WO2012049646A1 - Process for the preparation of an intermediate of cilazapril - Google Patents

Process for the preparation of an intermediate of 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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Prior art keywords
formula
acid
dioxo
butoxycarbonyl
isoindolebutyric
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PCT/IB2011/054520
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French (fr)
Inventor
Harish Kumar
Sanjeev Kumar Arora
Kaptan Singh
Mohan Prasad
Sudershan Arora
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Ranbaxy Laboratories Limited
Parekh, Amar
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Publication of WO2012049646A1 publication Critical patent/WO2012049646A1/en

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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.

Abstract

The present invention relates to a process for the preparation of optically pure (S,S)-6-t-butoxycarbonyl-hexahydro-1-pyridazinylcarbonyl-1,3-dioxo-2-isoindolebutyric acid, an intermediate for the preparation of cilazapril.

Description

PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF
CILAZAPRIL
Field of the Invention
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.
Background of the Invention
Optically pure (S,S)-6-t-butoxycarbonyl-hexahydro-l-pyridazinylcarbonyl-l,3- dioxo-2-isoindolebutyric acid of Formula I,
Figure imgf000002_0001
Formula I
is a useful intermediate for the preparation of cilazapril, an angiotensin converting enzyme (ACE) inhibitor. 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.
Figure imgf000002_0002
Formula II
Processes for the preparation of the compound of Formula I are described in U.S. Patent Nos. 4,512,924 and 6,201,118; PCT Publication Nos. WO 01/56997; WO
99/55724; WO 2005/122682; and Canadian Patent No. 2,500,558.
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;
Figure imgf000003_0001
Formula IA
for the preparation of cilazapril and involves enantiomeric separation in the later stage.
Summary of the Invention
Reported processes for the preparation of (S,S)-6-t-butoxycarbonyl-hexahydro-l- pyridazinylcarbonyl-l,3-dioxo-2-isoindolebutyric acid of Formula I are commercially unviable in one or more ways. They involve the use of low boiling, costly and highly inflammable solvents, use column chromatography at industrial scale, or enantiomeric separation at later, value-added stages, leading to unacceptable losses. Thus there is a need for a commercially viable process that can be easily used at commercial scale. 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. In 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. Detailed Description of the Invention
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,
Figure imgf000004_0001
Formula I
wherein, the process comprises:
a) treating a mixture of S,S and S,R-6-t-butoxycarbonyl-hexahydro-l- pyridazinylcarbonyl-l ,3-dioxo-2-isoindolebutyric acid of Formula IA with an ester solvent and an aliphatic hydrocarbon solvent; and
b) isolating optically pure (S,S)-6-t-butoxycarbonyl-hexahydro-l- pyridazinylcarbonyl-l ,3-dioxo-2-isoindolebutyric acid of Formula I from the reaction mixture thereof.
The mixture of S,S and S,R-6-t-butoxycarbonyl-hexahydro-l-pyridazinylcarbonyl- l,3-dioxo-2-isoindolebutyric acid of Formula I A
Figure imgf000004_0002
Formula I A
is prepared by the hydrogenation of 6-t-butoxycarbonyl-hexahydro-l-pyridazinyl-(N - benzyloxycarbonyl)-carbonyl-l,3-dioxo-2-isoindolebutyric acid benzyl ester of Formula
IB
Figure imgf000005_0001
Formula IB
in the presence of a solvent, such as methanol, tetrahydrofuran or dichloromethane and 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.
Examples of the ester solvent are ethyl acetate, methyl acetate, t-butyl acetate, for example, ethyl acetate or a mixture thereof. Examples of the aliphatic hydrocarbon solvent are 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. The 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.
(S,S)-6-t-Butoxycarbonyl-hexahydro- 1 -pyridazinylcarbonyl- 1 ,3-dioxo-2- isoindolebutyric acid of Formula I
Figure imgf000006_0001
Formula I
may be further converted to cilazapril of Formula II using the processes described in PCT Publication Nos. WO 2004/078761 and WO 2005/122682; Canadian Patent No.
2,500,558; and U.S. Patent No. 4,512,924.
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.
Figure imgf000006_0002
Formula III
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.
Figure imgf000006_0003
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|[l,2]diazepine-l-(S)carboxylic acid t-butyl ester of Formula V.
Figure imgf000007_0001
Formula V
9-Amino-octahydro-10-oxo-6H-pyridazo[l,2a][l ,2]diazepine-l-(S)carboxylic acid t-butyl ester of Formula V is reacted with Ethyl (+)-R-2-4-nitrobenzene-sulfonyloxy-4- phenyl-butyrate of Formula VI
