Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Reexamination Certificate
2000-09-13
2001-08-07
Padmanabhan, Sreeni (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
C556S441000, C556S465000, C560S121000, C568S379000, C568S420000, C568S382000, C568S838000
Reexamination Certificate
active
06271408
ABSTRACT:
FIELD OF THE INVENTION
The present invention is concerned with a multi-stage process for the manufacture of an oxidative metabolite of the carotenoid lycopene as well a novel intermediates produced in the manufacturing process.
BACKGROUND OF THE INVENTION
As is known, carotenoids, inter alia, lycopene, play an important role in the chemoprevention (prophylaxis) of cancer [see, for example, J. S. Bertram, Pure & Appl. Chem. 66, 1025-1032 (1994) and the literature references mentioned therein; N. I. Krinsky, Nat. Antioxid, Health Dis. 1994, 239-261; J. S. Bertram, Oxid. Stress Aging 1995, 221-235; as well as T. Narisawa et al., Cancer Lett. 107(1), 137-142 (1996)], and their use in clinical research is well established. [A. Bendich, Pure & Appl. Chem. 66, 1017-1024 (1994) and the literature references mentioned therein]. Levy et al., have demonstrated the preventative activity of lycopene, having the formula
against the growth of human endometrial, breast and lung cancer cells [Nutr. Cancer, 24, 257-266 (1995)]. E. Giovannucci et al. disclose in J. Natl. Cancer Inst. 87, 1767-1776 (1995) that a diet rich in lycopene reduces the risk of prostate cancer.
The red carotenoid lycopene is present in tomatoes and among other fruits. A finding that, with respect to the activity against cancer, cooked tomatoes are substantially more active than raw could be due to the fact that after boiling the lycopene has an improved bioavailability; on the other hand, the biologically active compound could be an oxidation product or a metabolite of lycopene. In recent investigations on the carotenoid content of human blood plasma, new lycopene metabolites have been identified, namely 2,6-cyclolycopene-1,5-diol and 5,6-dihydroxy-5,6-dihydrolycopene [F. Khachik et al., J. Cell Biochem. 1995 (Suppl. 22), 236-246 and 11th International Symposium on Carotenoids, Leiden 1996, O.P.I.3; as well as F. Khachik, Book of Abstracts, 213th ACS Nat. Meeting, San Francisco, Apr. 13-14, 1997], The first-mentioned known metabolite, having the formula
shows activity in and is useful in the prevention of cancer growth in human and mouse cells.
Two syntheses of oxidative metabolites of lycopene have been reported, namely in Biosci. Biotechn. Biochem. 59, 2153-2155 (1995; Y. Lu et al.) and in the aforementioned 11th Int. Symp. on Carotenoids, Leiden 1996 (O.P.3.5; F. Khachik et al.). These are partial syntheses, each of which starts from lycopene itself. It has now been found that 2,6-cyclolycopene-1,5-diol (II) can be made by a multi-stage process, namely starting from the readily available &agr;-terpinyl acetate. This process is the first total synthesis of an oxidatively produced methabolite of lycopene.
SUMMARY OF THE INVENTION
The invention is accordingly concerned with a process for making the compound of formula II, which comprises the steps of (a) oxidatively dihydroxylating &agr;-terpinyl acetate having the formula
to form 4-(1-acetoxy-1-methylethyl)-1-methyl-cyclohexane-1,2-diol having the formula
(cyclohexanediol (IV), (b) oxidatively cleaving the cyclohexanediol (IV) to form 3-(1-acetoxy-1-methylethyl)-6-oxo-heptanol having the formula
(ketoaldehyde (V)), (c) subjecting the ketoaldehyde (V) to an intramolecular aldol condensation to form 3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-cyclopentanol having the formula
(cyclopentanol (IV)), (d) silylating the cyclopentanol (VI) to form 3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-1-trimethylsilyloxy-cyclopentane having the formula
(formylcyclpentane (VII)), (e) subjecting the formylcyclopentane (VII) to a C
3
-chain lengthening with acetone and simultaneously to a saponification for the cleavage of the acetyl group to form 4-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-buten-2-one having the formula
(cyclopentylbutenone (VIII)), (f) reacting the cyclopentylbutenone (VIII) with vinylmagnesium bromide to form 5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methyl-penta-1,4-dien-3-ol having the formula
(pentadienol (IX)), (g) converting the pentadienol (IX) with deprotection of the silylated hydroxy group into a (5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methylcylopentyl]-3-methyl-penta-2,4-dienyl)triphenylphosphonium salt having the formula
wherein Rh is phenyl and X
1
- is halide or hydrogen sulphate, (phosphonium salt (X)), (h) subjecting the phosphonium salt (X) to a Wittig reaction with 2,7-dimethyl-2,4,6-octatriene-1,8-dial having the formula
(C
10
-dial (XI)) to form 2,7,11-trimethyl-13-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-trideca-2,4,6,8,10,12-hexenal having the formula
(tridecahexenal (XIII)), and (i) subjecting the tridecahexanel (XII) to a Wittig reaction with a (3,7,11-trimethyl-dodeca-2,4,6,10-tetraenyl)triphenylphosphonium salt having the formula
wherein Ph is phenyl and X
2
- is halide or hydrogen sulphate, (phosphonium salt (XIII)) to form the compound of formula II.
