WO2005122682A2

WO2005122682A2 - Process for the preparation of esters of piperazic acid

Info

Publication number: WO2005122682A2
Application number: PCT/IB2005/001726
Authority: WO
Inventors: Yatendra Kumar; Mohan Prasad; Kaptan Singh; Surender Kumar Dhingra; Kintali Venkata Ramana
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-06-18
Filing date: 2005-06-17
Publication date: 2005-12-29
Also published as: WO2005122682A3

Abstract

The present invention provides simple and cost effective processes to prepare esters of piperazic acid, which can be useful as intermediates in synthesizing cilazapril. Key feature is treating 2, 5-dibromovaleric acid with tert-butanol in the presence of acid catalyst.

Description

PROCESS FOR THE PREPARATION OF ESTERS OF PIPERAZIC ACID

Field of the Invention The present invention provides processes of preparing esters of piperazic acid, which can be useful intermediates in the synthesis of various medicinal compounds.

Background of the Invention Esters of piperazic acid are reportedly useful intermediates in preparing various 1 medicinal compounds. Tert-butyl esters of N ,N -Bιs(substituted carbonyl)piperazic acid of Formula I,

Formula I are useful intermediates in preparing cilazapril, an angiotensin converting enzyme (ACE) inhibitor used in treating and managing hypertension, which is represented by the compound of Formula II,

Formula II U.S. Patent No. 6,201,118 discloses a process for preparation of an ester of piperazic acid of Formula I, which involves esterifying 2,5-dibromovaleric acid using two equivalents of N,N-dimethylformamide di-tert-butyl acetal in toluene. The obtained intermediate is cyclized with

hydrazine using potassium tert- butoxide to form the compound of Formula I. WO 99/55724 discloses a process for preparing a compound of Formula I via esterification of 2,5-dibromovaleric acid using tert-butanol in the presence of potassium carbonate, followed by reacting the ester thus formed with N^N^bw-substituted hydrazine in diglyme and purification using silica gel column chromatographic. In view of the above, there remains a need for simple and cost-effective processes of preparing esters of piperazic acid. Summary of the Invention Provided herein are processes for preparing compounds of Formula I,

Formula I which comprise the steps of: a) forming a reaction mixture by treating 2,5-dibromovaleric acid of Formula III

with tert-butanol in the presence of one or more acid catalysts and optionally one or more dehydrating agents to form a compound of Formula IV,

Formula IV b) cyclizing the compound of Formula IV by adding to the reaction mixture

bis-substituted hydrazine of Formula V;

Formula V wherein Ri and R₂ are independently selected from alkyl, substituted alkyl, aryl, optionally substituted aralkyl or aralkyloxycarbonyl; in the presence of one or more bases and one or more phase transfer catalysts to form a compound of Formula I, and c) isolating the compound of Formula I from the reaction mixture. Also provided herein are processes for preparing cilazapril of Formula II,

Formula II which comprises the steps of: a) forming a reaction mixture by treating 2,5-dibromovaleric acid with tert-butanol in the presence of one or more acid catalysts and optionally one or more dehydrating agents to form a compound of Formula IV,

