U.S. patent application number 09/946083 was filed with the patent office on 2002-02-28 for process and intermediate compounds for the preparation of pyrrolidines.
This patent application is currently assigned to Board of Trustees operating Michigan state University. Invention is credited to Hollingsworth, Rawle I..
Application Number | 20020026073 09/946083 |
Document ID | / |
Family ID | 24528483 |
Filed Date | 2002-02-28 |
United States Patent
Application |
20020026073 |
Kind Code |
A1 |
Hollingsworth, Rawle I. |
February 28, 2002 |
Process and intermediate compounds for the preparation of
pyrrolidines
Abstract
Processes for the preparation of pyrrolidones (7 and 8) and
pyrrolidines (9 and 10) from tri-O-acetyl-D-erythro-4-pentulosonic
acid esters are described. The compounds are aza sugar analogs of
D-ribofuranoside and are intermediates to drugs which regulate
nucleoside and nucleic acid synthesis.
Inventors: |
Hollingsworth, Rawle I.;
(Haslett, MI) |
Correspondence
Address: |
MCLEOD & MOYNE
2190 COMMONS PARKWAY
OKEMOS
MI
48864
|
Assignee: |
Board of Trustees operating
Michigan state University
East Lansing
MI
|
Family ID: |
24528483 |
Appl. No.: |
09/946083 |
Filed: |
September 4, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09946083 |
Sep 4, 2001 |
|
|
|
09630765 |
Aug 2, 2000 |
|
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Current U.S.
Class: |
560/182 |
Current CPC
Class: |
C07C 69/716 20130101;
C07D 207/12 20130101; C07D 207/273 20130101; C07H 7/02
20130101 |
Class at
Publication: |
560/182 |
International
Class: |
C07C 069/66 |
Claims
I claim:
1. A process for the preparation of a
2,3,5-tri-O-acetyl-4-ketopentulosoni- c acid 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 pentose sugar with an
oxidizing agent to form the 2,3,5-tri-O-acetyl-4-pentulosonic acid
methyl ester.
2. A process for the preparation of
2,3,5-tri-O-acetyl-D-erythro-4-pentulo- sonic 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.
3. The process of claim 2 wherein in step (d) the oxidizing agent
is an oxygen providing metal compound in acetic anhydride.
4. The process of claim 2 wherein in step (d) the oxidizing agent
are ozone and dimethyl sulfoxide and an acid anhydride or
chloride.
5. A process which comprises: (a) reacting
tri-O-acetyl-4-pentulosonic acid methyl ester with hydroxylamine or
an amine or an ammonium ion in the presence of pyridine with the
hydroxylamine to form an oxime or imine of the formula: 18 wherein
R is selected from the group consisting of acyloxy, alkoxy,
hydrogen, hydroxyl, alkyl, aryl and hydrogen, R.sub.1 to R.sub.3
are hydrogen or a protecting group and Me is methyl; (b) separating
the oxime or imine from the reaction mixture.
6. The process of claim 5 wherein the reaction is conducted in a
non-reaction at about -10.degree. C. to 10.degree. C.
7. A process for the preparation of a pyrrolidone lactam of the
formula: 19which comprises reducing an oxime or imine of the
formula: 20with a source of singlet hydrogen (H) or hydride to form
the pyrrolidone lactam, wherein R is selected from the group
consisting of acyloxy, acetoxy, alkyloxy, hydroxyl, alkyl, aryl and
hydrogen, R.sub.1 to R.sub.3 are hydrogen or a protecting group and
Me is methyl.
8. The process of claim 7 wherein the reaction is conducted at
about -10.degree. C. to 30.degree. C.
9. A process for the preparation of a
1,4-dideoxy-1,4-imminopentitol which comprises: reacting a
pyrrolidone lactam of the formula: 21 with a source of singlet
hydrogen (H) or hydride to form the pentitol, wherein R is selected
from the group consisting of acyloxy, alkyloxy, hydroxyl, alkyl,
aryl and hydrogen and R.sub.1 to R.sub.3 are hydrogen or a
protecting group.
10. The process of claim 9 conducted in a non-reactive solvent at a
temperature between about -70 and 50.degree. C.
11. The process of any one of claims 5, 6 or 7 wherein the
1,4-dideoxy 1,4-iminopentitol has the D-ribo configuration.
