26864-56-2

Basic information

• Product Name: Penfluridol
• Synonyms: 1-[4,4-Bis(p-fluorophenyl)butyl]-4-(4-chloro-alpha,alpha,alpha-trifluoro-m-tolyl)-4-piperidinol;1-[4,4-Bis(p-flurophenyl)butyl]-4-(4-chloro-alpha,alpha,alpha-trifluoro-m-tolyl)-4-piperidinol;4-Piperidinol, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-;4-Piperidinol, 4-(4-chloro-alpha,alpha,alpha-trifluoro-m-tolyl)-1-(4,4-bis(p-fluorophenyl)butyl)-;4-piperidinol,1-(4,4-bis(4-fluorophenyl)butyl)-4-(4-chloro-3-(trifluoromethy;4-piperidinol,4-(4-chloro-alpha,alpha,alpha-trifluoro-m-tolyl)-1-(4,4-bis(p-fl;McN-JR-16,341;Penfuridol
• CAS NO: 26864-56-2
• Molecular Formula: C₂₈H₂₇ClF₅NO
• Molecular Weight: 523.97
• EINECS: 248-074-5
• Product Categories: API intermediates;ONCOVIN;API
• Mol File: 26864-56-2.mol

Chemical Properties

• Melting Point: 105-107°C
• Boiling Point: 587.7 °C at 760 mmHg
• Flash Point: 309.2 °C
• Appearance: white/powder
• Density: 1.2425 (estimate)
• Vapor Pressure: 1.17E-14mmHg at 25°C
• Refractive Index: 1.552
• Storage Temp.: 2-8°C
• Solubility: H2O: insoluble
• PKA: 13.49±0.20(Predicted)
• Merck: 14,7087
• CAS DataBase Reference: Penfluridol(CAS DataBase Reference)
• NIST Chemistry Reference: Penfluridol(26864-56-2)
• EPA Substance Registry System: Penfluridol(26864-56-2)

Safety Data

• Hazard Codes: T
• Statements: 25
• Safety Statements: 45
• RIDADR: UN 2811 6.1/PG 3
• WGK Germany: 3
• RTECS: TN6957000
• HazardClass: 6.1
• PackingGroup: III
• Hazardous Substances Data: 26864-56-2(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Penfluridol is used as an antipsychotic agent for the treatment of schizophrenia, paranoid, psychotic, and neuroleptic conditions in patients. Its long-lasting effects make it suitable for supportive therapy in ambulatory settings.
Used in Anticancer Applications:
Penfluridol is used as an antineoplastic agent to study its antimetastatic effects on triple-negative breast cancer cells, its effects on the growth of glioblastoma cell lines, and its impact on VEGF-induced angiogenesis in human umbilical vein endothelial cells (HUVECs).
Brand Name:
Semap (Ortho-McNeil) is the brand name under which Penfluridol is marketed.

Originator

Semap,Janssen-Le Brun ,W. Germany ,1975

Manufacturing Process

A mixture of 24 parts of 4,4-bis(p-fluorophenyl)butyl chloride, 20.9 parts of 4(4-chloro-α,α,α-trifluoro-m-tolyl)-4-piperidinol, 13.8 parts of sodium carbonate, a few crystals of potassium iodide in 600 parts of 4-methyl-2pentanone is stirred and refluxed for 60 hours. The reaction mixture is cooled and 150 parts of water is added. The organic layer is separated, dried, filtered and evaporated. The oily residue is crystallized from diisopropylether, yielding 4-(4chloro-α,α,α-trifluoro-m-tolyl)-1-[4,4-bis(p-fiuorophenyl)butyl]-4piperidinol; melting point 106.5°C.

Therapeutic Function

Antipsychotic

Biochem/physiol Actions

Penfluridol is studied in the treatment of schizophrenia, Tourette syndrome and acute psychosis. It also exhibits anticancer activity.

