Chiral derivatives of Hibiscus acid bearing lactone ring...

Details Chiral derivatives of Hibiscus acid bearing lactone ring... Chiral derivatives of Hibiscus acid bearing lactone ring...

2001-09-05

2004-03-09

Owens, Amelia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S313000

Reexamination Certificate

active

06703515

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to novel chiral derivatives of Hibiscus acid bearing lactone ring moiety and the process for preparing the same.
BACKGROUND OF THE INVENTION
Hibiscus acid [(+)-Hydroxycitric acid lactone or (2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid] can be isolated from the leaves/fruit calyxes of
Hibiscus sabdariffa
or from the leaves of
Hibiscus furcatus
, and
Hibiscus cannabinus
. Garcinia acid [(−)-Hydroxycitric acid lactone or (2S,3S)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid,], a diastereomer of Hibiscus acid is widely used as an important ingredient in many pharmaceutical formulations
1-10.
The non-availability of Hibiscus acid in the market, in the optically pure form, has resulted in the limited use of Hibiscus acid or its derivatives in the broad area of organic synthesis and pharmaceutical front. This is due to the lack of any commercially viable large-scale manufacturing process. In U.S. patent application Ser. No. 09/365,300 an economic, commercially viable, cost effective process for the large-scale isolation of Hibiscus acid has been described
11
.
Also during the past two decades there has been a great deal of interest to find cheap and potential chiral molecules from chiral pool to accomplish synthetic pathways with a high degree of asymmetric induction
12-25.
Added to this, substituted &ggr;-butyrolactones are known to be potent antagonists or agonists depending upon the substitution pattern of the &ggr;-aminobutyric acid receptor, the major inhibitory neurotransmitter in the mammalian central nervous system
26
.
The known methods for obtaining diversity functionalised chiral &ggr;-lactones are either by the cyclisation of acyclic starting materials such as the sterioselective iodolactonisation of unsaturated 3-hydroxy acids
27
or from sugars such as D-ribofuranose or D-glucosamine or carbohydrates such as D-ribose, D-glucose etc
28
. These chemical modifications involving carbohydrates require tedious protocols.
Existing Methods:
a. The method reported by Per. M. Boll, Else Sorensen and Eric Balieu
29
for the isolation of Hibiscus acid is from the calyxes of the fruits of
Hibiscus sabdariffa
. In this method dried, ground fruit calyxes of
Hibiscus sabdariffia
is extracted at room temperature for 68 hours several times with methanol containing 1.5% hydrogen chloride. To the pooled methanol extracts, ether is added and the coloring matter is deposited as a dark red syrupy mass. The ether layer is collected and syrup is dissolved in methanolic hydrogen chloride (1%) and again precipitated by the addition of ether. The pooled ether extracts is evaporated and the residue is dissolved in methanol. Upon cooling colorless crystals is obtained and the same is recrystallised from propanol and which was later hydrolysed to get Hibiscus acid.
b. Another method for the laboratory-scale production of Hibiscus acid described by C. Martius and R. Maue
30
, is purely a synthetic one. In this method Hibiscus acid is prepared from a number of chemical constituents and not from any natural source.
c. The method described by this author and co-workers is a general method for the isolation of Hibiscus acid in the optically pure crystalline form from the fresh or dried leaves and/or calyxes of
Hibiscus sabdariffa
and leaves of
Hibiscus furcatus
or
Hibiscus cannabinus
employ mostly organic solvents. The main extraction is done with acidic methanol, followed out by the removal of organic impurities by adding water. The resulting filtrate was further extracted with organic solvents to get crude Hibiscus acid, which was later purified by esterification followed by hydrolysis.
The Drawbacks of the Existing Method “a” are:
1. The method fails to get pure Ia when leaves of the plants is used and is applicable only in the case of the fruit calyxes of
Hibiscus sabdariffa.
2
. Hibiscus sabdariffa
is a seasonal flowering plant and hence the calyxes is not available at any given time.
3. Large quantities of expensive solvent ether is required for the process.
4. Crystallisation was effected only on prolonged (2 months) storage over drierite, in a desiccater.
Method “b” describes the synthesis of formula Ia from chemical constituents and is not economically viable.
None of the existing methods (a&b) describes the complete characterization and degree of purity of the compound.
Method “c” describes basically the extraction with undesirable methanol and expensive diethyl ether as solvents.
The object of the present invention therefore is to prepare chial derivatives bearing lactone ring moiety and to provide a new method obviating the drawbacks of the existing methods.
To achieve the objectives, this invention provides novel chiral derivatives of Hibiscus acid bearing lactone ring moiety of formula I
Wherein:
R
1
═R
2
═alkali salt of carboxylic acid or acid chloride or lower esters or the N-substituted cyclic imides.
R
3
═hydroxyl or protected hydroxyl group
In the above formula I
R
1
and R
2
is selected from
—COONa, —COCI, —COOCH
2
C
6
H
5
, —COOC
2
H
5
,
R
2
is —OH or protected hydroxyl group to form various chiral derivatives of Hibiscus acid bearing lactone ring moiety.
Chiral Derivatives of Hibiscus Acid Bearing Lactone Ring Moiety:
Ib-
R
1
= R
2
= —COONa,
R
3
= —OH
Ic-
R
1
= R
2
= —COCl,
R
3
= —OH
Id-
R
1
= R
2
= —COOCH
3
,
R
3
= —OCH
2
SCH
3
Ie-
R
1
= R
2
= —COOCH
2
C
6
H
5
,
R
3
= —OH
Ig-
R
1
= R
2
= —COOC
2
H
5
,
R
3
= —OH
Ih-
R
1
= R
2
= —COOCH(CH
3
)
2
,
R
3
= —OH