12. A process for the preparation of a
2,3,5-tri-O-acetyl-1,4-dideoxy-1,4-- imino pentitol which comprises
reacting 2,3,5-tri-O-acetyl-4-ketopentuloso- nic acid methyl ester
with a primary amine and then a reducing agent to form the
pentitol.
13. 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
a 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 .gamma.-lactone.
14. The process of claim 13 wherein the hydride in step (a) is
sodium borohydride and wherein the acid in step (b) is hydrochloric
acid.
15. The process of claim 13 wherein the 4-pentulosonic acid has the
D-erythro configuration.
16. The process of claim 13 wherein in step (b) the pentonic acid
or ester has the L-lyxo configuration.
17. The process of claim 13 wherein the ester is a methyl
ester.
18. 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 or pyrrolidone;
(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.
19. A process for the preparation of 1,4-dideoxy-1,4-aminopentitol
which comprises: (a) reductive cyclization of
tri-O-amino-4-pentonic acid methyl ester with 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-triacetyl-1,4-dideoxy-1,4-iminopentitol to form
1,4-dideoxy-1,4-imino pentitol.
20. A pentulosonic acid methyl ester which comprises: 22where
R.sub.1 to R.sub.3 is a protecting group or hydrogen and Me is
methyl.
21. A pentulosonic acid methyl ester oxime or imine of the formula
23wherein R is selected from the group consisting of acyloxy,
alkoxy, hydroxyl, alkyl, aryl and hydrogen, R.sub.1 to R.sub.3 are
hydrogen or a protecting group and Me is methyl.
22. A pyrrolidone of the formula: 24wherein R.sub.1 to R.sub.3 is a
protecting group or hydrogen, and R is selected from the group
consisting of acyloxy, alkyloxy, hydroxy, alkyl, aryl and
hydrogen.
23. A pyrrolidine of the formula: 25where R is selected from the
group consisting of acyloxy, alkyloxy, hydroxy alkyl, aryl and
hydrogen and R.sub.1 is a protecting group.
24. 2,3,5-Tri-O-acetyl-D-erythro-4-oximyl pentulosonic acid methyl
ester.
25. 2,3,5-Tri-O-acetyl-D-erythro-4-pentulosonic acid methyl
ester.
26. 3,4-Dihydroxy-5-hydroxymethyl-2-pyrrolidone.
27. (3R,4R,5R)-3,4-Dihydroxy-5-hydroxymethyl-2-pyrrolidone.
28. 2,3,5-Tri-O-acetyl-1,4-Dideoxy-1,4-imino-D-ribitol.
29. 2,3,5-Tri-O-acetyl-D-erythro-4-pentulosonic acid methyl
ester.
30.
N-benzyl(3R,4R,5R)3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidone.
31. 3,4-Diacetoxy-5-acetoxymethyl-2-pyrrolidone.
32. 2,3,5-tri-O-acetyl-L-lyxonic acid methyl ester.
33. Lyxono-.gamma.-lactone.
34. L-lyxono-.gamma.-lactone.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] None
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] None
BACKGROUND OF THE INVENTION
[0003] (1) Field of the Invention
[0004] 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.
[0005] (2) Description of Related Art
[0006] 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.
[0007] 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
[0008] 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
[0009] 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:
[0010] (a) reacting a pentose sugar with methanol in the presence
of an acid to form a 1-methyl pentose sugar;
[0011] (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
[0012] (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.
[0013] 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:
[0014] (a) reacting D-ribose with an acidic solution of methanol to
form 1-methyl D-ribofuranoside;
[0015] (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
[0016] (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.
[0017] The present invention also relates to a process for the
preparation of a second intermediate to the pyrrolidines which is a
process which comprises:
[0018] (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: 1
[0019] wherein R is selected from the group consisting of acyloxy,
alkyloxy, hydroxyl, alkyl, aryl and hydrogen and R.sub.1 to R.sub.3
are hydrogen or a protecting group;
[0020] (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.degree. C. to 10.degree. 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.sub.1 contains 0 to 10 carbon
atoms. R and R.sub.1 are generally groups which are non-labile
under the reaction conditions.