The present invention is concerned with novel intermediates used in the aforementioned process and in particular those intermediates of formulae V, VI, VII, VIII, IX, X and XII. In addition, the present invention is also concerned with the individual process steps IV→V, V→VI, VI→VII, VII→VIII, VIII→IX, IX→X, X+XI→XII and XII+XIII→II, that is, the one-stage processes described above for the production of the novel intermediates and the known final product II. The compounds of formula III, IV, XI and XIII are known: see, inter alia, T. Hirata et al., Chem. Lent. 1982, 671-674 (cyclohexanediol (IV)) as well as U.S. Pat. No. 5,166,445 and Helv. Chim. Acta 75, 1848-1865 (1992) (phosphonium salt (XIII)).
DETAILED DESCRIPTION OF THE INVENTION
The invention is accordingly concerned with a process making the compound of formula II, which comprises the steps of (a) oxidatively dihydroxylating &agr;-terpinyl acetate having the formula
to form 4-(1-acetoxy-1-methylethyl)-1-methyl-cyclohexane-1,2-diol having the formula
(cyclohexanediol (IV), (b) oxidatively cleaving the cyclohexanediol (IV) to form 3-(1-acetoxy-1-methylethyl)-6-oxo-heptanal having the formula
(ketoaldehyde (V)), (c) subjecting the ketoaldehyde (V) to an intramolecular aldol condensation to form 3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-cyclopentanol having the formula
(cyclopentanol (VI), (d) silylating the cyclopentanol (VI) to form 3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-1-trimethylsilyloxy-cyclopentane having the formula
(formylcyclopentane (VIII), (e) subjecting the formylcyclopentane (VII) to a C
3
-chain lengthening with acetone and simultaneously to a saponification for the cleavage of the acetyl group to form 4-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclpentyl]-3-buten-2-one having the formula
(cyclopentylbutenone (VIII)), (f) reacting the cyclopentylbutenone (VIII) with vinylmagnesium bromide to form 5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methyl-penta-1,4-dien-3-ol having the formula
(pentadienol (IX)), (g) converting the pentadienol (IX) with deprotection of the silylated hydroxy group in to a (5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methylcyclopentyl]-3-methyl-penta-2,4-dienyl)triphenylphosphonium salt having the formula
wherein Ph is phenyl and X
1
- is halide or hydrogen sulphate, (phosphonium salt (X)), (h) subjecting the phosphonium salt (X) to a Wittig reaction with 2,7-dimethyl-2,4,6-octatriene-1,8-dial having the formula
(C
10
-dial (XI)) to form 2,7,11-trimethyl-13-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-trideca-2,4,6,8,10,12-hexaenal having the formula
(tridecahexenal (XIII)), and (i) subjecting the tridecahexenal (XII) to a Wittig reaction with a (3,7,11-trimethyl-dodeca-2,4,6,10-tetraenyl)triphenylphosphonium and having the formula
wherein Ph is phenyl and X
2
- is halide or hydrogen sulphate, (phosphonium salt (XIII)) to form the compound of formula II.
Pfander Hanspeter
Traber Bruno
Bryan Cave LLP
Haracz Stephen M.
Padmanabhan Sreeni
Roche Vitamins Inc.
Waddell Mark E.
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