US 7326794, Process for the Preparation of High Purity Perindopril and Intermediates Used in its Synthesis

US 7326794

http://www.google.com/patents/US7326794

Process for the Preparation of High Purity Perindopril and Intermediates Used in its Synthesis

Les Laboratoires Servier, Courbevoie Cedex, France

Perindopril 3 is used in treating cardiovascular problems, and other related patents from this company on this compound were reviewed recently (Org. Process Res. Dev. 2008, 12, 146). This patent extends the work covered in the earlier patents and involves the same route that is shown in Reaction 1.

Reaction 1

The process involves acylation of 1a to give 1b that is activated using SOCl2 to form 1c, and this is coupled with 2 to form 3 that is isolated by formation of the tert-butyl salt in 45% yield. The main claim of this patent specifically mentions the synthesis of 3 or the salt that is free from contamination by the benzyl esters 4a and 4b. These compounds are present when DCC is used as a coupling reagent in the alternative synthesis from 1c and the Ts salt of the benzyl ester of 2 Benzyl Esters.The patent also describes the synthesis of the methyl and ethyl analogues of 1b and 1c (R1 = OMe or OEt) from the corresponding chloroformates and Et3N is used in place of K2CO3 in step (a). The But analogue is formed by using (BOC)2O in place of the chloroformates and K2CO3. All of these compounds are novel, and basic 1H NMR data are given for them.

Preparation of Perindopril Eburmine

Example 5 Acylation of perhydroindole-2-carboxylic acid using N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine

To a solution of N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine (10.1 g, 35 mmol) in dichloromethane (35 mL) thionyl chloride (4.2 mL, 6.9 g, 58 mmol) was added in drops at 0-5° C. It was stirred at ambient temperature for 2-3 h. The solvent was evaporated to give a reddish oil. The residue was dissolved in THF (37.5 mL) and it was added to a suspension of perhydroindole-2-carboxylic acid (4.7 g, 28 mmol) in THF (37.5 mL). The suspension was refluxed with stirring for 4-4.5 h until a brownish solution was formed. After evaporation of the solvent the residue was dissolved in ethyl acetate (120 mL), t-butylamine (2.8 mL, 1.95 g, 27 mmol) in ethyl acetate (60 mL) was added slowly to the stirred solution resulting in separation of a crystalline mass. The mixture was heated until a solution was formed, then treated with charcoal. The crystalline product obtained after cooling was filtered to give perindopril eburmine (6.8 g, 55%).

Example 6 Acylation of perhydroindole-2-carboxylic acid using N-[2-(ethoxycarbonyl)butyl]-N-methoxycarbonylalanine

Perindopril eburmine was prepared analogously to Example 5, using N-[2-(ethoxycarbonyl)butyl]-N-methoxycarbonylalanine (3.4 g, 12.5 mmol) and perhydroindole-2-carboxylic acid (1.7 g, 10 mmol). The crystalline product obtained was filtered to give perindopril eburmine (2.4 g, 54%).

Example 7 Acylation of perhydroindole-2-carboxylic Acid Using N-[2-(ethoxycarbonyl)butyl]-N-t-buthoxycarbonylalanine

Perindopril eburmine was prepared analogously to Example 5, using N-[2-5 (ethoxycarbonyl)butyl]-N-t-buthoxycarbonylalanine (0.69 g, 2.2 mmol) and perhydroindole-2-carboxylic acid (0.29 g, 1.7 mmol). The crystalline product obtained was filtered to give perindopril eburmine (0.37 g, 49%).

Example 8 Acylation of perhydroindole-2-carboxylic acid using N-[2-(ethoxycarbonyl)butyl]-N-benzyloxycarbonylalanine

Perindopril eburmine was prepared analogously to Example 5, using N-[2-(ethoxycarbonyl)butyl]-N-benzyloxycarbonylalanine (1.41 g, 4 mmol) and perhydroindole-2-carboxylic acid (0.51 g, 3 mmol). The crystalline product obtained was filtered to give perindopril eburmine (0.60 g, 45%).

Example 9 Acylation of perhydroindole-2-carboxylic acid using N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine

To a solution of N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine (1.45 g, 5 mmol) in dichloromethane (7.5 mL) thionyl chloride (0.6 mL, 0.98 g, 8.5 mmol) was added dropwise at 0-5° C. It was stirred at ambient temperature for 2-3 h. The excess of thionyl chloride and the sulphur dioxide and hydrogen chloride formed was eliminated in slight vacuo. To the dichloromethane solution thus obtained was added perhydroindole-2-carboxylic acid (0.71 g, 4.2 mmol) and dichloromethane (5.0 mL). The suspension was refluxed with stirring for 2 h until a brownish solution was formed. After evaporation of the solvent the residue was dissolved in ethyl acetate (20 mL), whereupon t-butylamine (0.42 mL, 0.29 g, 4.05 mmol) in ethyl acetate (5.0 mL) was added slowly to the stirred solution resulting in separation of a crystalline mass. The mixture was heated until a solution was formed, then treated with charcoal. The crystalline product obtained after cooling was filtered to give perindopril eburmine (0.64 g, 35%).

Cited Patent	Filing date	Publication date	Applicant	Title
US4914214 *	Sep 16, 1988	Apr 3, 1990	Adir Et Cie	Process for the industrial synthesis of perindopril
US6835843	Apr 5, 2001	Dec 28, 2004	Les Laboratoires Servier	Method for synthesis of perindopril and its pharmaceutically acceptable salts
US7060842	Jul 23, 2002	Jun 13, 2006	Les Laboratoires Servier	Method for synthesis of (2S, 3aS, 7aS)-1-{(S)-alanyl}-octahydro-1H -indole-2-carboxylic acid derivatives and use for synthesis of perindopril
US20040248814	Jul 23, 2002	Dec 9, 2004	Pau Cid	Process for the preparation of perindopril, its analgous compounds and salts therof using 2,5 dioxo-oxazolidine intermediate compounds
DE19721290A1	May 21, 1997	Dec 11, 1997	Krka Tovarna Zdravil D D	ACE-inhibiting substituted alanyl-derivatives of e.g. proline preparation
EP0308341A1	Sep 16, 1988	Mar 22, 1989	Adir Et Compagnie	Process for the industrial synthesis of perindopril and for its principal synthesis intermediates
EP1256590A1	Jul 23, 2002	Nov 13, 2002	Les Laboratoires Servier S.A.	Method for synthesis of (2S,3aS,7aS)-1-(S)-alanyl-octahydro-1H-indole-2- carboxylic acid derivatives and use in the synthesis of perindopril
EP1279665A2	Jul 23, 2002	Jan 29, 2003	Adir	A process for the preparation of perindopril, its analogous compounds and salts thereof using 2,5-dioxo-oxazolidine intermediate compounds
GB2095252A				Title not available
WO2001058868A1	Apr 5, 2001	Aug 16, 2001	Adir	Method for synthesis of perindopril and its pharmaceutically acceptable salts

Reference
1		Vincent, et al., Drug Design and Discovery, 1992, 9, Nov. 28.
2		Vincent, M., et al., "Synthesis and Ace Inhibitory Activity of the Stereoisomers of Perindopril (S9490) and Perindoprilate (S 9780)" Drug Design and Discovery, Hardwood Academic Publishers GmbH, vol. 9, No. 1, 1992, pp. 11-28 XP000885876 ISSN: 1055-9612, p. 11-p. 13.