[0021] 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:
2
[0022] which comprises reducing an oxime or imine of the formula:
3
[0023] 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.sub.1 to R.sub.3 are hydrogen or a
protecting group and Me is methyl. The reaction is conducted in a
non-reactive solvent, preferably methanol, at -10.degree. C. to
30.degree. C.
[0024] 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:
[0025] reacting a pyrrolidone lactam of the formula: 4
[0026] 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.sub.1 to R.sub.3 are hydrogen or a
protecting group. The reaction is preferably conducted at -20 to
40.degree. C.
[0027] The present invention also relates to a process for the
preparation of a lactone which comprises:
[0028] (a) reacting in a reaction mixture
2,3,5-tri-O-acetyl-4-pentulosoni- c 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
[0029] (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-.gamma.-lactone.
[0030] The present invention also relates to a process for the
preparation of a 1,4-dideoxy-1,4-imino pentitol which
comprises:
[0031] (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;
[0032] (b) reacting the lactam with a hydride to form
2,3,5-tri-O-acetyl 1,4-dideoxy-1,4-imino pentitol; and
[0033] (c) deacylating the
tri-O-acetyl-1,4-dideoxy-1,4-iminopentitol to form the
1,4-dideoxy-1,4-iminopentitol.
[0034] The present invention also relates to a process for the
preparation of 1,4-dideoxy-1,4-aminopentitol which comprises:
[0035] (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
[0036] (b) deacylating the
2,3,5-tri-O-acetyl-1,4-dideoxy-1,4-iminopentito- l to form
1,4-dideoxy-1,4-imino pentitol.
[0037] The present invention also relates to a pentulosonic acid
methyl ester which comprises: 5
[0038] where R.sub.1 to R.sub.3 is a protecting group or hydrogen
and Me is methyl.
[0039] The present invention also relates to a pentulosonic acid
methyl ester oxime or imine of the formula 6
[0040] wherein R is selected from the group consisting of acyloxy,
alkoxy, hydroxyl, alkyl, aryl and hydrogen, R.sub.1 to R.sub.3 are
protecting groups or hydrogen and Me is methyl.
[0041] The present invention also relates to a pyrrolidone of the
formula: 7
[0042] wherein R.sub.1 to R.sub.3 is a protecting group or
hydrogen, and R is selected from the group consisting of acyloxy,
alkyloxy, hydroxy, alkyl, aryl and hydrogen.
[0043] The present invention also relates to a pyrrolidine of the
formula: 8
[0044] where R is selected from the group consisting of acyloxy,
alkyloxy, hydroxy, alkyl, aryl and hydrogen and R.sub.1 to R.sub.3
is a protecting group.
[0045] The specific novel compounds are:
[0046] 2,3,5-Tri-O-acetyl-D-erythro-4-oximyl pentulosonic acid
methyl ester.
[0047] 2,3,5-Tri-O-acetyl-D-erythro-4-pentulosonic acid methyl
ester.
[0048] 3,4-Dihydroxy-5-hydroxymethyl-2-pyrrolidone.
[0049] (3R,4R,5R)-3,4-Dihydroxy-5-hydroxymethyl-2-pyrrolidone.
[0050] 2,3,5-Tri-O-acetyl-1,4-Dideoxy-1,4-imino-D-ribitol.
[0051] 2,3,5-Tri-O-acetyl-4-amino-4-deoxy-D-erythro-pentonic acid
methyl ester.
[0052] N-benzyl (3R,4R,5R)3,4-dihydroxy-5-hydroxymethyl
2-pyrrolidone.
[0053] 3,4-dihydroxy-5-hydroxymethyl-N-benzyl-2-pyrrolidone.
[0054] The present invention further relates to
2,3,5-tri-O-acetyl-L-lyxon- ic acid methyl ester.
[0055] The present invention also relates to
lyxono-.gamma.-lactone.
[0056] The present invention also relates to
L-lyxono-.gamma.-lactone.
BRIEF DESCRIPTION OF DRAWINGS
[0057] FIG. 1 is a proton NMR spectra for
tri-O-acetyl-D-erythro-4-pentulo- sonic acid methyl ester 6.
[0058] FIG. 2 is a 13C NMR spectra for the compound 6 of FIG.
1.
DESCRIPTION OF PREFERRED EMBODIMENTS
1,4-dideoxy-1,4-imino Pentitols from Triacetoxy Keto Pentonic Acids
(Tri-O-acetyl Pentulosonic Acid Esters).
