Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-09-04
2002-07-23
Powers, Fiona T. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
Reexamination Certificate
active
06423867
ABSTRACT:
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to the preparation of pyrrolidines, preferably chiral, from tri-O-acetyl-ketopentulosonic acid methyl esters. In particular the present invention relates to the preparation of 3,4-dihydroxy-5-hydroxymethyl pyrrolidines (1,4-dideoxy-1,4-imino pentitols) which can be substituted or unsubstituted in the N position.
(2) Description of Related Art
Aza-sugar analogs of D-ribofuranosides are important targets for the synthesis of drugs that regulate nucleic acid synthesis. (3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidone is an important aza-sugar intermediate.
The current routes (Fleet, G. W. J., et al., Tetrahedron 44(9) 2637-2647 (1988); and Fleet, G. W. J., et al., Tetrahedron 44 (9) 2649-2655 (1988)) to 1,4-dideoxy-1,4-imino-D-ribitol (a pyrrolidine) and its derivatives employ hexose sugars and require the removal of 1 carbon atom (usually by an oxidative process) that is difficult on large scale. One of the methods uses the L-gulono lactone which is a rare sugar and not a regular article of commerce available in significant quantities. There is no relatively simple and economic synthesis available.
OBJECTS
It is therefore an object of the present invention to provide novel intermediates and processes for the preparation of hydroxylated pyrrolidines, preferably chiral, as analogs of D-ribofuranoside. It is further an object of the present invention to provide a process which is relatively easy to perform and economical. These and other objects of the present invention will become increasingly apparent by reference to the following description and the drawings.
SUMMARY OF THE INVENTION
The present invention relates to the preparation of a first intermediate to the pyrrolidines by a process for the preparation of a 2,3,5-tri-O-acetyl-4-ketopentulosonic acid-1-methyl ester which comprises:
(a) reacting a pentose sugar with methanol in the presence of an acid to form a 1-methyl pentose sugar;
(b) reacting the 1-methyl pentose sugar with acetic anhydride in the presence of an amine to form a 1-methyl-2,3,5-tri-O-acetyl pentose sugar; and
(c) reacting the 1-methyl-2,3,5-tri-O-acetyl 1-methyl pentose sugar with an oxidizing agent to form the 2,3,5-tri-O-acetyl-4-ketopentulosonic acid-1-methyl ester.
In particular the present invention relates to a process for the preparation of 2,3,5-tri-O-acetyl-D-erythro-4-pentulosonic acid methyl ester which comprises:
(a) reacting D-ribose with an acidic solution of methanol to form 1-methyl D-ribofuranoside;
(b) reacting the 1-methyl D-ribose with acetic anhydride in the presence of pyridine to form 1-methyl-2,3,5 tri-O-acetyl-D-riboside in the reaction mixture; and
(d) reacting 1-methyl-2,3,5-tri-O-acetyl-D-riboside with an oxidizing agent to form the 2,3,5-tri-O-acetyl-D-erythro-4-pentulosonic acid methyl ester. The oxidizing agent is preferably chromium trioxide in acetic anhydride. The process is specifically shown in Scheme III.
The present invention also relates to a process for the preparation of a second intermediate to the pyrrolidines which is a process which comprises:
(a) reacting tri-O-acetyl-4-pentulosonic acid methyl ester with hydroxylamine, an amine or an ammonium ion in the presence of pyridine with the hydroxylamine to form an oxime or imine of the formula:
wherein R is selected from the group consisting of acyloxy, alkyloxy, hydroxyl, alkyl, aryl and hydrogen and R
1
to R
3
are hydrogen or a protecting group;
(b) separating the oxime or imine from the reaction mixture. The reaction is conducted in a non-reactive solvent with an amine base at low temperatures −10° C. to 10° C. and then poured over ice containing an acid to trap the excess amine base or hydroxylamine. In this and the following reactions, R preferably contains 0 to 10 carbon atoms and R
1
contains 0 to 10 carbon atoms. R and R
1
are generally groups which are non-labile under the reaction conditions.
The present invention also relates to a process for the preparation of a third intermediate to the pyrrolidines which is a process for the preparation of a pyrrolidone lactam of the formula:
which comprises reducing an oxime or imine of the formula:
with a source of singlet hydrogen (H) or a hydride to form the pyrrolidone lactam, wherein R is selected from the group consisting of acyloxy, alkyloxy, hydroxyl, alkyl, aryl, and hydrogen, and wherein R
1
to R
3
are hydrogen or a protecting group and Me is methyl. The reaction is conducted in a non-reactive solvent, preferably methanol, at −10° C. to 30° C.
