Dsm IP Assets B.v.

Tibotec Pharmaceuticals Ltd.

Robert Jan Vijn

Peter Jan Leonard Mario Quaedflieg

Franciscus Alphons Marie Lommen

Bart Rudolf Romanie Kesteleyn

Constantinus Simon Maria Liebregts

Jacob Hermanus Matheus Hero Kooistra

Danniël Adrianus Franciscus Jacobus Boxtel Van

Bart Rudolf Kesteleyn

Peter Jan Quaedflieg

Constantinus Simon Liebregts

Jacob Hermanus Kooistra

The present invention relates to methods for the preparation of diastereomerically pure (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol as well as a novel intermediate, (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one for use in said methods. More in particular the invention relates to a stereoselective method for the preparation of diastereomerically pure (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol, as well as methods for the crystallization of (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one and for the epimerization of (3aR,4R,6aS) 4-methoxy-tetrahydro-furo[3,4-b]-furan-2-one to (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one.

Methods for the preparation of (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol

The invention relates to a process for the preparation of (S)-glyceraldehyde acetonide in aqueous solution from 3,4-O-isopropylidene-L-threonic acid or a salt thereof in aqueous solution, and hypochlorite in aqueous solution wherein the aqueous hypochlorite solution has a pH&#x3e;7.5 and wherein during addition of at least 0.1 molar equivalents of hypochlorite based on the amount of 3,4-O-isopropylidene-L-threonic acid, an acid solution is not simultaneously added. The invention also relates to a process according to the invention, wherein 3,4-O-isopropylidene-L-threonic acid or a salt thereof is prepared from 5,6-O-isopropylidene-L-ascorbic acid or a salt thereof in the presence of HOand a base in a manner known per se, wherein excess HOis optionally removed by catalase. The invention also relates to a process according to the invention, wherein 5,6-O-isopropylidene-L-ascorbic acid or a salt thereof is prepared by reacting L-ascorbic acid or a salt thereof with an acetonide forming agent, preferably in the presence of an acid catalyst.

Process for the preparation of (S)-glyceraldehyde acetonide

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Venlo, Netherlands

Robert Jan Vijn