EP1663984A2 - Procede de preparation de benazepril - Google Patents

Procede de preparation de benazepril

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Publication number
EP1663984A2
EP1663984A2 EP04744090A EP04744090A EP1663984A2 EP 1663984 A2 EP1663984 A2 EP 1663984A2 EP 04744090 A EP04744090 A EP 04744090A EP 04744090 A EP04744090 A EP 04744090A EP 1663984 A2 EP1663984 A2 EP 1663984A2
Authority
EP
European Patent Office
Prior art keywords
formula
process according
butyl ester
amino
highly pure
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04744090A
Other languages
German (de)
English (en)
Inventor
Yatendra Kumar
Swargam Sathyanarayana
Shantanu De
Mohammad Rafeeq
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of EP1663984A2 publication Critical patent/EP1663984A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines

Definitions

  • the present invention relates to a process for preparation of benazepril of Formula I, wherein R is hydrogen or pharmacologically acceptable salt thereof by eliminating the impurity of 7-bromo analogue of benazepril of Formula la, wherein R is bromo group.
  • Benazepril is chemically (3S)-l-(carboxymethyl)-[[(lS)-l-(ethoxycarbonyl)-3- phenylpropyl] amino]-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one of Formula I as shown in the accompanied drawing. It is a well-known long acting angiotensin-converting enzyme (ACE) inhibitor primarily used for the treatment of hypertension. Benazepril was presumably reported for the first time in US Patent No. 4,410,520.
  • impurity of Formula Ila 7-bromo-l-t-butyloxycarbonylmethyl-3-(S)-amino-2,3,4,5- tetrahydro-lH-[l]benzazepin-2-one (hereinafter referred as impurity of Formula Ila) is typically present in the reaction product between 3 to 8%.
  • 4,692,522 provides benzof ⁇ ised lactams which are CCK antagonists, wherein preparation of intermediate II is disclosed.
  • the process does not disclose the synthesis of benazepril or pharmaceutically acceptable salts thereof using II.
  • the quantities of raw materials described for preparation of II are significantly high which is not economical from the commercial point of view. Summary of the Invention The present inventors now find that it is possible to prepare a highly pure benazepril of Formula I or its physiologically acceptable salts, which is devoid or essentially devoid of its 7-bromo analogue of Formula la.
  • the objective can be achieved by using pure 3-(S)-amino-l-carboxymethyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one or its 1-carboxymethyl protected derivatives of Formula II, which in turn is devoid or essentially devoid of corresponding 7-bromo analogue of Formula Ila. While working on the problem, the present inventors have removed the impurity of Formula Ila from compound of Formula II by reductive dehalo-hydrogenation using noble metal catalyst in presence of hydrogen or source of hydrogen.
  • the so-obtained compound of Formula II which does not contain any detectable quantity of the impurity of Formula Ila, is treated with compound of Formula III in presence of a base to get highly pure compound of Formula I or its physiologically accepted salts.
  • the desired compound of Formula II having no detectable impurity of Formula Ila is prepared by hydrogenating 3-azido t-butyl ester of Formula IN containing the 7-bromo-3-azido impurity of Formula IV a, up to about 8% in the presence of Raney nickel in methanol to get racemic compound of Formula II containing the impurity of Formula Ila, which after dehalo-hydrogenation over palladium on carbon in methanol gave pure racemic compound of Formula II, wherein the corresponding Ila impurity is not only removed but also essentially completely converted to the desired compound of Formula II.
  • the 7-bromo-3-azido impurity of Formula -TVa is typically present in this material in amounts of, for example, up to about 8%, for example, from about 2% to about 8%, or from about 3% to about 8%.
  • the purification of this intermediate is not carried out.
  • the processes described herein are suitable for preparing highly pure compounds when the amount of impurities (by wt. %) found in starting materials or intermediates are greater than specified herein.
  • the hydrogenation at step (a) is performed using a metal catalyst, which may be selected from palladium on carbon, platinum oxide, platinum black, palladium acetate, rhodium on carbon and the like.
  • the palladium on carbon catalyst is commercially available in several strengths ranging from 1 to 10% of palladium adsorbed on carbon.
  • the source of hydrogen can be hydrogen gas or compounds which generate hydrogen gas when used in hydrogenation.
  • the source of hydrogen can be selected from a group comprising ammonium formate, formic acid, alkali metal formats such as sodium formate, potassium formate. When such compounds are used as source of hydrogen, the reaction can be carried out at atmospheric pressure and at a lower temperature.