Figure imgf000007_0002
Formula VI
in the presence of a base, for example N-methylmorpholine, to obtain t-butyl (lS,9S)-9- { [(2S)- 1 -ethoxy- 1 -oxo-4-phenylbutan-2-yl] amino } - 10-oxooctahydro-6H-pyridazino[ 1 ,2- a][l,2]diazepine-l-carboxylate of Formula VII.
Figure imgf000007_0003
Formula VII t-Butyl ( 1 S,9S)-9- { [(2S)- 1 -ethoxy- 1 -oxo-4-phenylbutan-2-yl] amino } - 10- oxooctahydro-6H-pyridazino[l,2-a][l,2]diazepine-l-carboxylate of Formula VII is deprotected and optionally further purified to obtain ( lS,9S)-9-{[(2S)-l -ethoxy- l-oxo-4- phenylbutan-2-yl] amino} -10-oxooctahydro-6H-pyridazino[ 1 ,2-a] [ 1 ,2]diazepine-l - carboxylic acid, cilazapril of Formula II.
In the following section, embodiments are described by way of examples to illustrate the process of invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
EXAMPLES
Example 1 : Preparation of (S,S -6-t-Butoxycarbonyl-Hexahvdro-l-Pyridazinylcarbonyl- 1 ,3-Dioxo-2-Isoindolebutyric Acid
Step 1) Preparation of 6-t-butoxycarbonyl-hexahydro-l-pyridazinylcarbonyl-l,3- dioxo-2-isoindolebutyric acid
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/cm2 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.
Step 2) Preparation of (S,S)-6-t-butoxycarbonyl-hexahydro-l-pyridazinyl carbonyl- l,3-dioxo-2-isoindolebutyric acid
6-t-Butoxycarbonyl-hexahydro- 1 -pyridazinylcarbonyl- 1 ,3 -dihydro- 1 ,3 -dioxo-2- isoindoline butyric acid (170 g) (specific optical rotation [<X]D25 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).
Chromatographic Purity: 93.04%
Specific Optical Rotation [a]D 25 1% Methanol: -51.8°
Example 2: Preparation of Cilazapril
Step 1) Preparation of 6-t-butyl octahydro-6,10-dioxo-9-(S)-phthalimido-6H- pyridazo[l,2a] [l,2]diazepine-l-(S)carboxylate:
(S,S)-6-t-Butoxycarbonyl-hexahydro-l-pyridazinylcarbonyl-l,3-dioxo-2- isoindolebutyric acid (300 g) was added to dichloromethane (2400 mL) and stirred for 10 minutes to make a clear solution at 25°C to 30°C under nitrogen. The reaction mixture was cooled to 10°C to 15°C. A mixture of thionyl chloride (104.3 g) and dichloromethane (300 mL) was slowly added to the reaction mixture in 60 minutes at 10°C to 15°C under nitrogen. The reaction mixture was stirred for 2 hours. 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).
Step 2) Preparation of 6-t-butyl octahydro-10-oxo-9-(S)-phthalimido-6H- pyridazo [1,2a] [1 ,2] diazepine-1 -(S)carboxylate:
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.
Chromatographic Purity: 97.45%
Step 3) Preparation of 9-amino-octahydro-10-oxo-6H-pyridazo[l,2a] [l,2]diazepine-l- (S)carboxylic acid t-butyl ester:
6-t-Butyl octahydro- 10-oxo-9-(S)-phthalimido-6H-pyridazo[ 1 ,2a | [ 1 ,2]diazepine- 1 - (S)carboxylate (170 g) was dissolved in denatured spirit (1700 mL) and hydrazine hydrate (51 g) was added at 25°C to 30°C under nitrogen. The reaction mixture was stirred at 25°C to 30°C for 2 hours to 6 hours. Denatured spirit was recovered completely under vacuum and 2N acetic acid (1700 mL) was added. The reaction mixture was stirred for 5 hours, filtered and washed with deionized water (850 mL). The pH of the filtrate was adjusted to 7.9 to 8.0 with 2N sodium hydroxide (1690 mL), and dichloromethane (850 mL) was added. The reaction mixture was stirred for 15 minutes and the layers obtained were separated. The aqueous layer was extracted with dichloromethane (850 mL). The two layers were combined and dried over anhydrous sodium sulphate (34 g).
Dichloromethane was recovered completely under vacuum to get the title compound (110 g) which is used as such in situ for the next step.
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:
Toluene (550 mL), ethyl (+)-R-2-(4-nitrobenzene-sulfonyloxy)-4-phenyl butyrate
(168 g) and N-methyl morphline (47 g) were added to 9-amino-octahydro-10-oxo-6H- pyridazo[l,2a][l,2]diazepine-l-(S)carboxylic acid t-butyl ester, obtained above, at 25°C to 30°C. The temperature was increased to 75°C and stirred at 75°C to 80°C. The reaction mixture was cooled to 25 °C to 30°C and deionized water (330 mL) was added. The pH was adjusted to 8.5 to 8.8 with 2N aqueous sodium carbonate solution (350 mL). The 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. Diethyl ether (550 mL) and deionized water (550 mL) were added to the reaction mixture, stirred for 15 minutes and the layers obtained were separated. The aqueous layer was extracted with diethyl ether. The two organic layers were combined and washed with IN hydrochloride solution (363 mL). The two aqueous layers were combined and the pH was adjusted to 4.4 to 4.5 with 10% sodium hydroxide solution (350 mL) at 25°C to 30°C.
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.
Yield: 52 g
Chromatographic purity: 99.90%
Specific optical rotation [a]D 25 1% Methanol: -395.0°