[0059] The process preferably starts from the pentose D-ribose
which is available in ton quantities and has the correct number of
carbons and the correct stereochemistries. It is much shorter and
more efficient than the other routes. Other pentoses could be used
such as L-ribose, D or L arabinose, xylose or lyxose.
[0060] 1,4-Dideoxy-1,4-imino-D-ribitol is made from tri-O-acetyl
D-erythro-4-pentulosonic acid methyl ester or a related molecule by
one of several possible methods, the first two of which are:
[0061] (1) Reductive amination with an amine or ammonia to form a
4-amino-4-deoxy pentonic acid compound that can then be cyclized to
a lactam. Reduction of the lactam with borane or lithium aluminum
hydride yields the desired 1,4-dideoxy-1,4-imino-D-ribitol.
[0062] (2) Formation of an oxime which can be reduced by one of
several possible methods to yield a 4-amino-4-deoxy pentonic acid
compound that can then be cyclized to the lactam. Reduction of the
lactam with borane or lithium aluminum hydride will yield the
desired 1,4-dideoxy-1,4-imido-D-ribitol.
[0063] The tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester,
the oxime and the lactam (in these examples
(3R,4R,5R)-3,4-dihydroxy-5-hydrox- ymethyl-2-pyrrolidone and its
N-alkyl derivatives) have not been previously described. Once these
compounds can be prepared, the subsequent process step for
transformation to the desired 1,4-Dideoxy-1,4-imino-D-ribitol is in
the known art.
[0064] Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester, its
oxime and (3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidone
and its N-benzyl derivative (formed if benzylamine is used instead
of ammonia in the reductive amination) are new compounds.
[0065] The pyrrolidines are derived from an appropriately protected
(R.sub.1 to R.sub.3) or unprotected R.sub.1 to R.sub.3 is hydrogen
2,3,5-trihydroxy 4-ketopentulosonic acid esters 1 by any of several
routes as shown in Scheme I. 9
[0066] wherein R is OH. Steps 2 and 3 combine together, where R is
hydrogen or alkyl, aryl, acyloxy, alkoxy then the process follows
each of the steps. Generally R.sub.1 to R.sub.3 is acetyl. Other
groups are benzoyl, propanoyl and trifluoroacetyl.
[0067] It should be noted that in the present application the
compounds can be numbered using the carbohydrate system wherein the
carboxyl group is 1 and the compounds are "pyrrolidines. Scheme I
uses this carbohydrate system to show the position of the carbons.
In the pyrrolidone system the N in the ring is 1 in naming the
various compounds. The pyrrolidone system is preferred for purposes
of claiming the compounds.
[0068] In this scheme the protected trihydroxy 4-ketopentulosonic
acid ester 1 is reacted with ammonia or a primary amine or ammonium
ion or with hydroxylamine to form an imine (in the former case) or
an oxime 2 where R is OH which is then hydrogenated or reduced with
a metal or a metal hydride reagent to form an amine 3. The amine
spontaneously cyclizes to a lactam 4 which can be reduced with
borane or a hydride reagent to the desired pyrrolidine 5.
[0069] Starting with the previously unknown compound
tri-O-acetyl-D-erythro-4-pentulosonic acid methyl ester (R=methyl,
R.sub.1 to R.sub.3=acetyl in Scheme I) (6), direct syntheses of the
tri and di hydroxypyrrolidines (9 and 10 respectively) is obtained
with the D-ribo configuration (scheme II). The deoxygenation of the
5-position to form 10 was produced by reduction of the triacetate
of the oxime (2) with hydrogen on palladium in acetic acid and thus
this combination is not used as a reducing agent. Under these
conditions the amino group was also introduced by reduction of the
oxime 2. The amine cyclized to form the intermediate amide 8
(lactam) which was reduced to the pyrrolidine 10 with borane or
lithium aluminum hydride. Deoxygenation of the 5-position did not
occur if the molecule was deactylated first or if an imine was used
instead of an oxime for introducing the nitrogen. 10 11
[0070] Tri-O-acetyl-D-erythro-4-pentulosonic acid methyl ester (6)
was prepared by two routes as outlined in Schemes III and IV. 12
13
[0071] In the first route (Example 1, Scheme III), D-ribose is
converted to a mixture of its .alpha. and .beta. furanosides by
treatment with methanol in the presence of a catalytic amount of
sulfuric acid. The methyl glycosides are peracetylated and then
oxidized with chromium trioxide in acetic anhydride (Example 2).