Safety Profile

Poison by ingestion and intravenous routes. Experimental teratogenic and reproductive effects. A neuroleptic agent. When heated to decomposition it emits very toxic fumes of Cl-, F-, and NOx.

Synthesis

Penfluridol, 4-(4-chloro-3-trifluoromethylphenyl)-1-[4,4-bis-(p-fluorophenyl) butyl]-4-piperidinol (6.6.12), is synthesized implementing a Grignard reaction between 1-carbomethoxypiperidin-4-one and 4-chloro-3-trifluoromethylphenylmagnesium bromide, giving 1-carbomethoxy-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol (6.6.10). Upon alkaline hydrolysis of the carbomethoxy group, it turns into (4-chloro-3-trifluoromethylphenyl)-4-piperidinol (6.6.11), the alkylation of which with 1,1-bis(4-fluorophenyl)butyl bromide (6.6.3) gives penfluridol (6.6.12) [67–69].

InChI:InChI=1/C28H27ClF5NO/c29-26-12-7-21(18-25(26)28(32,33)34)27(36)13-16-35(17-14-27)15-1-2-24(19-3-8-22(30)9-4-19)20-5-10-23(31)11-6-20/h3-12,18,24,36H,1-2,13-17H2

Upstream product

• 21928-50-7 4-[4-chloro-3-trifluoromethylphenyl]-4-piperidinol 
• 57668-61-8 4,4'-(4-bromobutane-1,1-diyl)bis(fluorobenzene) 
• 357-77-7 1,1-bis(4-fluorophenyl)prop-2-yn-1-ol 
• 99734-06-2 α,α-bis(4-fluorophenyl)allyl alcohol 
• 20662-52-6 4,4-bis(4-fluorophenyl)butanoic acid 
• 1225599-16-5 3-(4-oxopiperidin-1-yl)propanenitrile 
• 51787-79-2 1,1-bis(-4-fluorophenyl)-4-iodobutane 
• 41979-39-9 4-piperidone hydrochloride 
• 50830-38-1 1-[4,4-bis(4-fluorophenyl)butyryl]-4-(3-trifluoromethyl-4-chlorophenyl)-4-piperidinol 
• 51787-96-3 5-(4-fluorophenyl)dihydrofuran-2(3H)-one 
• 462-06-6 fluorobenzene 
• 445-01-2 5-bromo-2-chlorobenzotrifluoride 
• 21928-40-5 1-ethoxycarbonyl-4-(3-trifluoromethyl-4-chlorophenyl)-4-piperidinol 
• 29976-53-2 N-ethoxycarbonyl-4-piperidone 

Downstream Products

• 80458-78-2 1-<4,4-Bis(4-fluorophenyl)butyl>-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidyl 3,4,5-Trimethoxybenzoate 
• 80458-76-0 penfluoridol decanoate 
• 80458-74-8 1-(4,4-bis(4-fluorophenyl)butyl)-4-(4-chloro-3-(trifluoromethyl)phenyl)piperidin-4-yl acetate 
• 1266656-84-1 N-(1-(4,4-bis(4-fluorophenyl)butyl)-4-(4-chloro-3-(trifluoromethyl)phenyl)piperidin-4-yl)acetamide 

Relevant articles and documents

Improved method for preparing penfuridol

The invention discloses an improved method for preparing penfuridol, comprising the following steps: using 4, 4-bis (4-fluorophenyl) butyric acid as a starting material, carrying out reduction synthesis to synthesize an intermediate I [4, 4-bis (4-fluorophenyl)-1-butanol]; carrying out esterification with a sulfonyl chloride compound to synthesize an intermediate II [4, 4-bis (4-fluorophenyl)-1 (4-methyl-phenyl)-butyl sulfonate] or [4, 4-bis (4-fluorophenyl)-1-methyl-butyl sulfonate]; and condensing with pipradrol to obtain penfuridol. According to the preparation method, 4, 4-bis (4-fluorophenyl) butyric acid is used as a raw material, penfuridol is obtained through a reduction reaction, an esterification reaction and a condensation reaction, the total yield is 81.3%, the whole process isconvenient to operate and mild in reaction, the obtained product is high in yield and purity, and the preparation method is more economical and more suitable for industrial application. The technicalproblems that an existing method is low in yield and poor in purity are solved. The reaction general formula is as shown in the specification.