Formula IV b) cyclizing the compound of Formula IV by adding to the reaction mixture N^!,N²- bis-substituted hydrazine in the presence of one or more bases and one or more phase transfer catalysts to form a compound of Formula I, c) isolating the compound of Formula I from the reaction mixture, and d) further converting compound of Formula I to compound of Formula II. These processes may also include one or more of the following embodiments. For example, the one or more acid catalysts can be selected from one or more mineral acids, one or more acidic resins, one or more acidic silicas, one or more acidic clays or mixtures thereof. Preferably, the one or more mineral acids comprise sulphuric acid, hydrochloric acid, phosphoric acid or mixtures thereof. In addition, the one or more dehydrating agents comprise sulphuric acid, anhydrous magnesium sulphate or mixtures thereof. The compound of Formula IV obtained in step (a) can have a purity greater than about 96 %. The cyclization reaction in step (b) can be carried out at reflux temperatures for about 5 to about 50 hours. The compound of Formula I is dried at a temperature of 25 °C to 40 °C under vacuum. The compound of Formula I can have a purity of greater than about 98 %, more preferably 98.5 %. In addition, the yield of compound of Formula I can be about 98 %. Compounds of Formula I can be converted to a compound of Formula II comprising the steps of: a) reacting (S)-(3-bromopropyl)-l, 3-dioxo-2-isoindolineacetic acid with PC1₅ at room temperature followed by reaction of the product thus obtained, with tert-butyl 1- benzyloxycarbonyl-hexahydro-3-pyridazinecarboxylate to form 1-benzyl 3-tertbutyl 2-(5- bromo-2-phthalimidovaleryl)-l, 3-pyridazinedicarboxylate; b) hydrogenating 1-benzyl 3-tertbutyl 2-(5-bromo-2-phthalimidovaleryl)-l,3- pyridazinedicarboxylate with 10 % palladium on carbon to form tert-butyl 2-(5-bromo-2- phthalimidovaleryl)-3-pyridazinecarboxylate (2 diastereoisomers); c) converting two diastereoisomers of tert-butyl 2-(5-bromo-2-phthalimidovaleryi)- 3-pyridazinecarboxylate to octahydro- 10-oxo-9(S)-phthalimido-6H-pyridazo[ 1 ,2- a] [ 1 ,2] diazepine- 1 (S)-carboxylic acid; d) reacting octahydro- 10-oxo-9(S)-phthalimido-6H-pyridazo [ 1 ,2-a] [ 1 ,2] diazepine- l(S)-carboxylic acid with hydrazine hydrate to obtain 9(S)-amino-octahydro-10-oxo-6H- pyridazo[ 1 ,2-a] [ 1 ,2] diazepine- 1 (S)-carboxylic acid; e) reacting 9(S)-amino-octahydro-10-oxo-6H-pyridazo[l,2-a][l,2]diazepine-l(S)- carboxylic acid with phenyldiazomethane to obtain benzyl 9(S)-amino-octahydro-10-oxo- 6H-pyridazo[ 1 ,2-a] [ 1 ,2] diazepine- 1 (S)-carboxylate; f) reacting benzyl 9(S)-amino-octahydro-10-oxo-6H-pyridazo[l,2- a][ 1,2] diazepine- l(S)-carboxylate with ethyl 2(R)-trifluoromethanesulphonyloxy-4- phenylbutanoate in the presence of triethylamine to obtain benzyl 9(S)- [ 1 (S)- ethoxycarbonyl-3-phenylpropylamino] -octahydro- 10-oxo-6H-pyridazo[ 1 ,2- a] [ 1 ,2] diazepine- 1 (S)-carboxylate; and g) hydrogenating benzyl 9(S)-[l(S)-ethoxycarbonyl-3-phenylpropylamino]- octahydro-10-oxo-6H-pyridazo[l,2-a] [1,2] diazepine- l(S)-carboxylate with 10 % palladium on carbon to obtain 9(S)-[l-(S)-ethoxycarbonyl-3-phenylpropylamino]- octahydro- 10-oxo-6H-pyridazo[ 1 ,2-a] [ 1 ,2] -diazepine- 1 (S)-carboxylic acid.

Detailed Description of the Invention In one aspect, provided herein are processes for preparing compounds of Formula I

Formula I wherein the processes comprise the steps of: a) treating 2,5-dibromovaleric acid of Formula ILT

Formula III with tert-butanol in the presence of one or more acid catalysts and optionally one or more dehydrating agents to obtain a compound of Formula IV;

Formula IV b) cyclizing the compound of Formula IV obtained in step (a) with N^N²-/)^- substituted hydrazine of Formula V,

Formula V wherein Ri and R₂ can independently be alkyl, substituted alkyl, aryl, optionally substituted aralkyl or aralkyloxycarbonyl; in the presence of one or more bases and one or more phase transfer catalysts to form a compound of Formula I, and c) isolating the compound of Formula I from the reaction mixture thereof. In a second aspect, provided herein are processes for preparing cilazapril of Formula II,

