132813-14-0

Basic information

• Product Name: 2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine
• Synonyms: 2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine;Cycloocta[b]pyridine, 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-;2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10...;2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctapyridine;Blonanserin Intermediate
• CAS NO: 132813-14-0
• Molecular Formula: C₁₇H₁₇ClFN
• Molecular Weight: 289.7749832
• EINECS: 1592732-453-0
• Mol File: 132813-14-0.mol

Chemical Properties

• Boiling Point: 414.7 °C at 760 mmHg
• Flash Point: 204.6 °C
• Appearance: /
• Density: 1.175
• Vapor Pressure: 1.05E-06mmHg at 25°C
• Refractive Index: 1.561
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: Chloroform (Slightly), Methanol (Slightly, Heated)
• PKA: 1.49±0.20(Predicted)
• CAS DataBase Reference: 2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine(CAS DataBase Reference)
• NIST Chemistry Reference: 2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine(132813-14-0)
• EPA Substance Registry System: 2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine(132813-14-0)

Safety Data

• Hazardous Substances Data: 132813-14-0(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine is used as a key intermediate in the synthesis of Blonanserin, which is a 5-HT2 serotonin receptor and D2 dopamine receptor antagonist. This dual action makes Blonanserin an effective antipsychotic agent, utilized for the treatment of various psychiatric disorders, including schizophrenia and bipolar disorder. Its mechanism of action involves modulating neurotransmitter activity, leading to an improvement in the symptoms associated with these conditions.

InChI:InChI=1/C17H17ClFN/c18-17-11-15(12-7-9-13(19)10-8-12)14-5-3-1-2-4-6-16(14)20-17/h7-11H,1-6H2

Synthetic route

4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine-(1H)-ketone (132812-72-7) → 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0)

Conditions	Yield
With trichlorophosphate	95%
With phosphorus pentachloride In N,N-dimethyl-formamide at 5 - 15℃; for 3h;	93.6%
With hydrogenchloride In water; acetic anhydride at 10 - 20℃; for 6h; Cooling with ice; Green chemistry;	93.24%

cycloactanone (502-49-8) → 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 64 percent / PPA / Heating 2: 95 percent / POCl3 View Scheme
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid; phosphoric acid / toluene / Reflux; Dean-Stark; Large scale 2: P,P-dichlorophenylphosphine oxide / toluene; dichloromethane / 80 - 148 °C / Large scale View Scheme

3-(4-fluorophenyl)-3-oxopropionitrile (4640-67-9) → 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 64 percent / PPA / Heating 2: 95 percent / POCl3 View Scheme
Multi-step reaction with 3 steps 1: methanesulfonic acid / water / 3 h / 65 - 70 °C 2: methanesulfonic acid / water / 2 h / 110 - 115 °C 3: Dichlorophenylphosphine / 4 h / 155 - 160 °C View Scheme
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid; phosphoric acid / toluene / Reflux; Dean-Stark; Large scale 2: P,P-dichlorophenylphosphine oxide / toluene; dichloromethane / 80 - 148 °C / Large scale View Scheme

3-(4-fluorophenyl)-3-oxopropanamide → 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanesulfonic acid / water / 2 h / 110 - 115 °C 2: Dichlorophenylphosphine / 4 h / 155 - 160 °C View Scheme

methyl 4-flurobenzoate (403-33-8) → 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hexamethyldisilazane / toluene; tetrahydrofuran / -5 - 0 °C / Large scale 2: toluene-4-sulfonic acid; phosphoric acid / toluene / Reflux; Dean-Stark; Large scale 3: P,P-dichlorophenylphosphine oxide / toluene; dichloromethane / 80 - 148 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1: sodium hydride / tert-butyl methyl ether; water / 90 °C 2: toluene-4-sulfonic acid; phosphoric acid / toluene / Reflux; Dean-Stark; Large scale 3: P,P-dichlorophenylphosphine oxide / toluene; dichloromethane / 80 - 148 °C / Large scale View Scheme

4-ethylpiperazine (5308-25-8) + 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0) → blonanserin

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 70℃; for 5h;	98.6%
Stage #1: 4-ethylpiperazine; 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine With sodium t-butanolate In toluene at 10℃; under 75.0075 Torr; for 0.0333333h; Inert atmosphere; Stage #2: With palladium diacetate; triphenylphosphine In toluene at 70℃; under 75.0075 Torr; for 7h; Reagent/catalyst; Solvent; Temperature; Inert atmosphere;	89.12%
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene at 75 - 85℃; for 3h; Large scale;	88%

2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0) → 2-chloro-4-(4-fluoro-phenyl)-5,6,7,8,9,10-hexahydro-cycloocta[b]pyridine 1-oxide (143213-96-1)

Conditions	Yield
With 3-chloro-benzenecarboperoxoic acid In chloroform	97%

1-t-Butoxycarbonylpiperazine (57260-71-6) + 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0) → 2-(piperazine-1-yl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine

Conditions	Yield
Stage #1: 1-t-Butoxycarbonylpiperazine; 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine With potassium iodide In N,N-dimethyl-formamide for 12h; Reflux; Stage #2: With hydrogenchloride In N,N-dimethyl-formamide at 30℃; for 2h; Temperature; Solvent; Reagent/catalyst;	80%

2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0) → 2-chloro-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-cycloocta[b]pyridine

Conditions	Yield
Multi-step reaction with 3 steps 1: 97 percent / m-CPBA / CHCl3 2: 97 percent / POCl3; Et3N / CHCl3 3: 84 percent / DBU / dimethylsulfoxide View Scheme

2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0) → 2-chloro-4-(4-fluoro-phenyl)-5,6,7,8,9,10-hexahydro-cycloocta[b]pyridin-8-ol (848301-81-5)

Conditions	Yield
Multi-step reaction with 6 steps 1: 97 percent / m-CPBA / CHCl3 2: 97 percent / POCl3; Et3N / CHCl3 3: 84 percent / DBU / dimethylsulfoxide 4: 99 percent / SeO2 / dioxane 5: 49 percent / HCl / methanol 6: 85 percent / H2 / PtO2 / ethanol View Scheme

2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0) → 2-chloro-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-cycloocta[b]pyridin-8-ol

Conditions	Yield
Multi-step reaction with 5 steps 1: 97 percent / m-CPBA / CHCl3 2: 97 percent / POCl3; Et3N / CHCl3 3: 84 percent / DBU / dimethylsulfoxide 4: 99 percent / SeO2 / dioxane 5: 49 percent / HCl / methanol View Scheme

2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0) → 2,10-dichloro-4-(4-fluoro-phenyl)-5,6,7,8,9,10-hexahydro-cycloocta[b]pyridine (143213-95-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 97 percent / m-CPBA / CHCl3 2: 97 percent / POCl3; Et3N / CHCl3 View Scheme

2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0) → formic acid 2-chloro-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-cycloocta[b]pyridin-8-yl ester

Conditions	Yield
Multi-step reaction with 4 steps 1: 97 percent / m-CPBA / CHCl3 2: 97 percent / POCl3; Et3N / CHCl3 3: 84 percent / DBU / dimethylsulfoxide 4: 99 percent / SeO2 / dioxane View Scheme

2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0) → 2-(4-ethyl-piperazin-1-yl)-4-(4-fluoro-phenyl)-5,6,7,8,9,10-hexahydro-cycloocta[b]pyridin-8-ol (848301-82-6)

Conditions	Yield
Multi-step reaction with 7 steps 1: 97 percent / m-CPBA / CHCl3 2: 97 percent / POCl3; Et3N / CHCl3 3: 84 percent / DBU / dimethylsulfoxide 4: 99 percent / SeO2 / dioxane 5: 49 percent / HCl / methanol 6: 85 percent / H2 / PtO2 / ethanol View Scheme

2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0) → 2-(4-ethyl-piperazin-1-yl)-4-(4-fluoro-phenyl)-5,6,7,8,9,10-hexahydro-cycloocta[b]pyridin-8-ol

Conditions	Yield
Multi-step reaction with 8 steps 1: 97 percent / m-CPBA / CHCl3 2: 97 percent / POCl3; Et3N / CHCl3 3: 84 percent / DBU / dimethylsulfoxide 4: 99 percent / SeO2 / dioxane 5: 49 percent / HCl / methanol 6: 85 percent / H2 / PtO2 / ethanol 7: resolution using CHIRACEL OJ column View Scheme

2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0) → 2-(4-ethyl-piperazin-1-yl)-4-(4-fluoro-phenyl)-5,6,7,8,9,10-hexahydro-cycloocta[b]pyridin-8-ol

Conditions	Yield
Multi-step reaction with 8 steps 1: 97 percent / m-CPBA / CHCl3 2: 97 percent / POCl3; Et3N / CHCl3 3: 84 percent / DBU / dimethylsulfoxide 4: 99 percent / SeO2 / dioxane 5: 49 percent / HCl / methanol 6: 85 percent / H2 / PtO2 / ethanol 7: resolution using CHIRACEL OJ column View Scheme

piperazine (110-85-0) + 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0) → 2-(piperazine-1-yl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine

Conditions	Yield
With potassium iodide at 165 - 170℃; for 8h;	8.5 g

4-ethylpiperazine (5308-25-8) + 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (132813-14-0) → blonanserin sulfate

Conditions

Yield

Stage #1: 4-ethylpiperazine; 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine With sodium t-butanolate In toluene at 10℃; under 75.0075 Torr; for 0.0333333h; Inert atmosphere; Stage #2: With palladium diacetate; triphenylphosphine In toluene at 70℃; under 75.0075 Torr; for 7h; Inert atmosphere; Stage #3: With sulfuric acid In ethanol; toluene at 0 - 10℃; for 0.5h; Inert atmosphere;