This yields the Tri-O-acetyl-D-erythro-4-pentulosonic acid methyl
ester (6) in very pure state as evidenced by the proton (FIG. 1)
and 13C NMR spectra (FIG. 2).
[0072] In the second route (Example 6, Scheme IV) the peracetylated
glycosides are oxidized with ozone to give the 2,3,5-triacetyl
aldonic acid methyl ester which is then oxidized to the
tri-O-acetyl-D-erythro-4-- pentulosonic acid methyl ester 6 by
treatment with DMSO and acetic anhydride or DMSO and
trifluoroacetic anhydride.
[0073] The pentulosonic acid methyl ester 6 can be converted to the
pyrrolidine nucleus by several routes:
[0074] (1) Conversion to the oxime 2 and reduction to the
4-amino-4-deoxy ester 3 with hydrogen Pd/C with concomitant
deoxygenation at the 5 position followed by cyclization to form 10
(Scheme II) where R=H and R.sub.1=R.sub.2=Ac.
[0075] (2) Deacetylation by acid methanolysis, oxime 2 formation,
and reduction with Pd/C to form 7 where
R=R.sub.1=R.sub.2=R.sub.3=H.
[0076] (3) Reductive amination with ammonia and a reductant to form
the 4-amino-4-deoxy ester 3 followed by cyclization to form 7 where
R=H R.sub.1=R.sub.2=R.sub.3=Ac.
[0077] (4) Conversion to the oxime 2, deacetylation with hydrazine,
reduction to the 4-amino-4-deoxy ester 3 with hydrogen Pd/C with
concomitant deoxygenation at the 5 position followed by cyclization
to from 7 where R=R.sub.1=R.sub.2=R.sub.3=H.
[0078] (5) Reductive amination with benzylamine and a reductant to
form the 4-amino-4-deoxy ester 3 followed by cyclization to form 7
where R=Benzyl and R.sub.1=R.sub.2=R.sub.3=Ac.
[0079] (6) Reductive amination with 2,4-dimethoxybenzyiamine and a
reductant to form the 4-amino-4-deoxy ester 3 followed by
cyclization to form 11 where R=Benzyl and
R.sub.1=R.sub.2=R.sub.3=Ac.
[0080] Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester 6 is
thus a key intermediate in the synthesis of
(3R,4R,5R)-3,4-dihydroxy-5-hydroxyme- thyl-2-pyrrolidone as a
1,4-dideoxy-1,4-imino-D-ribitol (9). These compounds are valuable
intermediates in the synthesis of "aza-sugar" analogs of
D-ribofuranose. 14
[0081] The transformation of tri-O-acetyl D-erythro-4-pentulosonic
acid methyl ester 6 and its oxime 2 to 9 via 7 and its
per-O-acetate was achieved via various chemical transformations.
Typical strategies are:
[0082] (1) Reduction of the oxime to an amine and cyclization to
the pyrrolidone with expulsion of methanol with reagents such as
hydrogen and palladium, hydrogen and platinum, hydrogen and Raney
nickel, zinc and acetic acid and sodium cyanoborohydride.
[0083] (2) Reductive amination of the ketone function of
tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester 6 with
ammonia or an amine using reagents such as sodium cyanoborohydride,
sodium borohydride or hydrogen and a catalyst followed by
cyclization to the pyrrolidone. The pyrrolidone is reduced to the
1,4-dideoxy-1,4-imino-D-ribitol with reagents such as lithium
aluminum hydride or borane.
EXAMPLE 1
Preparation of Tri-O-acetyl D-erythro-4-pentulosonic Acid Methyl
Ester 6
[0084] 15
[0085] There are two efficient routes to the preparation of
tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester 6. The
first route is by the oxidation of tri-O-acetyl methyl
.alpha.,.beta.-ribofuranoside with chromium trioxide in acetic
acid/acetic anhydride. The second method is by the oxidation of
tri-O-acetyl methyl .alpha.,.beta.-ribofuranoside with ozone to
produce 2,3,5-tri-O-acetyl D-ribo-pentonic acid methyl ester which
is then oxidized with a reagent such as DMSO/TFAA or
DMSO/Ac.sub.2O.
