Acyclic chiral derivatives of hibiscus acid and the process...

Details Acyclic chiral derivatives of hibiscus acid and the process... Acyclic chiral derivatives of hibiscus acid and the process...

2001-09-05

2002-12-03

Trinh, Ba K. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S508000, C560S081000, C560S098000, C560S182000

Reexamination Certificate

active

06489493

ABSTRACT:

This invention relates to novel acyclic chiral derivatives of hibiscus acid and the process of 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
. However 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. In U.S. patent application Ser. No. 09/365,300, the large scale manufacture of Hibiscus acid in the optically pure crystalline form has been described.
During the past two decades there has been a great deal of interest in finding cheap and potential chiral derivatives from chiral pool to accomplish synthetic pathways with a high degree of asymmetric induction.
The object of the present invention is to synthesize novel acyclic chiral derivatives of Hibiscus acid which are found to be important building blocks in organic synthesis and are extensively used for the preparation of optically active ligands and biologically active products.
To achieve the said objective this invention provides a novel acyclic chiral compound of Hibiscus acid of formula I,
wherein:
R
1
=R
5
=lower aryl or alkyl ester or substituted aryl or alkyl alcohol
R
3
=substituted aryl or alkyl ester or substituted aryl alcohol
R
2
=R
4
=hydroxyl or
In the above formula I:
R
1
& R
5
is selected from —COOCH
3
, —COOC
2
H
5
, —COOCH(CH
3
)
2
, —C(Ph)
2
OH, —C(4-MePh)
2
OH, —C(1-Naphth)
2
OH
R
2
and R
4
is OH or
R
3
is selected from —CH
2
COOCH
3
, —CH
2
COOC
2
H
5
, —CH
2
COOCH(CH
3
)
2
, —CH
2
C(Ph)
2
OH, —CH
2
C(4-MePh)
2
OH, —CH
2
C(1-Naphth)
2
OH
to form various chiral derivatives, namely, chiral triesters, chiral ketals, chiral alcohols.
Chiral Triester Derivatives
Ia—R
1
=R
5
=—COOCH
3
, R
2
=R
4
=—OH and R
3
=—CH
2
COOCH
3
Ib—R
1
=R
5
=—COOC
2
H
5
, R
2
=R
4
=—OH R
3
=—CH
2
COOC
2
H
5
Ic—R
1
=R
5
=—COOCH(CH
3
)
2
, R
2
=R
4
32
—OH and R
3
=—CH
2
COOCH(CH
3
)
2
Chiral Ketal Derivatives
Id—
 R
1
=R
5
=—COOCH
3
, R
3
=—CH
2
COOCH
3
Ie—
 R
1
=R
5
=—COOC
2
H
5
and R
3
=—CH
2
COOC
2
H
5
Chiral Alcohol Derivatives(diols)
If—
 R
1
=R
5
=—C(Ph)
2
OH and R
3
=—CH
2
CPh)
2
OH
Ig—
 R
1
=R
5
=—C(4-MePh)
2
OH and R
3
=—CH
2
C(4-MePh)
2
OH
Ih—
 R
1
=R
5
=—C(1-Naphth)
2
OH and R
3
=—CH
2
C(1-Naphth)
2
OH
Compound of formula Ia is trimethyl(1S,2R)-1,2-dihydroxy-1,2,3-propanetricarboxylate
Compound of formula Ib is Triethyl(1S,2R)-1,2-dihydroxy-1,2,3-propanetricarboxylate.
Compound of formula Ic is Tri isopropyl(1S,2R)-1,2-dihydroxy-1,2,3-propanetricarboxylate.
Compound of formula Id is dimethyl(4S,5R)-2,2-dimethyl-4-(2-oxo-2-methoxyethyl)-1,3-dioxolane-4,5-dicarboxylate (Id)
Compound of formula Ie is diethyl(4S,5R)-2,2-dimethyl-4-(2-oxo-2-ethoxyethyl)-1,3-dioxolane-4,5-dicarboxylate (Ie)
Compound of formula If is (4S,5R)-4-(2-hydroxy-2,2-diphenylethyl)-2,2-dimethyl-alpha,alpha,alpha′,alpha′-tetraphenyl-1,3-dioxolane-4,5-dimethanol (If).
The present invention further includes a process for preparing the acyclic chiral triester of formulae Ia-Ic comprising
refluxing hibiscus acid with appropriate alcohol in presence of an inorganic catalyst for 6-12 hours,
adjusting the pH of the reaction mixture to neutral using aqueous alkali solution,
concentrating the said reaction-mixture by evaporation,
extracting the said concentrate with an organic solvent,
concentrating the said extract to yield the said product.
The said appropriate alcohols are selected from methanol, ethanol and isopropanol.
The said catalyst is conc. HCl and said organic solvent is chloroform.
The present invention also includes a process for preparing the acyclic chiral triester of formulae If-Ih comprising:
adding solution of chiral acetal/ketal in an organic solvent to a solution of appropriate grignard reagent(ArMgX) in an organic solvent,
refluxing the mixture for 10-20 hours,
adding the inorganic salt solution to the chilled reaction mixture,
collecting the organic phase and extracting the aqueous layer further with a suitable organic acid,
drying the organic extract using a suitable salt,
evaporating the said extract,
subjecting the residue to chromatography.
The organic solvent is tetra hydro furan (THF).
The said appropriate grignard reagent is phenyl Mg bromide, methylphenyl Mg bromide, naphthyl Mg bromide.
The said inorganic salt is ammonium chloride.
The said organic solvent used for extraction is ether.
The said salt used for drying the extract is sodium sulphate.
The chromatography employed for purification is column chromatography. The gel used for chromatography is silica gel. The eluant used for chromatography is hexane chloroform mixture.
Summary of the chiral derivatives of Hibiscus acid is given below in scheme I:
Scheme I
1*/8
Ia: R
1
=R
5
=—COOCH
3
; R
2
=R
4
=—OH; R
3
=—CH
2
COOCH
3
Ib: R
1
=R
3
=—COOC
2
H
5
; R
2
=R=—OH; R
3
=—CH
2
COOCH
5
Ic: R
1
=R
5
=—COOCH(CH
3
)
2
; R
2
=R
4
=—OH; R
3
=—CH
2
COOCH(CH
3
)
2
Id:
 R
1
=R
5
=—COOCH
3
; R
3
=—CH
2
COOCH
3
Ie:
 R
1
=R
5
=—COOC
2
H
5
; R
3
=—CH
2
COOC
2
H
5
If:
 R
1
R
5
=—C(Ph)
2
OH; R
3
=—CH
2
C(Ph)
2
OH
Ig:
 R
1
=R
5
=—C(4MePh)
2
OH; R
3
=—CH
2
C(4-MePh)
2
OH
Ih:
 R
1
=R
5
=—C(1-Naphth)
2
OH; R
3
=—CH
2
C(1-Naphth)
2
OH
Standard procedures are followed for the preparation of various chiral ketals of the type Id and Ie.
The invention will now be described with reference to the foregoing examples:


REFERENCES:
patent: 6127553 (2000-10-01), Ibnusaud et al.

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