389573-45-9

Basic information

• Product Name: ent-Paroxol
• Synonyms: ((3R,4S)-4-(4-fluorophenyl)-1-Methylpiperidin-3-yl)Methanol;[(3R,4S)-4-(4-Fluorophenyl)-1- methylpiperidinyl]methanol,99%e.e.;ent-Paroxol
• CAS NO: 389573-45-9
• Molecular Formula: C₁₃H₁₈FNO
• Molecular Weight: 223.2865232
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Aromatics;Chiral Reagents;Heterocycles;Inhibitors
• Mol File: 389573-45-9.mol
• Article Data: 5

Chemical Properties

• Melting Point: 98-100°C
• Boiling Point: 300.3±42.0 °C(Predicted)
• Appearance: /
• Density: 1.092±0.06 g/cm3(Predicted)
• Storage Temp.: Refrigerator
• PKA: 14.93±0.10(Predicted)
• CAS DataBase Reference: ent-Paroxol(CAS DataBase Reference)
• NIST Chemistry Reference: ent-Paroxol(389573-45-9)
• EPA Substance Registry System: ent-Paroxol(389573-45-9)

Safety Data

• Hazardous Substances Data: 389573-45-9(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

Synthetic route

(3R, 4S)-trans-3-carbomethoxy-4-(4-fluorophenyl)-N-methyl-piperidine (335158-56-0) → (-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine (389573-45-9)

Conditions	Yield
Stage #1: (3R, 4S)-trans-3-carbomethoxy-4-(4-fluorophenyl)-N-methyl-piperidine With lithium aluminium tetrahydride In tetrahydrofuran at -30 - -25℃; for 0.5h; Stage #2: With water at 25 - 30℃; for 1h;

formaldehyd (50-00-0) + (3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (179463-85-5) → (-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine (389573-45-9)

Conditions	Yield
In ethanol; water; toluene

2,6-dichlorostyrene (28469-92-3) + (-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine (389573-45-9) → (3R,4S)-3-((2,6-dichlorophenethoxy)methyl)-4-(4-fluorophenyl)-1-methylpiperidine

Conditions	Yield
With phosphazene base-P4-tert-butyl In hexane; 1,3,5-trimethyl-benzene at 110℃; for 24h; Inert atmosphere;	92%

(E)-3-(4-fluorophenyl)acryloyl chloride (13565-08-7) + (-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine (389573-45-9) → C22H19F2NO4

Conditions	Yield
With triethylamine In dichloromethane at -5℃; for 0.166667h;	90%

Sesamol (533-31-3) + (-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine (389573-45-9) → (+)-trans-4-(4-fluorophenyl)-1-methyl-3-(3,4-methylenedioxyphenoxymethyl)piperidine hydrochloride

Conditions	Yield
With hydrogenchloride; sodium; triethylamine; benzenesulfonyl chloride 1.) toluene, 0 deg C, 72 h, 2.) toluene, 4-methyl-2-pentanol, reflux, 4 h; Multistep reaction;

4-methoxy-phenol (150-76-5) + (-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine (389573-45-9) → (-)-trans-4-(4-fluorophenyl)-3-[(4-methoxyphenoxy)methyl]-1-methylpiperidine hydrochloride

Conditions	Yield
With hydrogenchloride; sodium; triethylamine; benzenesulfonyl chloride 1.) toluene, 0 deg C, 72 h, 2.) toluene, 4-methyl-2-pentanol, reflux, 4 h; Multistep reaction;

(-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine (389573-45-9) → (3R,4S)-3-bromomethyl-4-(4-fluorophenyl)-1-methylpiperidine (742070-69-5)

Conditions	Yield
With dibromo sulfoxide In acetonitrile for 1h; Heating;

(-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine (389573-45-9) → 4-(4-fluorophenyl)-1,5-dimethyl-1,2,5,6-tetrahydropyridine (70256-12-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: SOBr2 / acetonitrile / 1 h / Heating 2: DBU / toluene / 3 h / 120 - 125 °C 3: KF; Al2O3 / 0.5 h / microwave irradiation View Scheme

(-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine (389573-45-9) → (4S)-4-(4-fluorophenyl)-1-methyl-3-methylenepiperidine (477788-80-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: SOBr2 / acetonitrile / 1 h / Heating 2: DBU / toluene / 3 h / 120 - 125 °C View Scheme