  • Step (a) can be conveniently carried out in an organic solvent selected from alkanols, esters and cyclic ethers or mixtures thereof.
  • the alkanols include methanol, ethanol, propanol and isopropanol or mixtures thereof.
  • the temperature range of hydrogenation reaction can be between 10 to 60°C.
  • the product (II) is then isolated from the reaction mass by filtration of catalyst followed by concentration of the solvent.
  • the residue obtained can be treated with second organic solvent in which (II) is insoluble or slightly soluble.
  • the separated (II) is then filtered and dried.
  • two changes are achieved in a single reaction. Firstly, the 3-azido groups present in the starting material as well as in the impurity are reduced to 3-amino group, and secondly the 7-bromo group present in the impurity is cleaved.
  • the impurity of Formula INa after subjecting it to hydrogenation using noble metal catalyst, gives the desired racemic compound of Formula II.
  • a second aspect provides a process for preparation of highly pure compound of Formula II having no detectable quantity of impurity of Formula Ila, wherein the process includes, a) hydrogenating a compound of Formula IN containing up to about 8% of impurity of Formula INa in presence of Raney nickel to yield the racemic compound of Formula II containing up to about 8% of impurity of Formula Ila;
  • the azido group present in the compound of Formula TV as well as the impurity of Formula IVa is reduced using Raney nickel in presence of hydrogen or a source of hydrogen.
  • the catalyst is removed, for example, by filtration, and the organic solvent is concentrated to get the racemic compound of Formula II containing the impurity of Formula Ila.
  • the reaction can be conveniently carried out in alcoholic solvents, which include, for example, methanol, ethanol and isopropanol or mixtures thereof.
  • the reduction can also be carried out in formic acid, acetic acid and the like.
  • the source of hydrogen can be selected from, for example, ammonium formate, formic acid, alkali metal formate such as sodium formate, potassium formate. When such compounds are used as source of hydrogen, the reaction can be carried out at atmospheric pressure and at a lower temperature.
  • Raney nickel as catalyst is not capable of removing the aromatic halogen and therefore step b) can be performed wherein the compound of Formula II containing about 8% of the impurity of Formula Ila is hydro genated further using noble metal catalyst.
  • the reaction conditions and isolation process are similar to that discussed in first aspect.
  • a third aspect provides processes for the preparation of highly pure compoimd of Formula I or a pharmaceutically acceptable salt, solvate and hydrate thereof, having no detectable quantity of impurity of Formula la, wherein the process includes
  • step (a) is performed using a metal catalyst, which may be selected from palladium on carbon, platinum oxide, platinum black, palladium acetate, rhodium on carbon, Raney nickel and the like.
  • the hydrogenation in step b) can be optional. For example, it must be performed when the hydrogenation in step a) is performed with Raney nickel.
  • step b) can be omitted.
  • the metal catalysts used in this step can be, for example, palladium on carbon, platinum oxide, platinum black, palladium acetate, or rhodium on carbon.
  • Racemic mixtures of prochiral amines can be converted to their diastereomeric salts by treating them with chirally active organic acids.
  • the mixture of diastereomers can then be separated by suitable means, such as crystallization or chromatography.
  • the desired diastereomer salt can then be converted back to a chiral amine by treating it with a base.
  • the chiral resolution at step c) is performed to get the desired (S) enantiomer of a compound of Formula II.
  • Organic acid used can be, for example, chirally active L-(+)- tartaric acid.
  • the organic solvent used in the salt formation can be selected from alkanol, ester, ether and ketone or a mixture thereof.
  • the alkanol can be selected' from, for example, methanol, ethanol, propanol and isopropanol or mixtures thereof. Seeding the reaction mixture with pure (S) enantiomer of a compound of Formula V followed by cooling can effect the crystallization of the pure (S) enantiomer of a compound of Formula V salt.
  • the (S) enantiomer of a compound of Formula V salt is hydrolyzed to generate the free (S) enantiomer of a compound of Formula II. This is achieved by treating (S) enantiomer of a compound of Formula V salt with a base in presence of water or an organic solvent selected from polar protic or polar aprotic solvents.
  • the pH of the reaction mass after addition of the base can be adjusted to a value between about 7.5 and about 12.
