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PROCESS FOR THE PREPARATION OF TELAPREVIR AND INTERMEDIATES THEREOF

IP.com Disclosure Number: IPCOM000233992D
Publication Date: 2014-Jan-06
Document File: 6 page(s) / 77K

Publishing Venue

The IP.com Prior Art Database

Abstract

Reported herein is a process for the preparation of telaprevir and its intermediates.

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PROCESS FOR THE PREPARATION OF TELAPREVIR AND INTERMEDIATES THEREOF

Abstract

Reported herein is a process for the preparation of telaprevir and its intermediates.

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Reported herein is a simple, efficient, industrially preferable, and economic process for the preparation of telaprevir of Formula I.

Formula I

The reported process involves the preparation of telaprevir of Formula I comprising the following steps:

a)            condensing (1S,3aR,6aS)-2-[(2S)-2-amino-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-1-carboxamide of Formula V

Formula V

with (2S)-{[(benzyloxy)carbonyl]amino}(cyclohexyl)ethanoic acid of Formula VI

Formula VI

to obtain benzyl [(1S)-1-cyclohexyl-2-({(2S)-1-[(1S,3aR,6aS)-1-{[(3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]carbamoyl}
hexahydrocyclopenta[c] pyrrol-2(1H)-yl]-3,3-dimethyl-1-oxobutan-2-yl}amino)-2-oxoethyl]carbamate of Formula VII;

Formula VII

b)            deprotecting benzyl [(1S)-1-cyclohexyl-2-({(2S)-1-[(1S,3aR,6aS)-1-{[(3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]carbamoyl}
hexahydrocyclopenta[c] pyrrol-2(1H)-yl]-3,3-dimethyl-1-oxobutan-2-yl}amino)-2-oxoethyl]carbamate of Formula VII to obtain (1S,3aR,6aS)-2-[(2S)-2-{[(2S)-2-amino-2-cyclohexylacetyl]amino}-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-1-carboxamide of Formula III;

Formula III

c)            condensing (1S,3aR,6aS)-2-[(2S)-2-{[(2S)-2-amino-2-cyclohexylacetyl]amino}-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-1-carboxamide of Formula III with pyrazine-2-carboxylic acid of Formula IV

Formula IV

to obtain hydroxy telaprevir of Formula II; and

Formula II

d)           oxidizing hydroxy telaprevir of Formula II to obtain telaprevir of Formula I.

Formula I

EXAMPLES

Example 1: Preparation of benzyl [(1S)-1-cyclohexyl-2-({(2S)-1-[(1S,3aR,6aS)-1-{[(3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]carbamoyl}hexahydrocyclopenta[c] pyrrol-2(1H)-yl]-3,3-dimethyl-1-oxobutan-2-yl}amino)-2-oxoethyl]carbamate(Formula VII)

(2S)-{[(Benzyloxy)carbonyl]amino}(cyclohexyl)ethanoic acid (3.5g) was dissolved in dichloromethane (110 mL).  N-Hydroxybenzotriazole (1.92 g) and N-ethyl-N’-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.9 g) were added to the reaction mixture.  (1S,3aR,6aS)-2-[(2S)-2-amino-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-1-carboxamide (5.5 g) was added to the reaction mixture at 0°C followed by the addition of N,N-diisopropylethylamine (2.2 mL).  The temperature of the reaction mixture was raised to 20°C to 25°C.  The reaction mixture was stirred for 18 hours at 20°C to 25°C.  The reaction mixture was washed with 1N HCl (200 mL), 5% sodium bicarbonate (100 mL), and water (100 mL) sequentially.  The dichloromethane layer was concentrate...