Preparation of N-acetyl neuraminic derivatives

Details Preparation of N-acetyl neuraminic derivatives Preparation of N-acetyl neuraminic derivatives

1994-06-14

1996-02-27

Chan, Nicky

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D30928

Patent

active

054950279

DESCRIPTION:

BRIEF SUMMARY
The present application was filed under 35 U.S.C. .sctn.371 as the U.S. National Phase of International Patent Application No. PCT/EP92/02904, filed Dec. 14, 1992.
The present invention relates to a process for the preparation of derivatives of N-acetyl neuraminic acid. More particularly the invention relates to a process for the preparation of 5 -acetamido-4-amino-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranos onic acid (the 4-amino analogue of DANA; also known as 5-(acetylamino)-4-amino-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non -2-enonic acid) and derivatives thereof and the preparation of intermediates for use in the process. Schreiner et. al. Ann. Chem 1991, 129-134 describe the preparation of the 4-amino analogue of DANA from the peracetylated methyl ester of sialic acid (peracetyl NANA methyl ester) by the route shown in Scheme 1.
PCT/AU91/00161 (publication no. WO91/16320) describes a number of derivatives of 5-acetamido 2,3,5-trideoxy-D-glycero-D-galacto-non-2-enopyranosonic acid (2,3-dideoxy-2,3-didehydro-N- acetyl-neuraminic acid; DANA) including the 4-amino analogue of DANA from the peracetylated methyl ester of DANA by a method similar to that of Schreiner et. al. with the exception that the peracetylated compound (3a) was reduced prior to deacetylation. The method is shown in Scheme 2.
A major problem with the known processes for preparing the 4-amino analogue of DANA lies in the fact that the conversion directly or indirectly of the compound (2) and any other compound with a leaving group in the 4-position with azide is not stereospecific and leads to significant amounts of the undesired .beta.-isomer (3b) in addition to the desired .alpha.-isomer (3a). This leads to both reduced yields of the desired compound and to the need for chromatographic purification at this or a subsequent step in the synthesis.
We have now found that by careful selection of the azide source the conversion of (2) to (3a) can be effected with high stereospecificity.
The invention thus provides in a first aspect a method for the preparation of the compound of formula (I) ##STR1## by reaction of the compound of formula (II) ##STR2## with trimethylsilylazide (TMSN.sub.3).
It is currently believed that the reason for the stereospecificity is that the reaction generates HN.sub.3 in situ; other reagents which generate HN.sub.3 in situ are well known to those skilled in the art.
The reaction is effected in a protic solvent. Preferably the solvent is a C.sub.1-8 alcohol in particular a hindered alcohol. Hindered alcohols include for example isopropyl alcohol and, particularly, tert-butyl alcohol.
The reaction is conveniently carded out at a temperature of for example 0.degree.-150.degree. C., preferably at 15.degree.-90.degree. C. such as about 80.degree. C. Conveniently the reaction will be effected at below the reflux temperature of the selected solvent.
The amount of TMSN.sub.3 employed will generally be in the range of from about 1 to about 6 molar equivalents of the compound of formula (II), preferably 1.5 to 2 molar equivalents.
A significant problem also arises with the reduction of compounds such as (3a) and (4), there being a risk of undesired reduction of the 2,3-double bond in addition to reduction of the azido group. Such potential for over-reduction leads both to reduced yield and to the presence of by-products which necessitates more extensive purification procedures. We have now found that yield and purity of the 4-amino analogue of DANA can be improved by reducing the compound (4) or a protected derivative thereof in the presence of certain catalysts.
The invention thus provides in a second aspect a method for the preparation of the compound of formula (III) ##STR3## which comprises catalytic hydrogenation of a compound of formula (IV) ##STR4## (wherein R is H or a C.sub.1-4 alkyl group and R.sup.1 is H or a hydroxyl protecting group for example an acyl group such as acetyl) followed where required by hydrolysis.
The compound of formula (IV) may optionally be protected by any suitable hydroxy

REFERENCES:
Schreiner et al.; "Synthesis of some 2,3-didehydro-2-deoxysilalic acids . . . "; Liebigs Annalen Der Chemie, No. 2, Feb. 1991, pp. 129-134.

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