  • the base used can be an inorganic base such as sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate. Ammonia or ammonium hydroxide can also be used as bases.
  • the organic bases such as triethylamine, diisopropylamine, and cyclohexylamine can be used.
  • the product is then extracted in a halogenated organic solvent such as methylene chloride or chloroform and the solvent was removed by vacuum distillation.
  • the residue can then be isolated from the residue by addition of another solvent, selected from, for example, diethyl ether, diisopropyl ether, cyclohexane, hexane and heptane or mixtures thereof.
  • step (d) highly pure compound of Formula II is treated with a compound of Formula III in presence of an organic solvent and a base.
  • Intermediate compound of Formula III is prepared by method described in Indian patent application 374/DEL/2001.
  • the organic solvent for condensation in step d) can be selected from, for example, haloalkanes such as chloroform, carbon tetrachloride, methylene chloride, ethylene bromide and ethylene chloride or mixtures thereof.
  • the base used can be selected from, for example, pyridine and its derivatives, morpholine and its derivatives, trialkyl amines and cyclic amines or mixtures thereof.
  • Benazepril of Formula I or physiologically acceptable salts, hydrates and solvates thereof, can be prepared by treating a compound of Formula VI obtained after the reaction with an acid in an organic solvent. The protecting t-butyl group can be removed along with salt formation during this treatment.
  • the acid can be hydrochloric acid used as a gas and purged through the solution of the compound of Formula I in an organic solvent, or can be a solution of hydrogen chloride gas in an organic solvent.
  • the organic solvent can be alkanol such as methanol, ethanol, isopropanol or ester such as ethyl acetate, ethyl formate, isopropyl acetate or ketone such as acetone, or ether such as diethyl ether, diisopropyl ether, tetrahydrofuran or mixtures thereof.
  • the crude I obtained can be subjected to solvent crystallization.
  • the solvents for crystallization include alkanol such as methanol, ethanol, propanol and isopropanol or esters such as ethyl acetate, ethyl formate, butyl acetate or ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diisobutyl ketone or mixtures thereof.
  • alkanol such as methanol, ethanol, propanol and isopropanol or esters
  • esters such as ethyl acetate, ethyl formate, butyl acetate or ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diisobutyl ketone or mixtures thereof.
  • a fourth aspect provides highly pure compound of Formula II having no detectable quantity of impurity of Formula Ila as determined by a sensitive HPLC method.
  • a fifth aspect provides highly pure bena
  • a sixth aspect provides a process of preparation of benazepril of Formula I or physiologically acceptable salt, solvate and hydrate thereof wherein highly pure compound of Formula II having no detectable quantity of impurity of Formula Ila is used as an intermediate.
  • a seventh aspect provides pharmaceutical compositions comprising highly pure benazepril of Formula I or physiologically acceptable salt, solvate and hydrate thereof having no detectable quantity of impurity of Formula la along with a pharmaceutically acceptable carriers or diluents.
  • An eighth aspect provides a method of antagonizing angiotensin-converting enzyme (ACE) wherein the said method comprises of administering to a mammal in need thereof a therapeutically effective amount of highly pure benazepril of Formula I or physiologically acceptable salt, solvate and hydrate thereof having no detectable quantity of impurity of Formula la.
  • ACE angiotensin-converting enzyme
  • the column used was Kromasil C-l 8, 5 ⁇ m (150 mm x 4.6 mm).
  • the mobile phase was a gradient, which started as 60% phosphate buffer (pH 5.6) : 20% methanol : 20% tetrahydrofuran. At 20 minutes, the gradient has continuously changed to 30% buffer : 50% methanol : 20% tetrahydrofuran. At 25 minutes the gradient has continuously changed to 60% buffer : 20% methanol : 20% tetrahydrofuran, where the gradient remain until 35 minutes after the 20 ⁇ L injection. The flow rate is l.O mL/minute. Detection is at 240 mm. By these parameters the Limit of Detection for the compound of Formula Ila was
  • Blank solution was prepared by diluting 5 mL of methanol with 50 ml of a 20 : 80 water : methanol solution (diluent).
  • System suitability solution was prepared by weighing about 20 mg of 3(S)-amine-t-butyl ester working standard and transferring to a 50 mL VSL metric flask, dissolving in 5 mL of methanol, filling to the mark with diluent, and filtering. Sample solutions were similarly prepared.
  • Example 1 Preparation of Highly Pure ( ⁇ ) l-t-butyloxycarbonylmethyl-3-amino-2.3,4,5- tetrahydro-lh-[llbenzazepin-2-one of Formula II Using 10% Palladium on Carbon and Hydrogen Gas To a solution of l-t-butyloxycarbonylmethyl-3-azido-2,3,4,5-tertrahydro-lH-
