2224-77-3

Usage

Uses

Used in Pharmaceutical Industry:
1-(4-CHLOROPHENYL)-3-OXOISOINDOLINE is used as an intermediate in the synthesis of Chlorthalidone (C427500), a diuretic and antihypertensive agent. It plays a vital role in the development of medications aimed at treating conditions such as high blood pressure and edema by facilitating the excretion of excess water and salt from the body.
As an intermediate, 1-(4-CHLOROPHENYL)-3-OXOISOINDOLINE is essential in the pharmaceutical industry for the production of Chlorthalidone, which is widely used to manage hypertension and related conditions. Its chemical properties and structure make it a suitable candidate for further chemical reactions and modifications, leading to the development of new therapeutic agents with improved efficacy and safety profiles.

Synthetic route

4-(4-chlorophenyl)-1H-2,3-benzoxazin-1-one (2224-83-1) → 3-(4'-chlorophenyl)-1-isoindolinone (2224-77-3)

Conditions	Yield
With acetic acid; zinc at 70 - 75℃;	91%
With acetic acid; zinc for 4h; Heating;	65%

(4-chlorophenyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methanaminium chloride + 2-bromobenzoic acid chloride (7154-66-7) → 3-(4'-chlorophenyl)-1-isoindolinone (2224-77-3)

Conditions	Yield
With [2,2]bipyridinyl; caesium carbonate; copper dichloride In water; 1,2-dichloro-ethane; toluene at 50℃; Inert atmosphere;	73%

3-Chlor-isoindolin-1-on (30696-82-3) + chlorobenzene (108-90-7) → 3-(4'-chlorophenyl)-1-isoindolinone (2224-77-3)

Conditions	Yield
With aluminium trichloride for 24h; Ambient temperature;	60%

2-(4-chlorobenzoyl)benzoic acid (85-56-3) → 3-(4'-chlorophenyl)-1-isoindolinone (2224-77-3)

Conditions	Yield
With formic acid; formamide at 140 - 150℃; for 6h;	60%
Multi-step reaction with 2 steps 1: sodium hydroxide; hydroxylamine hydrochloride / methanol / 25 - 65 °C 2: zinc; acetic acid / 70 - 75 °C View Scheme

chlorthalidon (77-36-1) → 3-(4'-chlorophenyl)-1-isoindolinone (2224-77-3) + 2-[(hydroxyamino)carbonyl]benzoic acid (17698-09-8) + 3-phenyl-2,3-dihydro-isoindol-1-one (835-18-7)

Conditions	Yield
With oxygen In methanol at 20℃; for 72h; Product distribution; Quantum yield; Further Variations:; Reagents; sensitizers and scavengers; Decomposition; photolysis; UV-irradiation;	A 46% B 12% C 42%

phthalimide (136918-14-4) → 3-(4'-chlorophenyl)-1-isoindolinone (2224-77-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 71 percent / aq. ammonium chloride, magnesium / methanol / 4 h / Heating 2: 90 percent / thionyl chloride / CHCl3 / 30 h / Ambient temperature 3: 60 percent / AlCl3 / 24 h / Ambient temperature View Scheme

3-hydroxy-2,3-dihydro-isoindol-1-one (26486-93-1) → 3-(4'-chlorophenyl)-1-isoindolinone (2224-77-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / thionyl chloride / CHCl3 / 30 h / Ambient temperature 2: 60 percent / AlCl3 / 24 h / Ambient temperature View Scheme

N-((4-chlorophenyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-2-methylpropane-2-sulfinamide → 3-(4'-chlorophenyl)-1-isoindolinone (2224-77-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / hexane; 1,4-dioxane / 0.17 h / 20 °C 2: copper dichloride; caesium carbonate; [2,2]bipyridinyl / toluene; 1,2-dichloro-ethane; water / 50 °C / Inert atmosphere View Scheme

(±)-N-(4-chlorobenzylidene)-2-methylpropane-2-sulfinamide → 3-(4'-chlorophenyl)-1-isoindolinone (2224-77-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: tricyclohexylphosphine tetrafluoroborate; copper(ll) sulfate pentahydrate; benzylamine / toluene; water / 0.5 h 2: hydrogenchloride / hexane; 1,4-dioxane / 0.17 h / 20 °C 3: copper dichloride; caesium carbonate; [2,2]bipyridinyl / toluene; 1,2-dichloro-ethane; water / 50 °C / Inert atmosphere View Scheme

3-(4'-chlorophenyl)-1-isoindolinone (2224-77-3) + methyl trifluoromethanesulfonate (333-27-7) → 3-Methoxy-1-(4-chlorophenyl)-1H-isoindolium-trifluoromethansulfonat (83889-44-5)