Formula II which comprise the steps of: a) treating 2,5-dibromovaleric acid with tert-butanol in presence of one or more acid catalysts and optionally one or more dehydrating agents to obtain a compound of Formula IV;

Formula IV b) cyclizing the compound of Formula IV obtained in step (a) with N¹, N²-bis substituted hydrazine in presence of one or more bases and one or more phase transfer catalysts to form a compound of Formula I; c) isolating the compound of Formula I from the reaction mixture thereof, and d) further converting the compound of Formula I to a compound of Formula II by a sequence of one or more reactions. Step (d) may be performed as per conventional process reported in U.S. Patent No. 4,512,924, which is incorporated herein by reference in its entirety. For example, a O 2005/122682

8 compound of Formula I can be converted to a compound of Formula II by processes comprising the steps of: i) reacting (S)-(3-bromopropyl)-l, 3-dioxo-2-isoindolineacetic acid with PCI₅ at room temperature followed by reaction of the product thus obtained, with tert-butyl 1- benzyloxycarbonyl-hexahydro-3-pyridazinecarboxylate to form 1 -benzyl 3-tertbutyl 2-(5- bromo-2-phthalimido valeryl)- 1 , 3 -pyridazinedicarboxylate; ii) hydrogenating 1-benzyl 3-tertbutyl 2-(5-bromo-2-phthalimidovaleryl)-l, 3- pyridazinedicarboxylate with 10 % palladium on carbon to form tert-butyl 2-(5-bromo-2- phthalimidovaleryl)-3-pyridazinecarboxylate (2 diastereoisomers); iii) converting two diastereoisomers of tert-butyl 2-(5-bromo-2- phthalimidovaleryl)-3-pyridazinecarboxylate to octahydro- 10-oxo-9(S)-phthalimido-6H- pyridazo [ 1 ,2-a] [ 1 ,2] diazepine- 1 (S)-carboxylic acid; iv) reacting octahydro- 10-oxo-9(S)-phthalimido-6H-pyridazo[l ,2-a] [ 1 ,2]diazepine- l(S)-carboxylic acid with hydrazine hydrate to obtain 9(S)-amino-octahydro-10-oxo-6H- pyridazo[l,2-a][l,2]diazepine-l(S)-carboxylic acid; v) reacting 9(S)-amino-octahydro- 10-oxo-6H-pyridazo[ 1 ,2-a] [ 1 ,2]diazepine- 1 (S)- carboxylic acid with phenyldiazomethane to obtain benzyl 9(S)-amino-octahydro-10-oxo- 6H-ρyridazo [ 1 ,2-a] [ 1 ,2] diazepine- 1 (S)-carboxylate; vi) reacting benzyl 9(S)-amino-octahydro-10-oxo-6H-pyridazo[l,2- a] [ 1 ,2]diazepine- 1 (S)-carboxylate with ethyl 2(R)-trifluoromethanesulphonyloxy-4- phenylbutanoate in the presence of triethylamine to obtain benzyl 9(S)-[1(S)- ethoxycarbonyl-3-phenylpropylamino] -octahydro- 10-oxo-6H-pyridazo[ 1 ,2- a] [ 1 ,2] diazepine- 1 (S)-carboxylate; and vii) hydrogenating benzyl 9(S)-[l(S)-ethoxycarbonyl-3-phenylpropylamino]- octahydro-10-oxo-6H-pvridazo[l,2-a][l,2]diazepine-l(S)-carboxylate with 10 % palladium on carbon to obtain 9(S)-[l-(S)-ethoxycarbonyl-3-phenylpropylamino]- octahydro- 10-oxo-6H-pyridazo [ 1 ,2-a] [ 1 ,2] -diazepine- 1 (S)-carboxylic acid (Cilazapril) . In a third aspect, provided herein are pure compounds of Formula I having purities of more than about 98 % by HPLC. Preferably, the purity is above about 98.5 % and more preferably the purity is above about 99 % by HPLC. 2,5-dibromovaleric acid of Formula ILT is prepared by a process involves treating 5-bromovaleric acid with bromine and thionyl chloride described as disclosed in US Patent No. 6,201,118, which is incorporated herein by reference in its entirety. Compounds of Formula I can be treated with tert-butanol in the presence of one or more acid catalysts and optionally one or more dehydrating agents, hi certain embodiments, dehydrating agents are not required, particularly when acid catalysts used are good dehydrating agents. Acid catalysts can include, for example, one or more mineral acids (e.g., sulphuric acid, hydrochloric acid, phosphoric acid and the like or mixtures thereof). Acidic resins can also be used as acid catalysts. Silicas, clays or mixtures thereof having strong acidic characteristics can also be used as acid catalysts.

