Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfonate esters
Reexamination Certificate
2002-08-30
2004-06-08
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfonate esters
C558S044000
Reexamination Certificate
active
06747166
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for preparing carotenoid polyene chain compounds. More specifically, it relates to intermediate compounds which are useful for synthesis of carotenoid compounds having polyene chain structure, and a process for preparing the same, and a process for preparing polyene chain compounds, especially lycopene, by using the intermediate compound.
BACKGROUND ART
Carotenoid compounds have polyene chain structure. Specific examples of the compounds include beta-carotene, lycopene, astaxanthin, bixin, and the like. The carotenoid compounds have been widely used as natural dyes, and recently, these compounds are reported to have excellent anti-tumor effect, by virtue of their selective reactivity with radicals and singlet oxygen known as carcinogens. In these circumstances, a variety of commercial products containing carotene, including cosmetics or taste food, have been merchandised. However, there still remain conflict opinions on the anti-tumor activity of beta-carotene, since beta-carotene is reported to have a harmful effect on smokers or patients having lung cancer. Thus, people pay more increasing attention to lycopene, having stronger anti-oxidation ability with no conflict opinion on the anti-tumor activity.
To meet such a tendency, the requirement of developing a process for effectively synthesizing polyene chain structures that construct lycopene also increases.
In the meanwhile, the most representative conventional synthetic process for preparing lycopene was developed by Isler; that is a process for synthesizing polyene chain on the basis of Wittig reaction (Reaction Scheme 1;
Helv. Chim. Acta
1956, 39, 463-473).
According to Reaction Scheme 1, C-10 dialdehyde compound is subsequently reacted with vinyl ether and propenyl ether compound to form a continuously conjugated carbon chain wherein each C-2 unit and C-3 unit was respectively added to the aldehyde groups of C-10 dialdehyde compound. Throughout the stage, C-10 unit has been added to the dialdehyde to form C-20 dialdehyde, of which the triple bond at the center of the molecule was then partially reduced to give crocetin.
Then, crocetin thus obtained is subjected to Wittig Reaction with Wittig salts to form lycopene. The Wittig salts used in this stage is what was prepared as a result of reaction of geranyl bromide with triphenylphosphine.
However, the synthetic process for lycopene according to Reaction Scheme 1 includes many reaction stages to carry out in order to form crocetin, and the synthetic efficiency is low owing to the trouble in treating phosphine oxide as the by-product obtained as a result of Wittig Reaction.
Another synthetic process for synthesizing lycopene is developed by Karrer. The process is based on coupling reaction by using alkynyl anion, partial hydrogenation and dehydration. The synthetic process is illustrated in Reaction Scheme 2 (
Helv. chim. Acta
1950, 33, 1349-1352).
According to Reaction Scheme 2, an anion obtained by adding metallic zinc to propargylic bromide is subjected to coupling reaction with &psgr;-ionone, to give C-16 intermediate. Then, two molecules of the alkynyl anion obtained by adding bases to the C-16 intermediate were coupled with C-8 diketone compound to form forwards containing 40 carbon atoms required for synthesis of lycopene. The partial hydrogenation of the two triple bonds and dehydration of the forward compound provide lycopene.
The synthetic process for lycopene according to Reaction Scheme 2 is relatively simple, however, it is not easy to form a double bond having trans configuration.
Thus, the first technical object of the present invention is to provide an allylic sulfide, that is, a C-5 compound usable for chain extension to effectively synthesize polyene chain structure described above.
Another technical object of the present invention is to provide a process for extending the carbon chain by the use of said allylic sulfide.
Still another object of the present invention is to provide a process for preparing polyene chain compounds, especially lycopene, by using said process for extending carbon chain.
DISCLOSURE OF THE INVENTION
In order to achieve the first technical object, the present invention provides allylic sulfides represented by Chemical Formula 1:
Chemical Formula 1
Wherein, X is selected from the group consisting of —Cl, —Br, —I, —OSO
2
CF
3
, —OSO
2
Ph, —OSO
2
C
6
H
4
CH
3
and —OSO
2
CH
3
, and Ph represents phenyl group.
