106927-97-3

Usage

Uses

Used in Pharmaceutical Industry:
(1S,9R)-tert-butyl 9-(1,3-dioxoisoindolin-2-yl)-10-oxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1 is used as a precursor or building block in the synthesis of novel pharmaceutical compounds for various therapeutic applications. Its unique molecular architecture allows for the modulation of specific biological pathways or targeting of particular diseases, making it a valuable asset in drug discovery and development processes.
Used in Medicinal Chemistry Research:
In the field of medicinal chemistry, (1S,9R)-tert-butyl 9-(1,3-dioxoisoindolin-2-yl)-10-oxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1 serves as a subject of study for understanding its potential pharmacological activities and interactions with biological systems. Researchers are interested in exploring its properties to identify new therapeutic opportunities and enhance the efficacy of existing treatments.

Synthetic route

(1S,9S)-t-butyl 1,2,3,4,7,8,9,10-octahydro-6,10-dioxo-9-phthalimidopyridazino<1,2-a><1,2>diazepine-1-carboxylate (106928-72-7) → (1S,9S)-t-butyl octahydro-10-oxo-9-phthalimido-6H-pyridazino<1,2-a><1,2>diazepine-1-carboxylate (106927-97-3)

Conditions	Yield
With borane-THF In tetrahydrofuran for 3h; Ambient temperature;	90%
With borane-THF In tetrahydrofuran at 0 - 5℃; for 3h; Inert atmosphere;

(S)-4-Chlorocarbonyl-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid benzyl ester (88767-16-2) → (1S,9S)-t-butyl octahydro-10-oxo-9-phthalimido-6H-pyridazino<1,2-a><1,2>diazepine-1-carboxylate (106927-97-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: NaHCO3 / toluene; H2O / 17 h / Ambient temperature 2: H2 / 5percent Pd-C / dimethylformamide / 18 h 3: SOCl2 / CH2Cl2 / 4 h / Ambient temperature 4: 90 percent / 1M borane in THF / tetrahydrofuran / 3 h / Ambient temperature View Scheme

(S,S)-5-(6-(tert-butoxycarbonyl)tetrahydropyridazin-1(2H)-yl)-4-(1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid (88767-18-4) → (1S,9S)-t-butyl octahydro-10-oxo-9-phthalimido-6H-pyridazino<1,2-a><1,2>diazepine-1-carboxylate (106927-97-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: SOCl2 / CH2Cl2 / 4 h / Ambient temperature 2: 90 percent / 1M borane in THF / tetrahydrofuran / 3 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: thionyl chloride / dichloromethane / 3 h / 10 - 15 °C / Inert atmosphere 2: borane-THF / tetrahydrofuran / 3 h / 0 - 5 °C / Inert atmosphere View Scheme

(S)-2-[(S)-4-Benzyloxycarbonyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyryl]-tetrahydro-pyridazine-1,3-dicarboxylic acid 1-benzyl ester 3-tert-butyl ester (106860-13-3) → (1S,9S)-t-butyl octahydro-10-oxo-9-phthalimido-6H-pyridazino<1,2-a><1,2>diazepine-1-carboxylate (106927-97-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: H2 / 5percent Pd-C / dimethylformamide / 18 h 2: SOCl2 / CH2Cl2 / 4 h / Ambient temperature 3: 90 percent / 1M borane in THF / tetrahydrofuran / 3 h / Ambient temperature View Scheme

(3S)-N1-benzyloxycarbonyl-piperazic acid tert-butyl ester (72064-51-8) → (1S,9S)-t-butyl octahydro-10-oxo-9-phthalimido-6H-pyridazino<1,2-a><1,2>diazepine-1-carboxylate (106927-97-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: NaHCO3 / toluene; H2O / 17 h / Ambient temperature 2: H2 / 5percent Pd-C / dimethylformamide / 18 h 3: SOCl2 / CH2Cl2 / 4 h / Ambient temperature 4: 90 percent / 1M borane in THF / tetrahydrofuran / 3 h / Ambient temperature View Scheme

(2S)-4-benzyloxicarbonyl-2-phthalimidobutanoic acid (88784-33-2) → (1S,9S)-t-butyl octahydro-10-oxo-9-phthalimido-6H-pyridazino<1,2-a><1,2>diazepine-1-carboxylate (106927-97-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: SOCl2 / toluene 2: NaHCO3 / toluene; H2O / 17 h / Ambient temperature 3: H2 / 5percent Pd-C / dimethylformamide / 18 h 4: SOCl2 / CH2Cl2 / 4 h / Ambient temperature 5: 90 percent / 1M borane in THF / tetrahydrofuran / 3 h / Ambient temperature View Scheme

