WO2012049646A1 - Procédé de préparation d'un intermédiaire de cilazapril - Google Patents

Procédé de préparation d'un intermédiaire de cilazapril Download PDF

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Publication number
WO2012049646A1
WO2012049646A1 PCT/IB2011/054520 IB2011054520W WO2012049646A1 WO 2012049646 A1 WO2012049646 A1 WO 2012049646A1 IB 2011054520 W IB2011054520 W IB 2011054520W WO 2012049646 A1 WO2012049646 A1 WO 2012049646A1
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WO
WIPO (PCT)
Prior art keywords
formula
acid
dioxo
butoxycarbonyl
isoindolebutyric
Prior art date
Application number
PCT/IB2011/054520
Other languages
English (en)
Inventor
Harish Kumar
Sanjeev Kumar Arora
Kaptan Singh
Mohan Prasad
Sudershan Arora
Original Assignee
Ranbaxy Laboratories Limited
Parekh, Amar
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 Limited, Parekh, Amar filed Critical Ranbaxy Laboratories Limited
Publication of WO2012049646A1 publication Critical patent/WO2012049646A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a process for the preparation of optically pure (S,S)-6-t-butoxycarbonyl-hexahydro-l-pyridazinylcarbonyl-l ,3-dioxo-2-isoindolebutyric acid of Formula I, an intermediate for the preparation of cilazapril.
  • Cilazapril is chemically described as (lS,9S)-9- ⁇ [(2S)-l-ethoxy-l-oxo- 4-phenylbutan-2-yl]amino ⁇ - 10-oxooctahydro-6H-pyridazino [ 1 ,2-a] [ 1 ,2]diazepine- 1 - carboxylic acid represented by Formula II.
  • U.S. Patent No. 4,512,924 describes a process for the preparation of (S,S)-6-t- butoxycarbonyl-hexahydro-1 -pyridazinylcarbonyl-1 ,3-dioxo-2-isoindolebutyric acid of Formula I having a specific optical rotation of -54.4° by crystallization from ethyl acetate and diethyl ether.
  • Canadian Patent No. 2,500,558 describes the use of mixture of S,S and S,R-6-t- butoxycarbonyl-hexahydro- 1 -pyridazinylcarbonyl- 1 ,3-dioxo-2-isoindolebutyric acid of Formula IA;
  • the present inventors have developed such a process, which involves the preparation of optically pure (S,S)-6-t-butoxycarbonyl-hexahydro- 1 -pyridazinylcarbonyl- 1 ,3-dioxo-2- isoindolebutyric acid of Formula I, which is further converted to cilazapril.
  • the process of the present invention instead of the four diastereomers (RR, SS, RS and SR), which are obtained and separated in the reported processes, only two diastereomers (SS and SR) are formed and only the SS diastereomer is carried forward though the purification of the uncyclized acid intermediate (compound of Formula I). This process avoids additional steps, such as column chromatography, and does not involve enantiomeric separation in the final stage and it provides significant cost and productivity advantages.
  • An aspect of the present invention provides a process for the preparation of optically pure (S,S)-6-t-butoxycarbonyl-hexahydro- 1 -pyridazinylcarbonyl- 1 ,3-dioxo-2- isoindolebutyric acid of Formula I,
  • a solvent such as methanol, tetrahydrofuran or dichloromethane
  • a catalyst such as palladium/carbon
  • 6-t-Butoxycarbonyl-hexahydro-l-pyridazinyl-(N'-benzyloxycarbonyl)-carbonyl- l ,3-dioxo-2-isoindolebutyric acid benzyl ester of Formula IB as a racemic mixture known in the art may be used for preparing a mixture of S,S and S,R-6-t-butoxycarbonyl- hexahydro-l-pyridazinylcarbonyl-l,3-dioxo-2-isoindolebutyric acid of Formula IA.
  • the mixture of S,S and S,R-6-t-butoxycarbonyl-hexahydro-l-pyridazinylcarbonyl-l,3-dioxo-2- isoindolebutyric acid of Formula IA may be first treated with an ester solvent followed by treatment with a mixture of an ester solvent and an aliphatic hydrocarbon solvent.
  • ester solvent examples include ethyl acetate, methyl acetate, t-butyl acetate, for example, ethyl acetate or a mixture thereof.
  • aliphatic hydrocarbon solvent examples include hexanes, n-pentane, heptane or a mixture thereof.
  • the ratio of the ester solvent to the aliphatic hydrocarbon solvent for treatment with compound of Formula IA may vary, from about 1.5:1.0 to about 5.0:1.0. The ratio is preferably from about 2.0: 1.0 to about 3.0: 1.0.
  • the treatment with the ester solvent and the aliphatic hydrocarbon solvent may be carried out at a temperature of about 10°C to about 70°C, preferably at about 25°C to about 40°C.