The second technical object of the present invention is achieved by a process for preparing an allylic sulfide of Chemical Formula 1, which comprises the steps of (a-1) oxidizing isoprene to obtain isoprene monoxide, (b-1) reacting the isoprene monoxide with benzene thiol to obtain 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A); and (c-1) reacting the compound (A) with a halogenating compound or sulfonylating compound.
In the formulas, X is selected from the group consisting of —Cl, —Br, —I, —OSO
2
CF
3
, —OSO
2
Ph, —OSO
2
C
6
H
4
CH
3
and —OSO
2
CH
3
, and Ph represents phenyl group.
The third technical object of the present invention is achieved by a process for extending carbon chain by the use of allylic sulfide of Chemical Formula 1, which comprises the steps of (a-2) deprotonating allylic sulfone compound (B), and reacting the resultant compound with allylic sulfide of Chemical Formula 1 to obtain thio-sulfone compound (C); and (b-2) selectively oxidizing the thio-sulfone compound (C) to obtain the corresponding allylic sulfone compound (D).
In the formulas, R is selected from the group consisting of hydrogen, C1~C30 alkyl group, C1~C30 alkenyl group, aryl group, —CN, —COOR′ (wherein, R′ is C1~C10 alkyl group) and —C(═O)H, X is selected from the group consisting of —Cl, —Br, —I, —OSO
2
CF
3
, —OSO
2
Ph, —OSO
2
C
6
H
4
CH
3
and —OSO
2
CH
3
, and Ph represents phenyl group.
The fourth technical object of the present invention is achieved by a process for preparing a carotenoid polyene chain compound represented by Chemical formula 2, which comprises the steps of (a-3) deprotonating the allylic disulfone compound (D), and reacting the resultant compound with not more than 0.5 equivalent of diallylic sulfide (E) (wherein, Y is a halogen atom) on the basis of 1 equivalent of allylic disulfone compound (D) to obtain allylic sulfide compound (F); (b-3) selectively oxidizing the allylic sulfide compound (F) to obtain allylic sulfone compound (G); (c-3) subjecting the allylic sulfone compound (G) to Ramberg-Baklund reaction to give tetra(phenylsulfonyl)-triene compound (H); and (d-3) reacting the compound (H) with a base. If R of Chemical Formula 2 is prenyl, the process provides lycopene.
In the formulas, R is selected from the group consisting of hydrogen, C1~C30 alkyl group, C1~C30 alkenyl group, aryl group, —CN, —COOR′ (wherein, R′ is C1~C10 alkyl group) and —C(═O)H, Y is selected from the group consisting of —Cl, —Br, —I, —OSO
2
CF
3
, —OSO
2
Ph, —OSO
2
C
6
H
4
CH
3
and —OSO
2
CH
3
, and Ph represents phenyl group.
In the process for preparing an allylic sulfide of Chemical Formula 1, the ring opening of isoprene monoxide of stage (b-1) is preferably performed by using Cu(I)-containing salt as a catalyst, and N,N-dimethylformamide (DMF) as solvent, because the objective compound having a double bond of trans configuration can be obtained as major product under such reaction conditions.
In the process for extending carbon chain by the use of allylic sulfide of Chemical Formula 1, specific examples of R include methyl, ethyl and propyl group for C1~C30 alkyl group, vinyl, allyl and prenyl group for C1~C30 alkenyl group, and phenyl and naphthyl group for aryl group. X is preferably Cl or Br in terms of reactivity, while R is preferably hydrogen or prenyl.
Further, the C-5 unit can be added as desired by repeating stage (a-2) and (b-2) one or more times by using compound (D) as the starting material.
Selective oxidation of stage (b-2) can be preferably performed by adding hydrogen peroxide solution dropwise to thio-sulfone co
Ji Minkoo
Koo Sangho
Abelman ,Frayne & Schwab
Killos Paul J.
Koo Sangho
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