6.76 g

Upstream product

• 403-33-8 methyl 4-flurobenzoate 
• 671188-82-2 3-(4-fluorophenyl)-3-oxopropanamide 
• 4640-67-9 3-(4-fluorophenyl)-3-oxopropionitrile 
• 502-49-8 cycloactanone 
• 132812-72-7 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine-(1H)-ketone 

Downstream Products

• 143213-96-1 2-chloro-4-(4-fluoro-phenyl)-5,6,7,8,9,10-hexahydro-cycloocta[b]pyridine 1-oxide 
• 143213-95-0 2,10-dichloro-4-(4-fluoro-phenyl)-5,6,7,8,9,10-hexahydro-cycloocta[b]pyridine 

Relevant articles and documents

Method for preparing blonanserin intermediate (BN-04)

The invention discloses a preparation method of a key Bnanserin intermediate (BN-04). The method comprises the following steps: reacting 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridine-2(1H)-ketone (BN-03) with a chlorinating reagent hydrochloric acid in acetic anhydride at a low temperature, and after the reaction, recovering a solvent under reduced pressure; cooling to below 50 DEGC, adding dichloromethane and water, adjusting the pH value with ammonia water, layering, drying with anhydrous sodium sulfate, and recovering the dichloromethane to be clean under reduced pressure; adding a proper amount of ethanol to be completely dissolved, cooling, crystallizing and filtering to obtain 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridine (BN-04). Compared withthe prior art, cheap and high-quality hydrogen chloride is taken as a chlorinating reagent, a high-temperature (170 DEG C) reaction is avoided, the generation of impurities is reduced, repeated recrystallization in the refining process is avoided, and acetic anhydride can be repeatedly used as a reaction solvent. Green, safe and environment-friendly modern production can be realized.

METHOD OF PRODUCING BLONANSERIN

PROBLEM TO BE SOLVED: To provide a method of producing blonanserin. SOLUTION: The invention relates to an improved method of producing high-purity 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (INN name blonanserin). The method is implemented through four successive steps starting from C1-4-alkyl 4-fluorobenzoate. The invention also relates to a method of producing 3-(4-fluorophenyl)-3-oxopropanenitrile (BLON1) being an intermediate. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT

Blonanserin and preparation method thereof

The invention relates to Blonanserin and a preparation method thereof. The preparation method comprises the following specific steps that firstly, the compound shown in the formula III is reacted with a chlorinating agent, namely phosphenylic oxychloride, and the compound shown in the formula II is obtained; secondly, in the presence of potassium iodide, the compound shown in the formula II is reacted with N-ethylpiperazine, and the compound shown in the formula I, namely Blonanserin, is obtained. The preparation method has the advantages shown in the description.

In the preparation method of the midbody blonanserin (by machine translation)

The present invention provides a process for the preparation of intermediates blonanserin key, comprises the following steps: the 4 [...] (the 4 [...] phenyl) - 3 the [...] 5, 6, 7, 8, 9, 10-hexahydro cyclooctane and pyridine -2 (1H)-one and chloropivaloyl reagent in the reaction under a certain condition, after the reaction, the reactants are poured into ice water, pH value is adjusted with ammonia water, stirring, filtering or offcenter the 2 [...] -4 the [...] (the 4 [...] phenyl) - 5, 6, 7, 8, 9, 10-hexahydro cyclooctane [b] pyridine (compound I) crude; compound I hot ethanol is dissolved, decolourizations, recrystallization, the refined product obtained. Compared with the prior art, the method, in the process of refining a plurality of extraction, the solvent loss in the process, the operation is simple and easy to operate, has improved the purity of the product and yield, amplifying and industrial production processes. (by machine translation)

Method for Preparing Blonancerin with Mild Condition

The present invention provides a novel producing method of blonanserin. A producing method of the present invention has mild reaction temperature and short reaction time, can produce high-purity and high-yield blonanserin and is suitable for mass producti

An investigation into formation of impurities during synthesis of blonanserin

During the process development of Blonanserin (1 ), we have observed formations of unknown impurities are in the final product at enhanced levels which was identified as Des ethyl impurity, di-N-ethylpiperazine impurity, Chloro impurity and des-fluoro impurity. The present work involves detailed optimization studies directed toward the development of an efficient process for the commercial production of Blonanserin substantially free from the chloro impurity and other impurities.

Syntheses and properties of the major hydroxy metabolites in humans of blonanserin AD-5423, a novel antipsychotic agent

Two major metabolites in humans of blonanserin, 2-(4-ethyl-1-piperazinyl)- 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta-[b]pyridine (code name AD-5423), were synthesized. The first, 7-hydroxylated AD-5423, was synthesized through a four-step process