Process for the preparation of 1, 5-dideoxy-1,5-imino hexitols from oximes or imines
AssigneeMichigan State University
InventorsRawle I. Hollingsworth, Gabriela Pistia-Brueggeman
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Abstract
A process for the preparation of 1,5-dideoxy-1,5-imino hexitols of a hexose sugars from novel hydroxyl protected oxime intermediates. The process includes formation of a lactam which is reduced to the hexitol. The hexitols are useful as drugs.
Claims36
1- A process for the preparation of an aldonic -5-oxime methyl ester of a hexose sugar which has protected hydroxyl groups which comprises:
- (a) reacting a ketoaldonic acid methyl ester of the sugar with the protected hydroxyl groups with a an alkylamine or hydroxylamine acid salt in an organic solvent with a tertiary amine to react with an acid generated in the reaction at a temperature of about 60° C. or less to produce the oxime methyl ester in a reaction mixture;
- and
- (b) separating the oxime methyl ester from the reaction mixture.
2- The process of claim 1 wherein the sugar has an arabino steroconfiguration.
3- The process of claim 1 wherein the sugar has a xylo steroconfiguration.
4- The process of claim 1 wherein the tertiary amine is pyridine which also acts as the organic solvent for the reaction.
5- The process of claim 1 wherein x is lower alkyl.
6- The process of claim 1 wherein x is hydroxyl.
7- A process for the preparation of methyl 2,3,4,6-tetra-O-acetyl-5-hexulosonic acid oxime which comprises:
- (a) reacting methyl 2,3,4,6 tetra-O-acetyl-5-hexulosonic acid methyl ester with hydroxylamine hydrochloride in a first organic solvent with a tertiary amine to react with an acid generated in the reaction mixture at a temperature of between about -10 and 6020 C.;
- (b) introducing the reaction mixture into water containing ice;
- (c) extracting the oxime from the reaction mixture with a second organic solvent for the oxime;
- and
- (d) separating the oxime from the second solvent.
8- A process for the preparation of an aldonic acid hydrazide oxime of a hexose sugar with protected hydroxyl groups which comprises:
- (a) reacting an aldonic acid-5-oxime or alkylimine methyl ester of the sugar with the protected hydroxyl groups with anhydrous hydrazine in an organic solvent at less than about 30° C. to produce the hydrazide oxime;
- and
- (b) separating the hydrazide oxime of the sugar from the reaction mixture.
9- The process of claim 8 wherein the sugar has an arabino steroconfiguration.
10- The process of claim 8 wherein the sugar has a xylo steroconfiguration.
11- The process of claim 8 which is the 5 oxime.
12- The process of claim 8 which is the 5-alkylimine.
13- A process for the preparation of the 5-lactam of a hexose sugar which has hydroxyl groups which comprises:
- (a) reacting an aldonic acid methyl ester oxime or alkylimine of the sugar with the protected hydroxyl groups with hydrogen and a hydrogenation catalyst in an acidic solvent at a temperature between about 20 and 80° C. and at a pressure between about 200 and 400 psi of the hydrogen to produce the acid lactam of the sugar in a reaction mixture;
- and
- (b) separating the lactam from the mixture.
14- The process of claim 13 wherein the ester and lactam have an arabino steroconfiguration.
15- The process of. claim 13 wherein the lactam has a xylo steroconfiguration.
16- The process of claim 13 which is the 5-oxime.
17- The process of claim 13 which is the 5-alkylimine.
18- A process for the preparation of a 1,5-imino-1,5-dideoxyhexitol which comprises:
- (a) reacting a 5-imino-5-deoxyhexonic acid lactam of a hexose sugar which has hydroxyl groups with a reducing agent in a solvent at a temperature between about 0° and 80° C. to produce the 1,5-imino-1,5-dideoxyhexitol in a reaction mixture;
- and
- (b) separating the imino 1,5-imino-1,5-dideoxyhexitol from the reaction mixture.
19- The process of claim 18 wherein the ester and lactam have an arabino steroconfiguration.
20- The process of claim 18 wherein the lactam has a xylo steroconfiguration.
21- A process for the preparation of 1,5-imino,-1,5-dideoxy hexitol with or without the protected hydroxyl groups which comprises:
- (a) reacting an acid ester or a hydrazide of a 5-hexulosonic acid oxime or alkylimine with or without the protected hydroxyl group with hydrogen and a hydrogenation catalyst in an acidic solvent at a temperature between about 20 and 80° C. and a pressure between about 200 and 400 psi to form a 5-imino-5-deoxyaldonic acid lactam;
- and
- (b) reducing, if necessary deprotecting the hydroxyl groups, the lactam with a reducing agent to form the 1,5-dideoxy-1,5-imino hexitol.
22- The process of claim 21 as the oxime.
23- The process of claim 21 as the alkylimine.
24- A process for the preparation of 1,5-imino,-1,5-6-trideoxy hexitol as a product which comprises:
- (a) reacting methyl-2, 3,4, 6-tetra-O-acetyl -5-hexulosonic acid oxime with hydrogen and a hydrogenation catalyst at a temperature between about 20 and 80° C. and a pressure between about 200 and 400 psi in an acidic solvent to form a 1,5,6-triacetoxy acid lactam;
- (b) reducing and deacetylating the lactam with a reducing agent to form the 1,5-imino hexitol.
25- The process of claim 24 wherein the 5-hexulosonic acid is L-xylo and hexitol is D-glucitol.
26- The process of claim 24 wherein 5-hexulosonic acid is L-arabino and hexitol is D-galactitol.
27- A process for producing a 1,5-imino hexitol which comprises:
- (a) reacting an aldonic acid hydrazine-5-oxime or alkylimine with a reducing agent in an organic solvent at a temperature between about 20 and 80° C. to produce the 1,5imino hexitol in a reaction mixture;
- and
- (b) separating the 1,5-imino hexitol from the reaction mixture.
28- The process of claim 27 wherein the ester and lactam have an arabino steroconfiguration.
29- The process of claim 27 wherein the lactam has a xylo steroconfiguration.
30- The process of claim 27 as the alkylimine.
31- The process of claim 27 as the oxime.
32- Methyl-2,3,4,6-tetra-O-acetyl-L-arabino-5-hexulosonic acid oxime.
33- Methyl-2,3,4,6-tetra-O-acetyl-D-xylo-5-hexulosonic acid oxime.
34- Tri-O-acetyl-5-amino-5,6-dideoxy-D-gluconic acid lactam.
35- Methyl-2,3,4,6-tetra-O-acetyl-L-xylo-5-hexulosonic acid hydrazide oxime.
36- L-xylo-5-hexulosonic acid hydrazide.