  • the treatment with ester solvent and aliphatic hydrocarbon solvent may be carried for about 10 minutes to about 5 hours, preferably for about 30 minutes to about 3 hours.
  • optically pure (S,S)-6-t- butoxycarbonyl-hexahydro-l-pyridazinylcarbonyl-l,3-dioxo-2-isoindolebutyric acid of Formula I may be isolated by filtration, decantation, or a combination thereof.
  • 6-t-Butoxycarbonyl-hexahydro-l-pyridazinylcarbonyl-l,3-dioxo-2- isoindolebutyric acid of Formula I is cyclized in the presence of a solvent, for example dichloromethane, to obtain 6-t-butyl octahydro-6,10-dioxo-9-(S)-phthalimido-6H- pyridazo[l,2a][l,2]diazepine-l-(S)-carboxylate of Formula III.
  • a solvent for example dichloromethane
  • 6-t-butyl octahydro-6,10-dioxo-9-(S)-phthalimido-6H- pyridazo[l,2a][l,2]diazepine-l-(S)-carboxylate of Formula III is reduced in the presence of a solvent, for example Tetrahydrofuran, and a Lewis acid, such as borane, to obtain 6-t- butyl octahydro- 10-oxo-9-(S)-phthalimido-6H-pyridazo[ 1 ,2a] [ 1 ,2]diazepine- 1 -(S)- carboxylate of Formula IV.
  • a solvent for example Tetrahydrofuran
  • a Lewis acid such as borane
  • Formula IV 6-t-Butyl octahydro- 10-oxo-9-(S)-phthalimido-6H-pyridazo [ 1 ,2a] [ 1 ,2] diazepine- 1 - (S)-carboxylate of Formula IV is hydrolyzed to obtain 9-amino-octahydro-10-oxo-6H- pyridazo[l,2a
  • 6-t-Butoxycarbonyl-hexahydro-l-pyridazinyl-(N-benzyloxycarbonyl)-carbonyl- l,3-dioxo-2-isoindolebutyric acid benzyl ester 300 g was added to methanol (900 mL) and the solution was stirred at 25°C to 30°C to make clear solution.
  • Activated carbon 15 g was added to the above solution at 25°C to 30°C. The solution was stirred for 25 minutes and filtered. 10% palladium/carbon (60 g, 50% wet) and deionized water (75 mL) were added to the filtrate in an autoclave at 25°C to 30°C.
  • the reaction mixture was hydrogenated at a pressure of 7.0 to 7.5 kg/cm 2 at 30°C to 35°C for 3 hours.
  • the reaction mixture was filtered and washed with methanol (600 mL). Methanol was recovered completely from the reaction mixture under vacuum to obtain the title compound.
  • 6-t-Butoxycarbonyl-hexahydro- 1 -pyridazinylcarbonyl- 1 ,3 -dihydro- 1 ,3 -dioxo-2- isoindoline butyric acid (170 g) (specific optical rotation [ ⁇ X]D 25 1% Methanol: -27.3° ) was added to ethyl acetate (340 mL) at 20°C to 30°C and stirred for 15 minutes. Ethyl acetate was recovered completely under vacuum. A mixture of ethyl acetate (340 mL) and hexanes (170 mL) at 25°C to 30°C was added to the residue and stirred for 2 hours at 25°C to 30°C.
  • the solid obtained was filtered and washed with a mixture of ethyl acetate (85 mL) and hexanes (85 mL).
  • the product obtained was dried in an air oven at 35°C to 40°C until moisture content was less than 3% to obtain the title compound (48 g).
  • the reaction mixture was added to a solution of sodium bicarbonate (300 g in 3000 mL deionized water) at 0°C to 5°C. The temperature was increased to 25°C to 30°C and 10% sodium chloride solution (1500 mL) was added to the reaction mixture. The solution was stirred for 15 minutes and the layers obtained were separated. The aqueous layer was extracted with dichloromethane (600 mL). The two organic layers were combined and dichloromethane was recovered completely under vacuum to obtain the title compound (246 g).
  • 6-t-Butyl octahydro-6, 10-dioxo-9-(S)-phthalimido-6H-pyridazo[l ,2a ] [1 ,2]- diazepine-l-(S)carboxylate (240 g) was added to tetrahydrofuran (1200 mL) at 25°C to 30°C under nitrogen. The reaction mixture was stirred for 10 minutes and cooled to 0°C to 5°C under nitrogen. Borane-tetrahydrofuran complex (720 mL) was added to the reaction mixture in 60 minutes at 0°C to 5°C under nitrogen and stirred for 2 hours at 0°C to 5°C.
  • Dichloromethane (2400 mL) was added to the reaction mixture at 0°C to 5°C.
  • the temperature of the reaction mass was increased to 5°C to 10°C and hydrochloride solution (1200 mL) was slowly added.
  • the reaction mixture was stirred and the layers obtained were separated.
  • the aqueous layer was extracted with dichloromethane (240 mL).