Tri-O-acetyl Methyl .alpha.,.beta.-ribofuranoside
[0086] Procedure 1.
[0087] D-ribose (100 g) was dissolved in methanol (1000 ml) and
conc sulfuric acid (2 ml) added. The mixture was left at room
temperature for 24 hours and then the solvent was removed at a bath
temperature of less than 30-350.degree. C. Pyridine (400 ml) was
added and the mixture cooled in ice to .about.50.degree. C. Acetic
anhydride (300) was then added over a 20 minute period. The mixture
was allowed to come to room temperature and left there for 10 hours
after which the solvents were removed by rotary evaporation at a
bath temperature of 45-50.degree. C. The syrup was dissolved in
ethyl acetate (1000 ml) and washed twice with cold saturated sodium
chloride (200 ml) containing .about.30 ml of conc HCl. After 1 wash
with cold saturated sodium chloride (100 ml), the solution was
dried (sodium sulfate) and concentrated to an oil. The crude
tri-O-acetyl methyl .alpha.,.beta.-D-ribofuranoside that was so
produced was used without further purification.
Tri-O-acetyl D-exythro-4-pentulosonic Acid Methyl Ester
[0088] The tri-O-acetyl methyl .alpha.,.beta.-ribofuranoside
prepared from 100 g of D-ribose by procedure 1 above was dissolved
in acetic acid (1500 ml) and acetic anhydride (330 ml) added. The
mixture was cooled in ice to 0-5.degree. C. and a stream of
nitrogen passed over the surface. Chromium trioxide (130 g) was
added over a period of 40 minutes and the temperature never allowed
to exceed 10.degree. C. The mixture was stirred at this temperature
for 1 hour then allowed to reach room temperature over a 30 minute
period. It was stirred at room temperature for 5 hours. The
solvents were then rapidly removed under vacuum at a temperature
not to exceed 50.degree. C. It was then diluted with 2000 ml of
ethyl acetate, stirred vigorously for 30 minutes and filtered. The
filter cake was washed with a further 500 ml of ethyl acetate. The
combined ethyl acetate extracts was washed with 2.times.300 ml of
cold water, dried and the solvent removed to yield the desired
product in over 92% yield (>92% pure by NMR spectroscopy).
.sup.1H NMR in chloroform, 2.0-2.3 (3.times.3H singlets), 4.8 (dd,
2H, J=12 Hz), 5.61 (s, 1H), 5.71 (s, 1H). .sup.13C NMR 30-31 ppm (3
signals), 53.2, 66.8, 71.3, 76.0, 166.7, 169.5, 170.5, 197.8.
Preparation of tri-O-acetyl D-erythro-4-pentulosonic Acid Methyl
Ester Oxime (2), Where R=H and R.sub.1 to R.sub.3=Acetyl
[0089] 16
[0090] Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester (5.5
g) was dissolved in pyridine (16 ml) and the solution cooled to
0.degree. C. Hydroxyamine hydrochloride (2 g, 29 mmol) was added
and the mixture was kept at 0.degree. C. for a further 15 minutes
and then at room temperature for 2 hours. It was poured into ice
containing 18 ml of concentrated HCl (sufficient to neutralize the
pyridine) and extracted with 3 times with 60 mol of chloroform. The
combined chloroform extracts were washed once with 15 ml of cold
saturated sodium chloride, dried (anhydrous sodium sulfate) and
concentrated to yield a colorless syrup which slowly formed white
crystals. Yield--5.7 g (97%). 13 C NMR-(d-chloroform) 21.0, 53.5,
57.8, 62.0, 68.3, 70.8, 72.0, 151.6, 168.0, 170.1, 171.1,
172.0.