5-(2-((benzyloxy)carbonyl)-6-(tert-butoxycarbonyl)tetrahydropyridazin-1(2H)-yl)-4-(1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid → (1S,9S)-t-butyl octahydro-10-oxo-9-phthalimido-6H-pyridazino<1,2-a><1,2>diazepine-1-carboxylate (106927-97-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogen / palladium 10% on activated carbon / water; methanol / 3 h / 30 - 35 °C / 5149.01 - 5516.79 Torr / Autoclave 2: thionyl chloride / dichloromethane / 3 h / 10 - 15 °C / Inert atmosphere 3: borane-THF / tetrahydrofuran / 3 h / 0 - 5 °C / Inert atmosphere View Scheme

(1S,9S)-t-butyl octahydro-10-oxo-9-phthalimido-6H-pyridazino<1,2-a><1,2>diazepine-1-carboxylate (106927-97-3) → 9-amino-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1-(S)carboxylic acid t-butyl ester (106860-20-2)

Conditions	Yield
With hydrazine hydrate In ethanol for 1h; Ambient temperature;
With hydrazine hydrate In ethanol at 25 - 30℃; Inert atmosphere;

(1S,9S)-t-butyl octahydro-10-oxo-9-phthalimido-6H-pyridazino<1,2-a><1,2>diazepine-1-carboxylate (106927-97-3) → cilazapril (88768-40-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrazine hydrate / ethanol / 1 h / Ambient temperature 2: 10percent aq. Na2CO3 / CH2Cl2 / 5 h / Ambient temperature 3: 91 percent / HCl / CH2Cl2 / 16 h / Ambient temperature View Scheme
Multi-step reaction with 3 steps 1.1: hydrazine hydrate / ethanol / 25 - 30 °C / Inert atmosphere 2.1: 4-methyl-morpholine / toluene / 25 - 80 °C 3.1: hydrogenchloride / dichloromethane / 7 h / -5 - 0 °C 3.2: pH 4.4 - 4.5 View Scheme

(1S,9S)-t-butyl octahydro-10-oxo-9-phthalimido-6H-pyridazino<1,2-a><1,2>diazepine-1-carboxylate (106927-97-3) → (1S,9S)-t-butyl 9-<(1S)-ethoxycarbonyl-3-phenylpropylamino>octahydro-10-oxo-6H-pyridazino<1,2-a><1,2>diazepine-1-carboxylate (106860-19-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / ethanol / 1 h / Ambient temperature 2: 10percent aq. Na2CO3 / CH2Cl2 / 5 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: hydrazine hydrate / ethanol / 25 - 30 °C / Inert atmosphere 2: 4-methyl-morpholine / toluene / 25 - 80 °C View Scheme

Upstream product

• 106928-72-7 (1S,9S)-t-butyl 1,2,3,4,7,8,9,10-octahydro-6,10-dioxo-9-phthalimidopyridazino<1,2-a><1,2>diazepine-1-carboxylate 
• 88767-16-2 (S)-4-Chlorocarbonyl-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid benzyl ester 
• 88767-18-4 (S,S)-5-(6-(tert-butoxycarbonyl)tetrahydropyridazin-1(2H)-yl)-4-(1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid 
• 106860-13-3 (S)-2-[(S)-4-Benzyloxycarbonyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyryl]-tetrahydro-pyridazine-1,3-dicarboxylic acid 1-benzyl ester 3-tert-butyl ester 
• 72064-51-8 (3S)-N¹-benzyloxycarbonyl-piperazic acid tert-butyl ester 
• 88784-33-2 (2S)-4-benzyloxicarbonyl-2-phthalimidobutanoic acid 

Downstream Products

• 106860-19-9 (1S,9S)-t-butyl 9-<(1S)-ethoxycarbonyl-3-phenylpropylamino>octahydro-10-oxo-6H-pyridazino<1,2-a><1,2>diazepine-1-carboxylate 
• 88768-40-5 cilazapril 
• 106860-20-2 9-amino-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1-(S)carboxylic acid t-butyl ester 

Relevant academic research and scientific papers

PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF CILAZAPRIL

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.

The Design and Synthesis of the Angiotensin Converting Enzyme Inhibitor Cilazapril and Related Bicyclic Compounds

The postulated binding functions for the active site of Angiotensin Converting Enzyme (A.C.E.), derived in an earlier study, have made possible the design of improved inhibitors.Consequently, (1S,9S)-9-octahydro-10-oxo-6H-pyridazodiazepine-1-carboxylic acid (Cilazapril), and related compounds, have been synthesized.They are very active inhibitors of A.C.E. and are highly potent antihypertensives in vivo.