Stereo-specific synthesis of shimikic acid derivatives with...

Details Stereo-specific synthesis of shimikic acid derivatives with... Stereo-specific synthesis of shimikic acid derivatives with...

2001-03-19

2003-02-11

Lilling, Herbert J. (Department: 1651)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing nitrogen-containing organic compound

C435S129000

Reexamination Certificate

active

06518048

ABSTRACT:

FIELD OF INVENTION
The present invention is related to stereo-specific synthesis and more particularly to a method of preselecting S or R stereo-isomerism of shikimic acid derivatives and a process for producing these compounds from readily available low-cost starting materials.
BACKGROUND OF THE INVENTION
The present invention relates to a multi-step process for the preparation of 4,5-diamino shikimic acid derivatives, especially for the preparation of (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethylester and its pharmaceutically acceptable addition salts starting from isophthalic acid derivatives, individual process steps thereof, as well as new specific intermediates.
4,5-diamino shikimic acid derivatives, especially the (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethylester and its pharmaceutically acceptable addition salts are potent inhibitors of viral neuraminidase (J. C. Rohloff et al., J. Org. Chem., 1998, 63, 4545-4550; WO 98/07685).
A multi step synthesis of (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethylester from (−)-quinic acid or (−)-shikimic acid is described in (J. C. Rohloff et al, loc.cit.).
Both (−)-quinic acid and (−)-shikimic acid are starting compounds which are rather expensive and hardly accessible in technical quantities. A multi-step synthesis capable to run on a technical scale should therefore preferably be based on starting compounds which are more attractive in price and available in technical quantities.
SUMMARY OF THE INVENTION
A process of the present invention for preparing a 4,5 di amino shikimic acid derivitive having formula 1a
wherein R
1
is an optionally substituted alkyl group, R
2
is an alkyl group and R
3
and R
4
, independently of each other are H or a substituent of an amino group, with the proviso that both R
3
and R
4
are not H includes hydrogenating an isophthalic acid derivative of formula II;
wherein R
5
is H or lower alkyl thereby forming an all-cis-cyclohexane dicarboxylate of formula III;
then selecting a stereo-selective hydrolysis and dealkylation sequence from the group consisting of: a) in the case when R
5
=H, stereo-selectively hydrolyzing the all-cis-cylohexane dicarboxylate of formula (III), thus forming the (S)- or (R)-cyclohexane monoacid of formula IVa or IVb, b) in the case where R
5
=lower alkyl, stereo-selectively hydrolyzing the alkoxy all-cis-cyclohexane dicarboxylate of formula (III), dealkylating to form the (S)- or (R)-cyclohexane monoacid of formula IVa or IVb and c) in the case where R
5
=lower alkyl, dealkylating the alkoxy all-cis-cyclohexane dicarboxylate of formula (III) and then stereo-selectively hydrolyzing the all-cis-cyclohexane dicarboxylate of formula (III) to form the (S)- or (R)-cyclohexane mono acid of the formulae IVa or IVb;
converting the cyclohexane monoacid of formula (IVa) to an oxazolidinone of the formula Va;
transforming the oxazolidinone (Va) into a cyclohexenol (VIa)
wherein R
6
is an amino protecting group; converting cyclohexenol (VIa) to an azide VIIa; and
reducing and acylating azide (VIIa); forming the respective acylated amine (VIIIa)
thereby forming the 4,5-diamino shikimic acid derivative (Ia) by removing the amino protecting group R
6
. In performing the series of steps of the process of the invention, the steps forming compounds from IVa are exemplary of similar steps forming a similar series of compounds from IVb to VIIIb. This alternate series of steps are equally preferred.
The stereo-selective synthethic method of the invention allows the use of lower-cost more accessible starting materials, provides the practitioner the ability to preselect the desired stereochemistry at several chiral centers on the molecule by selecting either an esterase or a lipase, thereby greatly improving the efficiency and accessiblity to shikimic acid derivatives that are known to be potent inhibitors of viral neuraminidase.