(-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine (389573-45-9) → (+)-trans-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)piperidine hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) benzenesulfonyl chloride, triethylamine, 2.) sodium, 3.) hydrochloric acid / 1.) toluene, 0 deg C, 72 h, 2.) toluene, 4-methyl-2-pentanol, reflux, 4 h 2: 1.) BrCN, 2.) LiAlH4 View Scheme

(-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine (389573-45-9) → (+)-(3R,4S)-trans-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) benzenesulfonyl chloride, triethylamine, 2.) sodium, 3.) hydrochloric acid / 1.) toluene, 0 deg C, 72 h, 2.) toluene, 4-methyl-2-pentanol, reflux, 4 h 2: 1.) BrCN, 2.) LiAlH4 View Scheme

p-toluenesulfonyl chloride (98-59-9) + (-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine (389573-45-9) → trans 4-(p-fluorophenyl)-3-(p-toluenesulfonyloxymethyl)-N-methylpiperidine (1258537-32-4)

Conditions	Yield
With triethylamine In ethyl acetate at 0 - 20℃; for 25h;

p-toluenesulfonyl chloride (98-59-9) + (-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine (389573-45-9) → (-)trans 4-(p-fluorophenyl)-3-(p-toluenesulfonyloxymethyl)-N-methylpiperidine

Conditions	Yield
With triethylamine In ethyl acetate

Upstream product

• 335158-56-0 (3R, 4S)-trans-3-carbomethoxy-4-(4-fluorophenyl)-N-methyl-piperidine 
• 50-00-0 formaldehyd 
• 179463-85-5 (3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine 

Downstream Products

• 742070-69-5 (3R,4S)-3-bromomethyl-4-(4-fluorophenyl)-1-methylpiperidine 
• 70256-12-1 4-(4-fluorophenyl)-1,5-dimethyl-1,2,5,6-tetrahydropyridine 
• 477788-80-0 (4S)-4-(4-fluorophenyl)-1-methyl-3-methylenepiperidine 
• 130855-30-0 (+)-(3R,4S)-trans-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine hydrochloride 
• 1258537-32-4 trans 4-(p-fluorophenyl)-3-(p-toluenesulfonyloxymethyl)-N-methylpiperidine 

Relevant articles and documents

ENANTIOSPECIFIC PROCESS FOR THE PREPARATION OF PAROXETINE INTERMEDIATE

A novel, improved, and enantiospecific process for the preparation of (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine of formula-(I), an advanced intermediate in the manufacture of antidepressant drug paroxetine is disclosed in the present invention. Compound of formula-(XXII) is prepared by resolution of compound of formula-(XX) using a chiral acid followed by hydrogenation of the resolved amine. Michael addition of the compound of formula-(XXII) onto acrylate esters gave the compounds of formula-(XXIII). Conversion of the hydroxy group present in compound of formula-(XXIII) into a leaving group followed by treatment with a strong base gave the enantiospecific intramolecularly cyclized piperidine derivative of formula-(XXV). Reduction of the ester group present in compound of formula-(XXV) with a metal hydride reducing agent gave the compound of formula-I with more than 97% chiral purity. Further purification of compound of formula-I to >99.5% is achieved by one recrystallization from a number of solvents. Present process is easily adaptable for commercial preparation of (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine of formula-(I).

Process for producing piperidinecarbinols

A process for producing a piperidinecarbinol represented by the general formula (2), which comprises reducing the trans isomer of a compound represented by the general formula (1): wherein R1is a hydrogen atom, a lower alkyl group or an aralkyl group, R2is a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group, and X is a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an aralkyl group, an alkoxy group, a dialkylamino group, an alkylthio group, an arylthio group or CmF2m+1— wherein m is an integer of from 1 to 20.

Process for preparing aryl-piperidine carbinols and novel intermediates used in the process

A process is disclosed for the preparation of a compound of formula (I): STR1 wherein Ar is aryl or substituted aryl and R3 is hydrogen, alkyl or aralkyl, which process comprises reducing a compound of formula (II): STR2 wherein Ar and R3 are as defined with respect to formula (I) and R4 is alkyl. Compounds of formula (I) are useful as chemical intermediates.