgr;-carotene by using the intermediate compounds, and “retinyl sulfide,” named by the present inventors, and a process for preparing the same.
BACKGROUND OF THE INVENTION
Carotenoid compounds have a polyene chain structure, and specific examples of such include &bgr;-carotene, tycopene, astaxanthin and the like. &bgr;-carotene is known as pro-vitamin A, which decomposes to vitamin A according to the needs of a living body.
Carotenoid compounds are generally used as natural pigments for foodstuffs, and are apt to selectively react with carcinogens such as singlet oxygen radical and the like, and as such, they are expected to have use as a prophylactic agent for cancers. In light of this expectation, there is an increasing need to develope a process that can effectively and efficiently synthesize the polyene chain structure.
&bgr;-carotene has been manufactured by Hoffmann-La Roche since 1954, and by BASF since 1972 [Paust, J.,
Pure Appl. Chem
., 63:45-58 (1991)].
According to the Roche process, two C
19
molecular units are connected by using bis(magnesium halide) acetylide, and the resulting product is subjected to partial hydrogenation of the triple bond and dehydration in the presence of acid catalyst, to provide &bgr;-carotene, as shown in Scheme 1 below:
As can be seen from Scheme 1, however, the synthesis of the C
19
compound from the C
14
compound is not a convergent process, and requires two consecutive enol ether condensations, thereby providing the process with a low effectiveness.
With regard to the BASF process, &bgr;-carotene is synthesized via a Wittig reaction of C
15
phosphonium salt and C
10
dialdehyde, as is shown in Scheme 2 below. According to this process, a double bond can be effectively formed by the Wittig reaction, but the process has a further problem in that phosphine oxide (Ph
3
P═O), produced as a by-product, cannot be easily separated or removed.
SUMMARY OF THE INVENTION
The present invention provides intermediate compounds useful for the efficient synthesis of the polyene chain structure, taking full advantage of its symmetry and which solve the problem of by-products such as phosphine oxide by the employment of the Julia-type sulfone olefination strategy; processes for preparing the same; and processes for preparing &bgr;-carotene using the same.
The present invention also provides a novel compound having a polyene chain structure which is synthesized via the aforementioned intermediate compound, and a process for preparing the same.
The present invention further provides an improved process for preparing 2,7-dimethyl-2,4,6-octatriene-1,8-dial, a compound used in the BASF process for preparing &bgr;-carotene, which requires fewer synthetic steps than the conventional process.
Accordingly, one embodiment of the invention is a diallylic sulfide, represented by Chemical Formula 1:
wherein, R
1
and R
2
are independently chosen from the group consisting of —CHO, —CH
2
Cl, —CH
2
Br, —CH
2
I, —CH
2
OH, —CH
2
OSO
2
CF
3
, —CH
2
OSO
2
Ph, —CH
2
OSO
2
C
6
H
4
CH
3
and —CH
2
OSO
2
CH
3
. Preferably, R
1
and R
2
are both —CHO or —CH
2
Cl.
Another embodiment of the present invention is a process for preparing a diallylic sulfide represented by Chemical Formula 1, which comprises the steps of:
(a) oxidizing isoprene to give isoprene monoxide;
(b) reacting the isoprene monoxide with cupric halide (CuX
2
)/lithium halide (LiX) to provide an allylic halide (A); and
(c) reacting the allylic halide (A) with sodium sulfide (Na
2
S) to produce a compound represented by Chemical Formula 1.
The process may be represented by:
wherein R
1
and R
2
are independently chosen from the group consisting of —CHO, —CH
2
Cl, —CH
2
Br, —CH
2
I, —CH
2
OH, —CH
2
OSO
2
CF
3
, —CH
2
OSO
2
Ph, —CH
2
OSO
2
C
6
H
4
CH
3
and —CH
2
OSO
2
CH
3
, and X is chosen from Cl, Br and I.
For the diallylic sulfides represented by Chemical Formula 1, wherein R
1
and R
2
are —CH
2
Cl, —CH
2
Br or —CH
2
I, the synthesis comprises the further step of reducing and halogenating the resultant product from step (c).