Late Stage Functionalization of Secondary Amines via a Cobalt-Catalyzed Electrophilic Amination of Organozinc Reagents

A general preparation of polyfunctional hydroxylamine benzoates from the corresponding secondary amines is reported. This convenient synthesis allows the setup of a late-stage functionalization of various secondary amines, including pharmaceuticals and peptidic derivatives. Thus, a cross-coupling of hydroxylamine benzoates with various alkyl-, aryl-, and heteroaryl-zinc chlorides in the presence of 5 mol % CoCl2 (25 °C, 2 h) provides a range of polyfunctional tertiary amines. This method was used to prepare penfluridol and gepirone.

Penfluridol preparation method

The invention discloses a penfluridol preparation method. The penfluridol preparation method includes the following steps of 1), subjecting succinic anhydride and fluorobenzene to Friedel-Crafts reaction prior to acid decomposition, and collecting a compound from the formula 2) as is shown in the description; 2), putting the compound in a solvent to collect a compound in formula 3) as is shown in the description in a solvent reduced through a reducing agent; 3), putting the compound into the fluorobenzene to perform the Friedel-Crafts reaction to collect a compound in the formula 4) as is shown in the description; subjecting the compound and ethyl chloroformate to action to generate a compound in formula 5) as is shown in the description; 5), subjecting the compound and a compound shown in formula (XVII) to reaction prior to hydrolyzation to collect a compound in formula 6) as is shown in the description; 6), performing reduction with the reducing agent prior to hydrolyzing a reduction product and then collecting penfluridol (I). The penfluridol preparation method is high in yield, low in cost, moderate in reaction condition, short in circuit, proper for industrial production, low in three wastes, easy to treat and suitable for industrial production.

Synthesis and SAR study of diphenylbutylpiperidines as cell autophagy inducers

A novel series of diphenylbutylpiperidines as autophagy inducers was described and extensive SAR studies resulted in derivatives (15d-e, 15i-j) with 10-fold greater activity than the lead compounds 1 and 2. Meanwhile, a new synthetic route to diphenylbutyl bromide (6) from bromobenzene and γ-butyrolactone was also reported here.

DIPHENYLBUTYPIPERIDINE AUTOPHAGY INDUCERS

Autophagy inducing compounds, methods of their preparation and use, and kits containg said compounds are disclosed herein.

Rhodium catalyzed hydroformylation of 1,1-bis(p-fluorophenyl)allyl or propargyl alcohol: A key step in the synthesis of Fluspirilen and Penfluridol

Fluspirilen (1) and Penfluridol (2), two neuroleptic agents, belong to a wide class of pharmaceuticals that contain in their molecules a 4,4-bis(p-fluorophenyl)butyl group bound to a nitrogen atom of a pyrrolidine, piperidine or piperazine moiety. A key intermediate for the synthesis of compounds 1 and 2,4,4-bis(p-fluorophenyl)butylbromide (15), has been prepared starting from commercially available 4,4′-difluorobenzophenone (7) following a preparative route involving the rhodium catalyzed hydroformylation in toluene or in the biphasic system toluene/water or cyclohexane/water of 1,1-bis(p-fluorophenyl)-2-propenol (8) and/or 1,1-bis(p-fluorophenyl)-2-propynol (12). Fluspirilen and Penfluridol were obtained in 70-80% yield by reaction of bromide 15 with 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (16) and 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol (17), respectively. The overall yields of the two pharmaceuticals 1 and 2, based on starting ketone 7, were about 35-40%.