  • [l]benzazepin-2-one of Formula IV (5 g, 15.8 mmol) containing 1-t- butyloxycarbonylmethyl-7-bromo-3-azido-2,3,4,5-tetrahydro-lH-[l]benzazepin -2-one of Formula IVa as impurity (7.67%) in methanol (25 ml) was added 10% palladium on carbon (0.5 g, 50% wet). The mixture was stirred at room temperature under hydrogen gas at a pressure of 40 to 50 psi with periodic venting. After 16 hours the reaction mass was filtered through celite bed to remove palladium on carbon and the filtrate was concentrated to dryness under vacuum to provide the title product as viscous oil which solidified on storage.
  • Example 3 Preparation of Highly Pure ( ⁇ ) l-t-butyloxycarbonylmethyl-3-amino-2-3,4,5- tetrahydro-lh-fT]benzazepin-2-one of Formula II Part a: preparation of ( ⁇ ) l-t-butyloxycarbonylmethyl-3-amino-2,3,4,5-tetrahydro- lh-[l]benzazepin-2-one of formula ii To a solution of l-t-butyloxycarbonylmethyl-3-azido-2,3,4,5-tertrahydro-lH- [l]benzazepin-2-one of Formula IV (5 g, 15.8 mmol) containing 1-t- butyloxycarbonylmethyl-7-bromo-3-azido-2,3,4,5-tetrahydro-lH-[l]benzazepin -2-one of Formula -Na as impurity (7.67%) in methanol (25 ml) was added Raney nickel (0.
  • the mixture was stirred at 50-55°C under hydrogen gas at a pressure of 40 to 50 psi with periodic venting. After 16 hours the reaction mass was filtered through celite bed to remove Raney nickel and the filtrate was concentrated to dryness under vacuum to provide the title product as viscous oil which solidified on keeping.
  • reaction mixture was stirred for 24 hours at 60-65°C, allowed to cool to 35-37°C and filtered at the same temperature to afford the crude product (2.75 g, 72%). This was suspended in alcohol (11 ml) and stirred at 62-65°C for 3 hours, allowed to cool to 45-47°C and filtered to afford the title compound.
  • Part B Generation of Highly Pure (S)-l-T-Butyloxycarbonylmethyl-3-Amino- 2,3,4,5-Tetrahydro-lh-[l]Benzazepin-2-One of Formula Ii From Highly Pure Tartrate Salt
  • a suspension of highly pure tartrate salt of Formula V 5.0 g, 11.36 mmol
  • water 50 ml
  • ammonium hydroxide ⁇ 5 ml
  • the solution was stirred and to it added methylene chloride (12.5 ml).
  • the reaction mixture was stirred for further 30 minutes and the layers were separated.
  • the solvent was concentrated under vacuum to get residue, which was crystallized from ether to get title compound.
  • Example 5 Preparation Of Highly Pure Benazepril Hydrochloride Part B: Preparation of Highly Pure Benazepril T-Butyl Ester of Formula Vi
  • a solution of trifluoromethane sulphonic ester of ethyl (R)-2-hydroxy-4- phenylbutyrate of Formula III in 15 ml of methylene chloride was added a solution of 5.67 gm of highly pure (S)-l-t-butyloxycarbonylmethyl-3-amino-2,3,4,5-tetrahydro-lH- [l]benzazepin-2-one of Formula II and 2.46 gm of N-methyl morpholine in methylene chloride drop-wise at room temperature.
  • reaction mixture was stirred for 2 hours. The completion of the reaction was monitored by HPLC.
  • the reaction was quenched by addition of 40 ml of water and 60 ml of methylene chloride,. The pH adjusted to 8.5 with 10% sodium bicarbonate solution. The organic layer was separated and washed twice with water. It was then dried over anhydrous sodium sulphate and solvent was distilled off to afford the title compound as an oily residue.
  • the product obtained was dissolved in methanol and treated with activated charcoal. The solution was filtered through celite bed to remove charcoal and then concentrated under vacuum to recover methanol to get a oily residue. Ethyl acetate was added to this residue drop-wise till slight haziness starts. The hazy solution was seeded with pure benazepril hydrochloride and stirred. More ethyl acetate was added drop-wise and cooled to about 5-10°C. The mixture was stirred for further 5 hours and the separated product was filtered. The slurry of wet product was stirred in ethyl acetate. The product was filtered and dried in a vacuum oven at 45-50°C to get highly pure benazepril hydrochloride.
  • Diastereoisomer ratio of SS : SR 99.36 : 0.18. Purity: 99.75%
  • Impurity la Not detected by HPLC.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention se rapporte à un procédé amélioré destiné à la préparation de bénazépril de pureté élevée selon la formule I, dans laquelle R représente hydrogène ou un sel pharmaceutiquement acceptable de ce dernier, ce procédé consistant à éliminer entièrement l'impureté constituée par l'analogue 7-bromo de bénazépril selon la formule Ia, dans laquelle R est un groupe bromo.
EP04744090A 2003-07-31 2004-07-30 Procede de preparation de benazepril Withdrawn EP1663984A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN950DE2003 2003-07-31
PCT/IB2004/002437 WO2005009972A2 (fr) 2003-07-31 2004-07-30 Procede de preparation de benazepril