Suitable dehydrating agents include those known to a person of ordinary skill in art, which include, for example, sulphuric acid, anhydrous magnesium sulphate and the like, or mixtures thereof. Esterification reactions can be carried out in presence of one or more solvents, including, for example, chlorinated hydrocarbons, aromatic hydrocarbons, ethers, polar aprotic solvents or mixtures thereof. In one embodiment, the reaction can be carried out in tert-butanol, more particularly using a large excess of tert-butanol. After completion of reaction, the reaction mixture can be neutralized by adding one or more bases and product can be extracted using one or more suitable organic solvents selected from the solvents in which the ester of Formula IV is soluble. Suitable bases for neutralizing reaction mixtures include, for example, one or more carbonates and or one or more bicarbonates of alkali and alkaline earth metals, or mixtures thereof. Preferred bases include, for example, one or more alkali metal carbonates. More preferably, the base used for neutralizing the reaction mass is sodium carbonate. After separating the organic layer containing the ester of Formula IV from the aqueous layer, the organic layer can be dried and concentrated under vacuum to yield compounds of Formula IV having purity greater than about 96 % as measured by GC. Cyclization of compounds of Formula IV with N¹, N²-bis substituted hydrazine of Formula V can be carried out at elevated temperatures in the presence of one or more bases containing one or more phase transfer catalysts in one or more suitable organic solvents for about 5 to about 50 hours. After completion of the reaction, the reaction mixture can be cooled and filtered. The solids can be washed with acetone and the combined acetone washings can be mixed with the filtrate. The resulting filtrate can be concentrated to dryness under vacuum and one or more suitable anti-solvents can be added to the residue. The mixture can be stirred for two hours and the precipitated solid can be filtered and washed with the anti-solvent(s) to obtain a compound of Formula I. Suitable organic solvents used in cyclization reactions can include, for example, one or more dipolar aprotic solvents (e.g., lower dialkyl ketones, lower alkyl acetates, acetonitrile, N, N-dimethylformamide and the like or mixtures thereof). Preferably, the suitable organic solvent is acetone. Organic solvents in which compounds of Formula I are insoluble, slightly soluble or sparingly soluble may be used as an antisolvent. The antisolvent can include, for example, n-hexane, n-heptane, cyclohexane or mixtures thereof. Compounds of Formula I can be further dried under vacuum at 25 °C to 40 °C to yield compounds of Formula I having purities of greater than about 98 % by HPLC. In one embodiment, the overall yields of the compound of Formula I obtained by the processes of present invention is about 98 %. The conversion of compound of Formula I to compound of Formula II can be carried out by processes known to one of ordinary skill in the art, including the process described in US Patent No. 4,512,924, which is incorporated herein by reference in its entirety. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

Examples Example 1: Preparation of tert-butyl 2,5-dibromovalerate A mixture of methylene chloride (200 mL), magnesium sulfate (93 g) and sulfuric acid (10.5 mL) was stirred at room temperature for 1 hour. A solution of 2,5- dibromovaleric acid (50 g) and tert-butyl alcohol (71.3 g) in 50 mL methylene chloride was added to the reaction mixture at room temperature. The reaction mixture was stirred in a closed vessel for about 20 to 24 hours at room temperature. The progress of reaction was monitored by Gas Chromatography (GC). After completion of the reaction, the reaction mixture was slowly added to a solution of 5 % sodium bicarbonate (1500 mL) and stirred for 1 hour. The organic layer was separated and the aqueous layer was further extracted with methylene chloride (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and then evaporated under vacuum at 40 °C to 45°C to yield title compound as an oil.