EXAMPLE 3
N-benzyl (3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidone
[0091] Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester 6
(15.2 g) was dissolved in methanol (85 ml) and acetic acid (3.1 g)
and benzylamine (5.4 g) added. Sodium cyanoborohydride (3.lg) was
then added and the mixture kept at room temperature for 24 hours to
reduce the imine to an amine 3. Sodium bicarbonate (6 g) and water
20 ml was added and the mixture heated for 4 hours at 70.degree. C.
to effect cyclization to the lactam 7. The mixture was concentrated
to a syrup and partitioned between ethyl acetate (300 ml) and cold
saturated sodium chloride (100 ml). The ethyl acetate layer was
recovered, dried (sodium sulfate) and concentrated to a syrup. The
syrup was dissolved in methanol (200 ml) to which was added
potassium carbonate 20 g and water 2 ml. The resulting mixture was
stirred at room temperature for 14 hours, filtered, the filtrate
concentrated and the resulting syrup dissolved in methanol (400
ml). Concentrated HCl (4.1 ml) was added. A white solid was formed.
This was removed by filtration and the filtrate concentrated to
dryness. Methanol was added again and the solution again
concentrated. This was repeated one more time to give the crude
N-benzyl pyrrolidone which can be converted to the pyrrolidine to
reduction.
EXAMPLE 4
(3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidone
[0092] Procedure 1
[0093] Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester 6
(15.2 g) was dissolved in methanol (100 ml) and ammonium acetate
(3.0 g) and acetic acid (0.2 ml) added. Sodium cyanoborohydride
(3.1 g) was then added and the mixture kept at room temperature for
24 hours to reduce the ammoniated compound to an amino group which
are rearranged to the tri-acetylated product 4. The triacetylated
product was deacetylated with potassium carbonate-methanol to form
the pyrrolidone.
[0094] Procedure 2
[0095] Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester
oxime wherein R=H and R.sub.1 to R.sub.3=acetyl (3.1 g) was
dissolved in methanol (40 ml) and Raney nickel (0.5 g) added. The
mixture was hydrogenated at 2 atmospheres for 6 hours, filtered and
concentrated to give the crude triacetylated product. The product
was deactylated with potassium carbonate-methanol to form the
pyrrolidone.
[0096] Procedure 3
[0097] The oxime derivative formed above was treated with 4
equivalents of hydrazine in methanol for 4 hours and then
hydrogenated with 10% Pd/C in ethanol containing 10% acetic acid at
50 psi and room temperature for 5 hours. The product was
deacetylated with potassium carbonate--methanol to form the
pyrrolidone.
[0098] In these procedures, the intermediate steps of 3 and 4
Scheme I are by-passed to produce the tri-O-acetylated intermediate
pyrrolidone and the intermediate tri-O-acetylate pyrrolidone is
then deacylated and reduced to the pyrrolidine (pentitol 5 in
Scheme I).
EXAMPLE 5
[0099] The following is an additional procedure (Scheme V) for
using the tri-O-acetyl-D-erythro-4-pentulosonic acid methyl ester 6
to form the pyrrolidine. 17
[0100] In a typical step, the 4-pentulosonic acid (30 g) is
dissolved in 150 ml of methanol and 0.5 molar equivalents of sodium
borohydride is added after the solution is cooled to 0.degree. C.
The mixture is maintained at 0-50 for 2 hours and then 4
equivalents of acetic acid are added to decompose the borohydride.
The methanol is removed by rotary evaporation. 200 ml of methanol
is added and removed and this process of adding method and removing
repeated four times to remove all borate esters. The product 11 is
refluxed in 300 ml of methanol containing 1% HCl for 3 hours, to
effect deacylation and concentrated to effect lactonization. The
crude L-lyxono-.gamma.-lactone 12 so obtained is converted to the
iminopentitol 9 using procedures such as that described by Fleet et
al, cited previously.
EXAMPLE 6
[0101] Methyl tri-O-acetyl-.alpha.,.beta.,D-ribofuranoside (2 g)
was dissolved in ethyl acetate (30 ml) and the solution was cooled
to 0-10.degree. C. Ozone was passed through for 2 hours at the rate
of 20 mM per hour. The ethyl acetate was then removed and the
product dissolved in dimethyl pentoxide (30 ml) and acetic
anhydride (2 ml) added. The mixture was left at room temperature
for 24 hours. The keto ester was isolated by concentration, and
partitioning between water/ethyl acetate. The product was recovered
from the ethyl acetate layer.
[0102] It is intended that the foregoing description be only
illustrative of the present invention and that the present
invention be limited only by the hereinafter appended claims.
* * * * *