  • the two organic layers were combined and washed with 5% sodium bicarbonate (2400 mL).
  • the solvents were recovered completely from organic layer under vacuum.
  • a mixture of denatured spirit (180 mL) and deionized water (72 mL) was added to the reaction mixture and stirred for 30 minutes.
  • Deionized water (84 mL) was added to the reaction mixture, stirred for 30 minutes and the solid obtained was filtered. The solid obtained was washed with a mixture of denatured spirit (60 mL) and deionized water (180 mL). The product was dried in an air oven at 35°C to 40°C until moisture content was less than 5% (192 g) to obtain the title compound.
  • Step 4) Preparation of t-butyl (lS,9S)-9- ⁇ [(2S)-l-ethoxy-l-oxo-4-phenylbutan-2- yl]amino ⁇ -10-oxooctahydro-6H-pyridazino[l,2-a] [l,2]diazepine-l-carboxylate:
  • reaction mixture was stirred for 15 minutes, the layers were separated and the organic layer was washed with deionized water (330 mL). Toluene was recovered completely under vacuum to get the title compound (205 g) which is used as such in situ for the next step.
  • Step 5 Preparation of crude (lS,9S)-9- ⁇ [(2S)-l-ethoxy-l-oxo-4-phenylbutan-2- yl]amino ⁇ -10-oxooctahydro-6H-pyridazino[l,2-a][l,2]diazepine-l-carboxylic acid:
  • Dichloromethane (550 mL) was added to t-butyl(lS,9S)-9- ⁇ [(2S)-l-ethoxy-l-oxo- 4-phenylbutan-2-yl]amino ⁇ - 10-oxooctahydro-6H-pyridazino[ 1 ,2-a ] [ 1 ,2]diazepine- 1 - carboxylate at 25°C to 30°C. The reaction mixture was cooled to -5°C and anhydrous HCl gas was added at -5°C to 0°C for 7 hours. Dichloromethane was recovered completely under vacuum.
  • Dichloromethane (550 mL) was added to the reaction mixture and stirred for 15 minutes, the layers were separated and aqueous layer was extracted with dichloromethane (220 mL). Dichloromethane was recovered under vacuum.
  • Denatured spirit (550 mL) was added to the reaction mixture, temperature was raised to 40°C and stirred at 35°C to 40°C.
  • Activated carbon (11 g) was added at 35°C to 40°C and stirred for 30 minutes at 35°C to 40°C. The reaction mixture was filtered and washed with denatured spirit (220 mL) at 25°C to 30°C.
  • Denatured spirit (660 mL) was recovered under vacuum and deionized water (230 mL) was added slowly in 1 hour to 2 hours at 40°C to 45 °C. The reaction mixture was stirred for 2 hours at 40°C to 45°C and cooled to 30°C to 35°C. The reaction mixture was stirred for 2 hours at 30°C to 35°C and the solid obtained was filtered. The solid obtained was washed with a mixture of denatured spirit (44 mL), deionized water (176 mL) and hexanes (110 mL) at 25°C to 30°C. The solid obtained was washed with diethyl ether (220 mL) and dried under vacuum at 30°C to 35°C until the moisture content was less than 8% to obtain the title compound (74 g).
  • Step 6 Purification of crude (lS,9S)-9- ⁇ [(2S)-l-ethoxy-l-oxo-4-phenylbutan-2- yl]amino ⁇ -10-oxooctahydro-6H-pyridazino[l,2-a] [l,2]diazepine-l-carboxylic acid: Denatured spirit (325 mL) was added to (lS,9S)-9- ⁇ [(2S)-l-ethoxy-l-oxo-4- phenylbutan-2-yl] amino ⁇ - 10-oxooctahydro-6H-pyridazino[ 1 ,2-a ] [ 1 ,2] diazepine- 1 - carboxylic acid (65 g) at 25°C to 30°C.
  • the temperature was increased to 40°C and stirred at 35°C to 40°C.
  • Activated carbon (3.6 g) was added at 30°C to 40°C.
  • the reaction mixture was stirred for 30 minutes, filtered and washed with denatured spirit (130 mL).
  • Denatured spirit (390 mL) was recovered under vacuum and deionized water (140 mL) was added slowly in 1 hour to 2 hours at 40°C to 45°C.
  • the reaction mixture was cooled to 35°C, stirred for 2 hours and filtered at 30°C to 35°C.
  • the solid obtained was washed with a mixture of previously chilled denatured spirit (26 mL) and deionized water (104 mL) at 5°C to 8°C.
  • the solid obtained was dried under vacuum at 30°C to 35°C until the water content was 3.5% to 4.5% to obtain the title compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un procédé de préparation de (S,S)-6-t-butoxycarbonyl-hexahydro-1-pyridazinylcarbonyl-1,3-dioxo-2-acide isoindolebutyrique optiquement pur, intermédiaire dans la préparation du cilazapril.
PCT/IB2011/054520 2010-10-12 2011-10-12 Procédé de préparation d'un intermédiaire de cilazapril WO2012049646A1 (fr)