Yield: 55 g (90.5 %)

Purity: not less than 96 % w/w by GC.

Example 2: Preparation of Tert-butyl ester of N¹,N²-Bis(benzyloxycarbonyl piperazic acid of Formula I A mixture of N\N²-bis(benzyloxycarbonyl)hydrazine (40 g), acetone (400 mL), powdered potassium carbonate (73.6 g), tetrabutyl ammonium bromide (4.0 g) and 2,5- dibromovaleric acid-tert-butyl ester (72 g), as prepared above in Example 1, was heated to reflux and maintained at reflux for 20 hours. Progress of reaction was monitored by HPLC. After completion of reaction, the reaction mixture was cooled to room temperature, filtered and washed with acetone (80 mL). The mother liquor was concentrated under vacuum at 35 °C to 40 °C to yield an oily residue. Hexanes (200 mL) were added to the residue and the resultant mixture was stirred for 2 hours at room temperature, yielding a solid precipitate, which was then filtered and washed with hexanes (40 mL). The product was dried under vacuum at room temperature for 8 hours to yield the title compound.

Yield: 140 g (98 %) Purity: 98.6 % by HPLC.

Example 3: Preparation of Tert-butyl ester of N¹,N²-Bis(ethoxycarbonyl)piperazic acid of Formula I A mixture of N¹,N²-bis(ethoxycarbonyl)hydrazine (10 g), acetone (100 mL), potassium carbonate (39.2 g), tetrabutyl ammonium bromide (1.0 g) and 2,5- dibromovaleric acid-tert-butyl ester (19.8 g) was refluxed for 20 hours. The reaction mixture was cooled to room temperature, filtered and washed with acetone (20 mL). The mother liquor was concentrated under vacuum to yield the title compound as a thick oily residue. Yield: 20 g (98 %).

Claims

We claim: 1. Processes for preparing compounds of Formula I,

Formula III with tert-butanol in the presence of one or more acid catalysts and optionally one or more dehydrating agents to form a compound of Formula IV,

Formula IV b) cyclizing the compound of Formula TV by adding to the reaction mixture N^N^bis-substituted hydrazine of Formula V;

Formula V wherein Ri and R are independently selected from alkyl, substituted alkyl, aryl, optionally substituted aralkyl or aralkyloxycarbonyl; in the presence of one or more bases and one or more phase transfer catalysts to form a compound of Formula I, and c) isolating the compound of Formula I from the reaction mixture.

2. The process of claim 1, wherein the one or more acid catalysts comprise one or more mineral acids, one or more acidic resins, one or more acidic silicas, one or more acidic clays or mixtures thereof.

3. The process of claim 3, wherein the one or more mineral acids comprises sulphuric acid, hydrochloric acid, phosphoric acid or mixtures thereof.

4. The process of claim 1, wherein the one or more dehydrating agents comprise sulphuric acid, anhydrous magnesium sulphate or mixtures thereof.

5. The process of claim 1, wherein the compound of Formula IV obtained in step (a) has purity greater than about 96 %.

6. The process of claim 1, wherein the cyclization reaction in step (b) is carried out at reflux temperatures for about 5 to about 50 hours.

7. The process of claim 1, wherein the compound of Formula I is dried at a temperature of 25 °C to 40 °C under vacuum.

8. The process of claim 1, wherein the compound of Formula I has a purity of greater than about 98 %.

9. The process of claim 8, wherein the compound of Formula I has a purity of greater than about 98.5%.

10. The process of claim 1, wherein the yield of compound of Formula I is about 98 %.

11. Processes for preparing cilazapril of Formula II,

Formula II which comprises the steps of: a) forming a reaction mixture by treating 2,5-dibromovaleric acid with tert- butanol in the presence of one or more acid catalysts and optionally one or more dehydrating agents to form a compound of Formula IV,

Formula IV b) cyclizing the compound of Formula IV by adding to the reaction mixture N ,N -bis-substituted hydrazine in the presence of one or more bases and one or more phase transfer catalysts to form a compound of Formula I, c) isolating the compound of Formula I from the reaction mixture, and d) further converting compound of Formula I to compound of Formula II.