The present invention also relates to a process for the preparation of a 2,3,5-tri-O-acetyl-1,4-dideoxy-1,4-iminopentitol which comprises:
reacting a pyrrolidone lactam of the formula:
with a source of singlet hydrogen (H) or a hydride to form the pentitol, wherein R is selected from the group consisting of alkyl, aryl and hydrogen and R
1
to R
3
are hydrogen or a protecting group. The reaction is preferably conducted at −20 to 40° C.
The present invention also relates to a process for the preparation of a lactone which comprises:
(a) reacting in a reaction mixture 2,3,5-tri-O-acetyl-4-pentulosonic acid or ester with a hydride or hydrogen and a catalyst to produce 2,3,5-tri-O-acetyl-pentonic acid or ester in a reaction mixture; and
(b) reacting the 2,3,5-tri-O-acetyl-pentonic acid or ester with an acid in water to form a lactone. A preferred lactone is L-lyxono-&ggr;-lactone.
The present invention also relates to a process for the preparation of a 1,4-dideoxy-1,4-imino pentitol which comprises:
(a) reacting tri-O-acetyl -4-pentulosonic acid methyl ester in methanol ammonium acetate and acetic acid in the presence of a hydride reducing agent to form an ammonium compound which spontaneously cyclizes to a lactam;
(b) reacting the lactam with a hydride to form 2,3,5-tri-O-acetyl 1,4-dideoxy-1,4-imino pentitol; and
(c) deacylating the tri-O-acetyl-1,4-dideoxy-1,4-iminopentitol to form the 1,4-dideoxy-1,4-iminopentitol.
The present invention also relates to a process for the preparation of 1,4-dideoxy-1,4-aminopentitol which comprises:
(a) reductive cyclization of tri-O-acetyl-4-amino pentonic acid methyl ester with a reducing agent to form 2,3, 5-tri-O-acetyl 1,4-dideoxy-1,4-iminopentitol via an intermediate lactam; and
(b) deacylating the 2,3,5-tri-O-acetyl-1,4-dideoxy-1,4-iminopentitol to form 1,4-dideoxy-1,4-imino pentitol.
The present invention also relates to a pentulosonic acid methyl ester which comprises:
where R
1
to R
3
is a protecting group or hydrogen and Me is methyl.
The present invention also relates to a pentulosonic acid methyl ester oxime or imine of the formula
wherein R is selected from the group consisting of acyloxy, alkoxy, hydroxyl, alkyl, aryl and hydrogen, R
1
to R
3
are protecting groups or hydrogen and Me is methyl.
The present invention also relates to a pyrrolidone of the formula:
wherein R
1
to R
3
is a protecting group or hydrogen, and R is selected from the group consisting of acyloxy, alkyloxy, hydroxy, alkyl, aryl and hydrogen.
The present invention also relates to a pyrrolidine of the formula:
where R is selected from the group consisting of acyloxy, alkyloxy, hydroxy, alkyl, aryl and hydrogen and R
1
to R
3
is a protecting group.
The specific novel compounds are:
2,3,5-Tri-O-acetyl-D-erythro-4-oximyl pentulosonic acid methyl ester.
2,3,5-Tri-O-acetyl-D-erythro-4-pentulosonic acid methyl ester.
3,4-Dihydroxy-5-hydroxymethyl-2-pyrrolidone.
(3R,4R,5R)-3,4-Dihydroxy-5-hydroxymethyl-2-pyrrolidone.
2,3,5-Tri-O-acetyl-1,4-Dideoxy-1,4-imino-D-ribitol.
2,3,5-Tri-O-acetyl-4-amino-4-deoxy-D-erythro-pentonic acid methyl ester.
N-benzyl (3R,4R,5R)3,4-dihydroxy-5-hydroxymethyl 2-pyrrolidone.
3,4-dihydroxy-5-hydroxymethyl-N-benzyl-2-pyrrolidone.
The present invention further relates to 2,3,5-tri-O-acetyl-L-lyxonic acid methyl ester.
The present invention also relates to lyxono-&ggr;-lactone.
The present invention also relates to L-lyxono-&ggr;-lactone.
REFERENCES:
Torii et al., Journal of Organic Chemistry, 50(24)
Board of Trustees of Michigan State University
McLeod Ian C.
Powers Fiona T.
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