Process for the preparation of (1-{9-[(4S, 2R, 3R, 5R)-3, 4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide

Abstract

The present invention relates to a novel process for the preparation of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide.

Claims

1. A process for the preparation of Regadenoson of formula I, which comprises condensation of compound of formula III with 1H-pyrazole-4-carboxylic acid amide in the presence of a base and in the absence of copper catalysts, wherein the amide group of reactant 1H-pyrazole-4-carboxylic acid amide is not protected, ##STR00003##

2. The process as claimed in claim 1, wherein the base employed is selected from the group potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium methoxide, sodium ethoxide & potassium tertiary butoxide.

3. The process as claimed in claim 1, wherein the base employed is selected from sodium hydride, potassium hydride & calcium hydride.

4. The process as claimed in claim 1, wherein the reaction is carried out in solvents selected from the group toluene, t-amyl alcohol, N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMA), dimethylformamide (DMF) & dimethylsulfoxide (DMSO).

5. The process as claimed in claim 1, wherein the reaction is carried out in the presence of cesium carbonate as base and NMP as solvent at temperature ranging from 25-150 C.

6. A process for the preparation of compound of formula II ##STR00004## in pure anomeric form which comprises the steps of: i) reaction of 2,6-dichloropurine and 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribose optionally in the presence of Lewis acid; ii) dissolving the obtained product in protic solvents selected from the group of methanol, ethanol, isopropyl alcohol, tertiary butanol and tertiary amyl alcohol or in an aprotic solvent DMSO; iii) addition of purified water to above mixture and filtering the solid; iv) drying the final product under vacuum wherein the temperature does not exceed 50 C.

7. The process as claimed in claim 6 which further involves the preparation of pure Regadenoson of formula I from anomerically pure compound of formula II, ##STR00005##

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The object of the invention was to develop shortest possible synthetic route to obtain (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide.

(2) Yet another object of the invention was to develop a process devoid any anomer impurity and provide an improved method for the synthesis of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide.

(3) In one embodiment this invention provides an alternative method for preparing (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide may be represented as shown in Scheme 1. Preparing 2-chloro adenosine in two steps followed by coupling with pyrazole-2-carboxamide to obtain 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide.

(4) ##STR00002##

Preparation of Compound of Formula II

(5) Compound of formula II is prepared by the reaction of 2,6-dichloropurine and 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribose

(6) Preparation of compound of Formula II can be carried out in presence of a Lewis acid such as SnCl.sub.4, TiCl.sub.4, BBr.sub.3, ZnCl.sub.2, TMSOTf& and also other strong acids like H.sub.2SO.sub.4& PTSA. This reaction can be carried out in acetonitrile, EDC, DMF, DMA, and Toluene, preferably in EDC or in acetonitrile at 60-100 C.

(7) And alternatively the reaction can be carried out at 150-180 C. in absence of any solvents or Lewis acid.

(8) The product can be isolated as apure anomer by dissolving the product in a suitable solvent, for example DMSO or protic solvents like MeOH, EtOH, IPA, t-Butanol& t-amyl alcohol.

(9) The product is also purified by dissolving the compound in protic solvents, addition of purified water and filtering the slurry that formed & washing the solid with water followed by ethanol and drying the solid that remains under vacuum at a temperature that does not exceed 50 C.

Preparation of Compound of Formula III

(10) The compound of Formula III is prepared by reaction of Formula II with methanolic ammonia at room temperature in a sealed pressure reactor.

Preparation of Compound of Formula I

(11) The compound of Formula I is prepared by the condensation reaction of compound of formula III with 1H-pyrazole-4-carboxylic acid amide

(12) The reaction is carried out in presence of sodium hydride, potassium hydride &calcium hydride potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium methoxide, sodium ethoxide& potassium tertiary butoxide and preferably in presence of cesium carbonate at temperature of 25-150 C.

(13) This reaction can be carried out in solvents like toluene, t-amyl alcohol, N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO). Preferably in NMP or DMA.

(14) The product obtained is purified by recrystallizations in methanol, ethanol, isopropyl alcohol or acetonitrile water mixtures.

EXAMPLE I

2,6-Dichloro-9-beta-D-(2,3,5-tri-O-benzoyl)-ribofuranosylpurine (Formula II)

(15) 10.7 g of 2,6-dichloropurine and 30 g of 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribose were combined and heated to 100 C. with stirring. The reaction was allowed to stir at the same temperature until it became clear. The reaction was cooled and HOAc was removed under vacuum. Ethanol was added to the reaction and the solid isolated by filtration yielded 32 g of the crude product. The crude product was recrystallized from t-butanol to yield 28 g of 2,6-Dichloro-9-beta-D-(2,3,5-tri-O-benzoyl)-ribofuranosylpurine.

EXAMPLE II

2-Chloro-9-(beta-D-ribofuranosyl)adenine (Formula III)

(16) A solution of Formula II (30 g) in 600 mL of methanolic ammonia was heated in an autoclave at 100 C. for 24 hours. The solution was evaporated to dryness and codistilled with methanol to remove ammonia. The residue was recrystallized from Acetone. The product was dried in vacuo at 50 C. for 12 hours to yield 14 g of 2-Chloro-9-(beta-D-ribofuranosyl) adenine as a solid.

EXAMPLE III

Method A