Publications (1)

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EP1663984A2 true EP1663984A2 (fr) 2006-06-07

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EP04744090A Withdrawn EP1663984A2 (fr) 2003-07-31 2004-07-30 Procede de preparation de benazepril

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EP (1) EP1663984A2 (fr)
CN (1) CN1829696A (fr)
WO (1) WO2005009972A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE425146T1 (de) * 2005-05-12 2009-03-15 Lupin Ltd Verbessertes verfahren zur kristallisierung von benazeprilhydrochlorid
CN109234325A (zh) * 2017-07-11 2019-01-18 上海弈柯莱生物医药科技有限公司 一种乳酸脱氢酶在不对称合成手性羟基化合物中的应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5515418A (en) * 1978-07-17 1980-02-02 Ranbakushii Lab Ltd Manufacture of 1*44benzodiazepinn22ones
US4575503A (en) * 1983-02-10 1986-03-11 Ciba-Geigy Corporation 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids
US4692522A (en) * 1985-04-01 1987-09-08 Merck & Co., Inc. Benzofused lactams useful as cholecystokinin antagonists
US6919450B2 (en) * 2001-03-27 2005-07-19 Ranbaxy Laboratories Limited Process for the preparation of benazepril

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005009972A3 *

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WO2005009972A3 (fr) 2005-03-17
WO2005009972A2 (fr) 2005-02-03
CN1829696A (zh) 2006-09-06

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