# US 5,344,924 A · Solvent-free synthesis of ethereally substituted blocked monosaccharides and the selective hydrolysis thereof

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- Number: US 5,344,924 A
- Document ID: US5344924A
- Status: Granted
- Kind: A
- Application number: 08/044,085
- Filed: 1993-04-06
- Granted: 1994-09-06
- Earliest claimed: 1991-02-20
- Assignees: Greenwich Pharmaceuticals Incorporated
- Inventors: Sudershan K. Arora
- Web page: https://patentgrep.com/patent/US5344924A

## CPC

- C07H 15/04: attached to an oxygen atom of the saccharide radical
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

A solvent-free method for synthesizing an ethereally-substituted, blocked monosaccharide comprising the steps of: 1) mixing, in the absence of solvent, a partially blocked monosaccharide unblocked at one position, an alkyl halide or a substituted alkyl halide, and an anhydrous alkali base; 2) heating the mixture to a temperature sufficient to allow the mixture to react; 3) maintaining the mixture at a suitable temperature for a time sufficient to form an ethereally-substituted blocked monosaccharide and drive off any water produced; 4) removing any unreacted alkyl halide or substituted alkyl halide from the mixture; 5) recovering the ethereally-substituted blocked monosaccharide product from the mixture; and, optionally, 6) selectively hydrolyzing the ethereally-substituted blocked monosaccharide product to remove one or more of the acetal blocking groups.

## Claims

### Claim 1

A solvent-free method for synthesizing 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha., D-glucofuranose comprising the steps of:
forming, in the absence of solvent, a single mixture containing 1,2:5,6-di-O-isopropylidene-.alpha.,D-glucofuranose, a halodimethylaminopropane, and an anhydrous alkali base;
heating said mixture to a temperature sufficient to allow said mixture to react;
maintaining said mixture at a temperature of at least about 110.degree. C. for a time sufficient to form 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha., D-glucofuranose and drive off any water produced;
removing any unreacted halodimethylaminopropane from said mixture; and
recovering said 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylanmino-n-propyl)-.alpha. ,D-glucofuranose.

### Claim 2 (depends on 1)

The method of claim 1, wherein said mixture contains 0.1-0.2 molar excess of said halodimethylaminopropane and 2 molar excess of said anhydrous alkali base.

### Claim 3 (depends on 2)

The method of claim 2, wherein said halodimethylaminopropane is chlorodimethylaminopropane and said anhydrous alkali base is sodium hydroxide.

### Claim 4 (depends on 1)

The method of claim 1, wherein said halodimethylaminopropane is chlorodimethylaminopropane and said anhydrous alkali base is sodium hydroxide.

### Claim 5 (depends on 2)

The method of claim 2, wherein said removal step is accomplished under reduced pressure.

### Claim 6 (depends on 2)

The method of claim 2, wherein said recovery step comprises the steps of
dissolving said 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha., D-glucofuranose in an organic solvent which is immiscible with water;
separating any solids from the resultant solution;
washing said solution with water to yield a liquid system containing a separate aqueous phase and a separate organic phase;
separating the aqueous phase from the organic phase; and
recovering said 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha., D-glucofuranose from the organic phase.

### Claim 7 (depends on 6)

The method of claim 6, further comprising, after said recovery step, the step of selectively hydrolyzing said 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha., D-glucofuranose to form 1,2-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha.,D-gluco furanose or the acid addition salt thereof.

### Claim 8 (depends on 3)

The method of claim 3 wherein said selective hydrolysis is carried out using about 2 molar equivalents of H.sub.2 O in 20% HCl in an ethanol environment.

### Claim 9 (depends on 8)

The method of claim 8, further comprising the steps of washing said 1,2-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha.,D-gluco furanose or the acid addition salt thereof with alcohol; and
drying said 1,2-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha.,D-gluco furanose or the acid addition salt thereof.

### Claim 10 (depends on 2)

The method of claim 2, further comprising, after said recovery step, the step of selectively hydrolyzing said 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha., D-glucofuranose to form 1,2-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha.,D-gluco furanose or the acid addition salt thereof.

### Claim 11 (depends on 1)

The method of claim 1, further comprising, after said recovery step, the step of selectively hydrolyzing said 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha., D-glucofuranose to form 1,2-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha.,D-gluco furanose or the acid addition salt thereof.

### Claim 12 (depends on 11)

The method of claim 11, wherein said halodimethylaminopropane is chlorodimethylaminopropane, and said anhydrous alkali base is sodium hydroxide.

### Claim 13 (depends on 1)

The method of claim 1, wherein said mixture is maintained at a temperature of from about 110.degree. C. to about 135.degree. C.

### Claim 14 (depends on 1)

The process of claim 1, wherein said mixture is maintained at a temperature of from about 110.degree. C. to about 120.degree. C.

### Claim 15 (depends on 1)

The process of claim 1, wherein said mixture is heated to a temperature of at least about 80.degree. C.

### Claim 16 (depends on 1)

The process of claim 1, wherein said time sufficient to form 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha., D-glucofuranose and drive off any water produces is from about 30 minutes to about 120 minutes.

### Claim 17

A solvent-free synthesis to prepare 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha., D-glucofuranose by the following reaction: ##STR4## wherein R is a dimethylaminopropyl group, X is chloro, and the reactants are combined in a single mixture which is heated at a temperature of at least about 110.degree. C. for a time sufficient to form 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha., D-glucofuranose.

### Claim 18 (depends on 17)

The method of claim 17, further comprising the step of selectively hydrolyzing said 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha., D-glucofuranose to form 1,2-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha.,D-gluco furanose or the acid addition salt thereof.