12. The process of claim 12, wherein the compound of Formula I is converted to a compound of Formula II comprising the steps of: a) reacting . (S)-(3-bromopropyl)-l, 3-dioxo-2-isoindolineacetic acid with PC1₅ at room temperature followed by reaction of the product thus obtained, with tert-butyl l-benzyloxycarbonyl-hexahydro-3-pyridazinecarboxylate to form 1- benzyl 3-tertbutyl 2-(5-bromo-2-phthalimidovaleryl)-l, 3-pyridazinedicarboxylate; b) hydrogenating 1 -benzyl 3-tertbutyl 2-(5-bromo-2-phthalimidovaleryl)- 1,3- pyridazinedicarboxylate with 10% palladium on carbon to form tert-butyl 2-(5- bromo-2-phthalimidovaleryl)-3-pyridazinecarboxylate (2 diastereoisomers); c) converting two diastereoisomers of tert-butyl 2-(5-bromo-2- phthalimidovaleryl)-3-pyridazinecarboxylate to octahydro- 10-oxo-9(S)- phthalimido-6H-pyridazo [ 1 ,2-a] [ 1 ,2] diazepine- 1 (S)-carboxylic acid; d) reacting octahydro- 10-oxo-9(S)-phthalimido-6H-pyridazo[ 1,2- a] [ 1 ,2] diazepine- 1 (S)-carboxylic acid with hydrazine hydrate to obtain 9(S)- amino-octahydro- 10-oxo-6H-pyridazo [ 1 ,2-a] [ 1 ,2] diazepine- 1 (S)-carboxylic acid; e) reacting 9(S)-amino-octahydro-10-oxo-6H-pyridazo[l,2-a][l,2]diazepine- l(S)-carboxylic acid with phenyldiazomethane to obtain benzyl 9(S)-amino- octahydro- 10-oxo-6H-pyridazo[ 1 ,2-a] [ 1 ,2] diazepine- 1 (S)-carboxylate; f) reacting benzyl 9(S)-amino-octahydro-10-oxo-6H-pyridazo[l,2- a] [1,2] diazepine- l(S)-carboxylate with ethyl 2(R)-trifluoromethanesulphonyloxy- 4-phenylbutanoate in the presence of triethylamine to obtain benzyl 9(S)-[ 1 (S)- ethoxycarbonyl-3-phenylpropylamino]-octahydro- 10-oxo-6H-pyridazo[ 1 ,2- a] [1,2] diazepine- l(S)-carboxylate; and g) hydrogenating benzyl 9(S)-[l(S)-ethoxycarbonyl-3-phenylpropylamino]- octahydro-10-oxo-6H-pyridazo[l,2-a][l,2]diazepine-l(S)-carboxylate with 10% palladium on carbon to obtain 9(S)-[l-(S)-ethoxycarbonyl-3-phenylpropylamino]- octahydro- 10-oxo-6H-pyridazo[ 1 ,2-a] [ 1 ,2] -diazepine- 1 (S)-carboxylic acid.

13. The process of claim 11 , wherein the one or more acid catalysts comprises one or more mineral acids, one or more acidic resins, one or more acidic silicas, one or more acidic clays or mixtures thereof.

14. The process of claim 13, wherein the one or more mineral acids comprises sulphuric acid, hydrochloric acid, phosphoric acid or mixtures thereof.

15. The process of claim 11 , wherein the one or more dehydrating agents comprises sulphuric acid, anhydrous magnesium sulphate or mixtures thereof.

16. The process of claim 11 , wherein the compound of Formula IV obtained in step (a) has purity greater than about 96 %.

17. The process of claim 11, wherein the cyclization reaction in step (b) is carried out at reflux temperatures for about 5 to about 50 hours.

18. The process of claim 11 , wherein the compound of Formula I is dried at a temperature of 25 °C to 40 °C under vacuum.

19. The process of claim 11, wherein the compound of Formula I has a purity of greater than about 98 %.

20. The process of claim 19, wherein the compound of Formula I has a purity of greater than about 98.5 %.

21. The process of claim 11 , wherein the yield of the compound of Formula I is about 98 %.