Step (c) is preferably performed via the sequence of: (1) adding a catalytic amount of acid to the allylic halide (A) in alcoholic solvent to form an acetal in situ; (2) reacting said acetal with sodium sulfide for a predetermined period; and (3) evaporating the solvent and hydrolyzing the residue.
Another embodiment of the present invention provides a process for preparing 2,7-dimethyl-2,4,6-octatriene-1,8-dial represented by Chemical Formula 2, which comprises the steps of:
(a) protecting the aldehyde group of allylic halide (A) to provide the corresponding acetal compound (G);
(b) reacting the acetal compound (G) with Na
2
S to provide di(3-formyl-3-methyl-2-propenyl)sulfide, dialkyl diacetal (H);
(c) selectively oxidizing the di(3-formyl-3-methyl-2-propenyl) sulfide, dialkyl diacetal (H) to provide the corresponding allylic sulfone compound (I);
(d) applying a Ramberg-Backlund reaction to the allylic sulfone compound (I) to provide the corresponding triene compound (J); and
(e) hydrolyzing the triene compound (J) to provide 2,7-dimethyl-2,4,6-octatriene-1,8-dial, represented by Chemical Formula 2.
Here, X represents a halogen atom and R
3
and R
4
independently represent hydrogen or a methyl group.
In this embodiment, the selective oxidation reaction of step (c) is preferably performed by adding a mixture of urea-hydrogen peroxide (hereinafter, referred to as “UHP”) and phthalic anhydride dropwise to a solution containing di(3-formyl-3-methyl-2-propenyl)sulfide, dialkyl diacetal at low temperature.
Yet another embodiment of the invention provides a process for preparing &bgr;-carotene represented by Chemical Formula 3, which comprises the steps of:
(a) deprotonating the sulfone compound (B), and reacting not more than ½ equivalent (based on the sulfone compound) of allylic sulfide (C) represented by Chemical Formula 1 (R
1
, R
2
=CH
2
X, X=halogen atom) thereto, to provide sulfide compound (D);
(b) selectively oxidizing the sulfide compound (D) to prepare the sulfone compound (E);
(c) subjecting the sulfone compound (E) to a Ramberg-Backilund reaction to prepare 11,20-di(benzenesulfonyl)-11,12,19,20-tetrahydro-&bgr;-carotene (F); and
(d) reacting 11,20-di(benzenesulfonyl)-11,12,19,20-tetrahydro-&bgr;-carotene (F) with a base to provide -&bgr;-carotene, represented by Chemical Formula 3.
In this embodiment, when X is Cl, step (a) is preferably performed by adding a stoichiometric amount of sodium iodide (Naf) in terms of reactivity. The selective oxidation of step (b) is preferably carried out by adding a mixture of UHP and phthalic anhydride dropwise to a solution containing the sulfide compound (D) at low temperature.
The base used in step (d) is not specifically restricted. Appropriate bases include, but are not limited to, for example, NaNH
2
/NH
3
, metal alkoxides such as CH
3
OK/CH
3
OH, CH
3
CH
2
OK/CH
3
CH
2
OH and CH
3
CH
2
ONa/CH
3
CH
2
OH, and t-BuOK/t-BuOH. Among these example, metal alkoxides are more preferable.
Yet another embodiment of the present invention provides a novel compound, retinyl sulfide, represented by Chemical Formula 4:
Still another embodiment of the present invention provides a process for preparing retinyl sulfide represented by the Chemical Formula 4, which comprises a Wittig reaction of diallylic sulfide (C-1) represented by Chemical Formula 1 (R
1
and R
2
are each —CHO) and the Wittig salt (K).


REFERENCES:
patent: 3686326 (1972-08-01), Oswald et al.
patent: 3859360 (1975-01-01), Oswald et al.
patent: 0 523 534 A2 (1993-01-01), None
Julia et al, Tetrahedron Letters, vol. 24, No. 17, pp. 1783-1786 (1983).*
Choi et al., “Diallylic Sulfides as Key Structures for Carotenoid Synthese

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