DETAILED DESCRIPTION OF THE INVENTION
The preferred embodiments of the invention are described herein in detail and should be considered exemplary, not limitive. The scope of the invention is measured by the appended claims and their equivalents. The present invention relates to a process for the preparation of a 4,5-diamino shikimic acid derivatives of formula Ia
and pharmaceutically acceptable addition salts thereof
wherein R
1
is an optionally substituted alkyl group,
R
2
is an alkyl group and
R
3
and R
4
, independent of each other are H or a substituent of an amino group, with the proviso that both R
3
and R
4
are not H
and which is characterized in that
in step a)
an isophthalic acid derivative of the formula
wherein R
1
and R
2
are as above and R
5
is H or lower alkyl
is hydrogenated to form an all-cis-cyclohexane dicarboxylate of the formula
wherein R
1
, R
2
and R
5
are as above,
in step b)
the cyclohexane dicarboxylate of formula (III) is, if R
5
=H, stereo-selectively hydrolyzed to form the (S)- or (R)-cyclohexane monoacid of formulas IVa or IVb or, if R
5
=lower alkyl, either dealkylated first and then stereo-selectively hydrolyzed or stereo-selectively hydrolyzed first and then dealkylated to form the (S)- or (R)-cyclohexane mono acid of the formula
wherein R
1
and R
2
are as above,
in step c)
the cyclohexane monoacid of the formula (IVa) is further converted to an oxazolidinone of the formula
wherein R
1
and R
2
are as above,
in step d)
the oxazolidinone of formula (V) is transformed into a cyclohexenol of the formula
wherein R
1
and R
2
are as above and R
6
is an amino protecting group
in step e)
the cyclohexenol of formula (VI) is further converted into an azide of formula
wherein R
1
, R
2
and R
6
are as above,
in step f)
the azide of formula (VII) is reduced and acylated to form the acylated amine of the formula
wherein R
1
, R
2
, R
3
, R
4
and R
6
are as above, and in step g)
the acylated amine of the formula (VIII) is finally transferred into the 4,5-diamino shikimic acid derivative of formula (I) by removing the amino protecting group R
6
and if necessary by forming the respective pharmaceutically acceptable salt.
The term alkyl in R
1
has the meaning of a straight chain or branched alkyl group of 1 to 20 C-atoms, expediently of 1 to 12 C-atoms. Examples of such alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its isomers, undecyl and its isomers and dodecyl and its isomers. This alkyl group can be substituted with one or more substituents as defined in e.g. WO 98/07685. Suitable substituents are alkyl of 1 to 6 C-atoms (as defined above), alkenyl of 2 to 6 C-atoms, cycloalkyl with 3 to 6 C-atoms, hydroxy, alkoxy with 1 to 6 C-atoms, alkoxycarbonyl with 1 to 6 C-atoms, F, Cl, Br, and J.
Preferred meaning for R
1
is 1-ethylpropyl.
R
2
is a straight chain or branched alkyl group of 1 to 12 C-atoms, expediently of 1 to 6 C-atoms as exemplified above.
Preferred meaning for R
2
is ethyl.
R
5
is a lower n-alkyl group of 1 to 3 C-atoms, preferably methyl.
R
3
and R
4
are substituents of an amino group used and known in the art and described e.g. in WO 98/07685.
R
3
and R
4
preferably stand for alkanoyl groups, more preferably lower alkanoyl with 1 to 6 C-atoms such as hexanoyl, pentanoyl, butanoyl (butyryl), propanoyl (propionyl), ethanoyl (acetyl) and methanoyl (formyl). Preferred alkanoyl group and therefore preferred meaning for R
3
is acetyl and for R
4
is H.
R
6
is a common amino protecting group used and known in the art and described e.g. in “Protective Groups in Organic Chemistry”, Theodora W. Greene et al., John Wiley & Sons Inc., New York, 1991, 315-385.
R
6
suitably is benzyloxycarbonyl (Z), tert-butyloxycarbonyl (BOC), allyloxycarbonyl (AllOC) or 9-fluorenylmethoxycarbonyl (FMOC), preferably tert-butoxycarbonyl (BOC).
Preferred 4,5-diamino shikimic acid deri

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