Conditions	Yield
In dichloromethane for 72h; Ambient temperature;	87%
In dichloromethane a) reflux, 30 min, b) room temperature, 48 h;	87%

3-(4'-chlorophenyl)-1-isoindolinone (2224-77-3) → 3-(3'- chlorosulphonyl-4'-chlorophenyl)phthalimidine

Conditions	Yield
Stage #1: 3-(4'-chlorophenyl)-1-isoindolinone With chlorosulfonic acid at 0 - 80℃; Stage #2: With trichlorophosphate at 75 - 80℃; for 2h;

3-(4'-chlorophenyl)-1-isoindolinone (2224-77-3) → chlorthalidon (77-36-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: chlorosulfonic acid / 0 - 80 °C 1.2: 2 h / 75 - 80 °C 2.1: ammonium hydroxide / acetone; water / 0 - 5 °C 3.1: dihydrogen peroxide; sodium hydroxide / water / 0 - 26 °C View Scheme

3-(4'-chlorophenyl)-1-isoindolinone (2224-77-3) → 3-(3'-sulfamyl-4'-chlorophenyl)phthalimidine

Conditions	Yield
Multi-step reaction with 2 steps 1.1: chlorosulfonic acid / 0 - 80 °C 1.2: 2 h / 75 - 80 °C 2.1: ammonium hydroxide / acetone; water / 0 - 5 °C View Scheme

Upstream product

• 2224-83-1 4-(4-chlorophenyl)-1H-2,3-benzoxazin-1-one 
• 30696-82-3 3-Chlor-isoindolin-1-on 
• 108-90-7 chlorobenzene 
• 85-56-3 2-(4-chlorobenzoyl)benzoic acid 
• 136918-14-4 phthalimide 
• 7154-66-7 2-bromobenzoic acid chloride 
• 26486-93-1 3-hydroxy-2,3-dihydro-isoindol-1-one 
• 77-36-1 chlorthalidon 

Downstream Products

• 82875-49-8 3-(3'-sulfamyl-4'-chlorophenyl)phthalimidine 
• 77-36-1 chlorthalidon 
• 83889-44-5 3-Methoxy-1-(4-chlorophenyl)-1H-isoindolium-trifluoromethansulfonat 

Relevant academic research and scientific papers

IMPROVED PROCESS FOR THE PREPARATION OF CHLORTHALIDONE

The present invention relates to methods for preparing chlorthalidone. In particular, the disclosed processes are feasible on an industrial scale and provide substantially pure chlorthalidone.

Exploiting the Bis-Nucleophilicity of α-Aminoboronates: Copper-Catalyzed, Intramolecular Aminoalkylations of Bromobenzoyl Chlorides

α-Aminoboronate salts are interesting examples of heteroatomic species containing adjacent nucleophilic centers. We have developed an acylation/arylation reaction using 2-bromobenzoyl chlorides as bis-electrophiles that harnesses the nucleophilicity of both positions, leading to isoindolinones. The reactions proceed under mild conditions via an intramolecular, Cu-catalyzed sp3-sp2 coupling, giving products in up to 95% yield. These conditions enable arylation of α,α-disubstituted aminoboronates, which are difficult to accomplish using methods based on less abundant and more expensive transition metals.

Study of the photochemical and in vitro phototoxicity of chlortalidone [2-chloro-5-(1-hydroxy-3-oxo-1-isoindolinyl)benzene sulfonamide]

The photodegradation process of the phototoxic diuretic drag chlorthalidone was studied. The products of its photolysis under UV-B were isolated and identified. Chlorthalidone was found to be active when examined by photohemolysis on human erythrocytes, but not in the presence of the isolated photoproducts. Inhibition of the photohemolysis process induced by chlorthalidone on addition of reduced glutathione (GSH) or ascorbic acid suggests the involvement of radicals species. The inhibition with 1,4- diazabycyclo [2.2.2] octane (DABCO), sodium azide (NAN3) sowie 2,5- dimethylfuran proof the participation of singlet oxygen (1O2) in this process.

Untersuchungen zur Chemie von Isoindolen und Isoindoleninen, XXXVIII. 3-Alkoxy-1H-isoindole mit Substituenten am 5-Ring - Heterocycliche Imidsaeureester mit fixierter benzoider Struktur.

3-Alkoxy-1H-isoindoles bearing substituents at the five-membered ring have been synthesized starting with substituted isoindoline-1-ones via regiospecific O-alkylation with trialkyl oxonium tetrafluoroborates or alkyl trifluoromethanesulfonates and subsequent NH-deprotonation.The dependence of spectroscopic properties on the substituents has been investigated.The heterocyclic imidates exist exclusively in the benzenoid 1H-structure; the tautomeric o-quinonoid 2H-form cannot be detected by spectroscopic means.