Applications Claiming Priority (2)

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IN2429/DEL/2010 2010-10-12
IN2429DE2010 2010-10-12

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109438449A (zh) * 2018-11-16 2019-03-08 厦门医学院 一种含六氢哒嗪酸结构的西拉普利的合成方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4512924A (en) 1982-05-12 1985-04-23 Hoffmann-La Roche Inc. Pyridazo[1,2-a][1,2]diazepines
WO1999055724A1 (fr) 1998-04-27 1999-11-04 Hoechst Marion Roussel NOUVEAUX DERIVES DE L'ACIDE OCTAHYDRO-6,10-DIOXO-6H-PYRIDAZINO[1,2-a] [1,2] DIAZEPINE-1-CARBOXYLIQUE, LEUR PROCEDE DE PREPARATION ET LEUR APPLICATION A LA PREPARATION DE COMPOSES THERAPEUTIQUEMENT ACTIFS
US6201118B1 (en) 1998-08-19 2001-03-13 Vertex Pharmaceuticals Inc. Process for forming an N-acylated, N,N-containing bicyclic ring from piperazic acid or an ester thereof especially useful as an intermediate in the manufacture of a caspase inhibitor
WO2001056997A1 (fr) 2000-02-04 2001-08-09 Lonza Ag Procede de preparation de derives d'acide piperazique de ce dernier
WO2004078761A1 (fr) 2003-03-06 2004-09-16 Ranbaxy Laboratories Limited Cilazapril de purete enantiomerique et procede pour sa preparation
WO2005122682A2 (fr) 2004-06-18 2005-12-29 Ranbaxy Laboratories Limited Procede de preparation d'esters d'acide piperazique
CA2500558A1 (fr) 2005-03-10 2006-09-10 Apotex Pharmachem Inc. Methode de preparation de composes bicycliques du type aza et utilisation connexe desdits composes dans la synthese de cilazapril

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4512924A (en) 1982-05-12 1985-04-23 Hoffmann-La Roche Inc. Pyridazo[1,2-a][1,2]diazepines
WO1999055724A1 (fr) 1998-04-27 1999-11-04 Hoechst Marion Roussel NOUVEAUX DERIVES DE L'ACIDE OCTAHYDRO-6,10-DIOXO-6H-PYRIDAZINO[1,2-a] [1,2] DIAZEPINE-1-CARBOXYLIQUE, LEUR PROCEDE DE PREPARATION ET LEUR APPLICATION A LA PREPARATION DE COMPOSES THERAPEUTIQUEMENT ACTIFS
US6201118B1 (en) 1998-08-19 2001-03-13 Vertex Pharmaceuticals Inc. Process for forming an N-acylated, N,N-containing bicyclic ring from piperazic acid or an ester thereof especially useful as an intermediate in the manufacture of a caspase inhibitor
WO2001056997A1 (fr) 2000-02-04 2001-08-09 Lonza Ag Procede de preparation de derives d'acide piperazique de ce dernier
WO2004078761A1 (fr) 2003-03-06 2004-09-16 Ranbaxy Laboratories Limited Cilazapril de purete enantiomerique et procede pour sa preparation
WO2005122682A2 (fr) 2004-06-18 2005-12-29 Ranbaxy Laboratories Limited Procede de preparation d'esters d'acide piperazique
CA2500558A1 (fr) 2005-03-10 2006-09-10 Apotex Pharmachem Inc. Methode de preparation de composes bicycliques du type aza et utilisation connexe desdits composes dans la synthese de cilazapril

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ATTWOOD M R ET AL: "THE DESIGN AND SYNTHESIS OF THE ANGIOTENSIN CONVERTING ENZYME INHIBITOR CILAZAPRIL AND RELATED BICYCLIC COMPOUNDS", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, CHEMICAL SOCIETY, LETCHWORTH; GB, 1 January 1986 (1986-01-01), pages 1011 - 1019, XP000196065, ISSN: 0300-922X, DOI: 10.1039/P19860001011 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109438449A (zh) * 2018-11-16 2019-03-08 厦门医学院 一种含六氢哒嗪酸结构的西拉普利的合成方法
CN109438449B (zh) * 2018-11-16 2020-08-11 厦门医学院 一种含六氢哒嗪酸结构的西拉普利的合成方法

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