Ij-
R
3
= —OCOCH
3

Ik-
R
3
= —OCOCH
3
Summary of the Chiral Derivatives of Hibiscus Acid Bearing Lactone Ring Moiety is Given Below in Scheme I:
Compound of formula Ib is Disodium (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate
Compound of formula Ic is (2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarbonylchloride
Compound of formula Id is Dimethyl (2S,3R)-tetrahydro-3-oxo-[(methylthio)methoxy]-5-oxo-2,3-furandicarboxylate
Compound of formula Ie is (phenylmethyl)(2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3 furandicarboxylate
Compound of formula Ig is Diethyl (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate.
Compound of formula Ih is s Diisopropyl (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate.
Compound of formula Ij is (3aR,6aS)-3a-(acetyloxy)dihydro-5-(4-methoxy-phenyl methyl)-6H-furo[2,3-c]pyrrole-2,4,6(3H,4H)-trione
The present invention further provides a process of isolation of compound of Formula Ia, comprising:
extracting the Calyxes/leaves of
Hibiscus sabdariffa
, leaves of
Hibiscus furcatus
and
Hibiscus cannabinus
using water (X),
washing the extract (X) with organic solvent to remove impurities,
concentrating the aqueous layer,
adding an organic solvent to remove insoluble impurities,
evaporating the organic layer,
adding aqueous alkali to the concentrate to yield the alkali salt,
purifying the alkali salt by the addition of alcohol,
readjusting the pH by the addition of mineral acid,
concentrating and extracting the solution with organic solvents,
further concentrating the solution to get a syrup,
extracting the said syrup with solvents,
concentrating the obtained solution to get pure Ia in crystalline form.
The organic solvent used for washing is hexane.
The organic solvent used for removing impurities is selected from methanol or acetone.
The invention further includes a process for preparing the chiral derivative of Hibiscus acid of formula Ib comprising:
treating the aqueous solution of Ia with aqueous solution of alkali till the pH of the solution is neutral,
evaporating the resultant solution to dryness,
washing the residue with water miscible organic solvent,
drying the product Ib under vacuum.
The said alkali is sodium bicarbonate.
The invention further includes a process for preparing the chiral derivative of formula Ic comprising:
adding an organic halide to a suspe

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