Claims

We claim
1. A process for the preparation of optically pure (l S,9S)-9-{ [(2S)-l-ethoxy-l -oxo-4- phenylbutan-2-yl] amino} - 10-oxooctahydro-6H-pyridazino[l ,2-a] [1 ,
2]diazepine-l - carboxylic acid of Formula II
Figure imgf000013_0001
Formula II wherein the process comprises: a) treating a mixture of S,S and S,R-6-t-butoxycarbonyl-hexahydro-l- pyridazinylcarbonyl-l ,3-dioxo-2-isoindolebutyric acid of Formula IA with an ester solvent and an aliphatic hydrocarbon solvent, and;
COOH
O 0 COOtBu Formula IA
b) isolating optically pure (S,S)-6-t-butoxycarbonyl-hexahydro-l- pyridazinylcarbonyl- 1 ,3 -dioxo-2-isoindolebutyric acid of Formula I from the reaction mixture thereof.
Figure imgf000013_0002
Formula I 2. A process according to claim 1, wherein mixture of S,S and S,R-6-t- butoxycarbonyl-hexahydro-1 -pyridazinylcarbonyl- 1, 3 -dioxo-2-isoindolebutyric acid is first treated with ester solvent followed by treatment with an ester solvent and an aliphatic hydrocarbon solvent.
3. A process according to claims 1 or 2, wherein the ester solvent is ethyl acetate, methyl acetate or t-butyl acetate.
4. A process according to claim 3, wherein the ester solvent is ethyl acetate.
5. A process according to claims 1 or 2, wherein the aliphatic hydrocarbon solvent is hexanes, n-pentane or heptane.
6. A process according to claim 5, wherein the aliphatic hydrocarbon solvent is hexanes.
PCT/IB2011/054520 2010-10-12 2011-10-12 Process for the preparation of an intermediate of cilazapril WO2012049646A1 (en)

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