Process for the preparation of cyclopropane derivatives

Abstract

The present invention relates to cyclopropane derivatives, especially 2-amino-9-[[(1S,2R)-1,2-di(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H- Purin-6-one, especially via the [(1S,7R)-4-phenyl-3,5-dioxabicyclo[5.1.0]octane-1-yl]methanol intermediate.

Description

field of invention

[0001] The present invention relates to the preparation of cyclopropane derivatives and to intermediates obtained in said preparation. Background of the invention

[0002] Known cyclopropane derivatives such as 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-purine- 6-keto has potent antiviral activity.

[0003] For the preparation of 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-purin-6-one A first method is disclosed in patent EP0502690. The reaction sequence disclosed in these documents involves the preparation of (1S,5R)-2-oxo-3-oxabicyclo[3.1. 0] Ethyl hexane-1-carboxylate. Subsequent conversion to (1S,2R)-1,2-bis(benzoyloxymethyl)cyclopropylmethyl-p-toluenesulfonate requires 8 additional steps including multiple protection and deprotection steps . (1S,2R)-1,2-Bis(benzoyloxymethyl)cyclopropylmethyl-p-toluenesulfonate was then coupled with 2-amino-6-benzyloxy-purine. Finally, removal of...

Examples

Embodiment

[0226] The following examples are provided for the purpose of illustrating the invention but are in no way intended and should in no way be construed as limiting the scope of the invention.

[0227] 1) Preparation of (1R, 2R)-1,2-two (hydroxymethyl) ethyl cyclopropanecarboxylate (2c)

[0228]

[0229] In the reactor, ethanol (82.4 L) was added followed by ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate (10.3kg, 64.6mol) and cooled to 10°C. Sodium borohydride (1.85 kg, 51.7 mol) was added in portions over a period of 1 hour by maintaining the reaction temperature between 10-15°C. The reaction temperature was raised to 20-25°C and maintained for 1 hour. The progress of the reaction was monitored by HPLC. After the reaction was complete, the reaction mass was cooled to 0-5°C. The pH of the reaction mass was adjusted to 7.0 using 1.5N aqueous HCl at 0-5°C during 1 hour. Ethyl acetate (34.0 L) was added to the reaction mass and the solid was filtered. The clear...

field of invention

[0001] The present invention relates to the preparation of cyclopropane derivatives and to intermediates obtained in said preparation. Background of the invention

[0002] Known cyclopropane derivatives such as 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-purine- 6-keto has potent antiviral activity.

[0003] For the preparation of 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-purin-6-one A first method is disclosed in patent EP0502690. The reaction sequence disclosed in these documents involves the preparation of (1S,5R)-2-oxo-3-oxabicyclo[3.1. 0] Ethyl hexane-1-carboxylate. Subsequent conversion to (1S,2R)-1,2-bis(benzoyloxymethyl)cyclopropylmethyl-p-toluenesulfonate requires 8 additional steps including multiple protection and deprotection steps . (1S,2R)-1,2-Bis(benzoyloxymethyl)cyclopropylmethyl-p-toluenesulfonate was then coupled with 2-amino-6-benzyloxy-purine. Finally, removal of...

Examples

Embodiment

[0226] The following examples are provided for the purpose of illustrating the invention but are in no way intended and should in no way be construed as limiting the scope of the invention.

[0227] 1) Preparation of (1R, 2R)-1,2-two (hydroxymethyl) ethyl cyclopropanecarboxylate (2c)

[0228]

[0229] In the reactor, ethanol (82.4 L) was added followed by ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate (10.3kg, 64.6mol) and cooled to 10°C. Sodium borohydride (1.85 kg, 51.7 mol) was added in portions over a period of 1 hour by maintaining the reaction temperature between 10-15°C. The reaction temperature was raised to 20-25°C and maintained for 1 hour. The progress of the reaction was monitored by HPLC. After the reaction was complete, the reaction mass was cooled to 0-5°C. The pH of the reaction mass was adjusted to 7.0 using 1.5N aqueous HCl at 0-5°C during 1 hour. Ethyl acetate (34.0 L) was added to the reaction mass and the solid was filtered. The clear...

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