61869-08-7 Usage
Synthesis
Accordingly, methyl acrylate 8 was refluxed with BnNH2 9 in the presence of Et3N
to give correspondong double Michael adduct, which upon Dieckmann condensation using
NaH in refluxing benzene furnished β-ketoester, which exists as a mixture of 10 and 11.
Borohydride reduction of the ketoester followed by mesylation of the resultant alcohol and
subsequent elimination provided α,β-unsaturated ester 12. Benzyl protection was then
exchanged with methyl carbamate to furnish compound 13 and was subjected to Heck
coupling under solvent-free conditions. Delightingly, carbamate 13 furnished the
corresponding free amine 14, albiet in moderate yields (scheme 4). Conversion of 14 to
paroxetine 7 is reported in the literature. Also, carbamate of 15 was prepared from 14
whose conversion to paroxetine 7 is known.
Description
Paroxetine is a new highly selective serotonin reuptake inhibitor, mechanistically
similar to fluoxetine, fluvoxamine and sertraline, introduced for the treatment of all
types of depressive illnesses including depression associated with anxiety. It is
reportedly non-sedating and non-stimulatory and compared to fluoxetine has a shorter
duration of action (half-life of 24 hours versus 2 to 3 days). Paroxetine is also being
investigated as a treatment for obesity, alcoholism and obsessive-compulsive disorders.
Chemical Properties
White Solid
Originator
As Ferrosan (Novo-Nordisk) (Denmark)
Uses
A istopically labelled selective serotonin reuptake inhibitor. Used as an antidepressant
Manufacturing Process
251 g of methyl-4-(4-fluorophenyl)-N-methyl-nipecotinate, 8 g of sodium methoxide and 500 ml benzene were refluxed for 2 h. The benzene solution was washed with cold water and evaporated to give the pure α-ester which was dissolved in a mixture of 320 ml of water and 450 ml concentrated hydrochloric acid. The solution was slowly distilled to remove methanol and finally evaporated to dryness in vacuo.
400 ml thionyl chloride were added in small portions to the solid. The mixture was allowed to stand for 3 h at room temperature and was then evaporated to dryness in vacuo with tetrachloroethane giving methyl-4-(4-fluorophenyl)-Nmethylnipecotic acid chloride. The acid chloride was added in small portions to a solution of 160 g (-)-menthol in 800 ml pyridine at a temperature of 0°-5°C. The mixture was allowed to stand at room temperature to the next day. Ice water and 50% sodium hydroxide were added, and the mixture was extracted with ether. The ether was dried with anhydrous magnesium sulphate, filtered and evaporated. Distillation in vacuo gave the menthol ester in a yield of 7580%. Boiling point at 0.05 mm Hg was 165°-170°C.
Racemic 4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (50 g) was dissolved in a mixture of 21.6 ml of concentrated sulfuric acid and 50 ml of water. To the solution were added 25 ml of concentrated hydrochloric acid and 22.4 ml of 37% formaldehyde solution. The mixture was refluxed for 5 h, cooled, and 125 ml of concentrated ammonia were added. The mixture was extracted with 50 ml of toluene. Drying of the toluene solution and distillation gave 38 g of 4-(4-fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6tetrahydropyridine with boiling point 110°-120°C at 0.1 mm Hg.
13 g of the racemic compound and 22 g of (-)-dibenzoyltartaric acid were dissolved in 105 ml of hot methanol. On cooling, 9 g of salt of (-)-4-(4fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6-tetrahydropyridine crystallized. Melting point 167°-168°C.
38 g of (-)-4-(4-fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6tetrahydropyridine were dissolved in 350 ml of 99% ethanol, 5 g of 5% palladium on carbon were added, and the mixture was treated with hydrogen until 4500 ml were absorbed. The catalyst was filtered off, and the solution was evaporated to yield 37.5 g of (+)-b-4-(4-fluorophenyl)-3-hydroxymethyl1-methylpiperidine.
To a solution of sodium in methanol (125 ml) were added 3,4methylenedioxyphenol (29 g) and the (+)-b-4-(4-fluorophenyl)-3hydroxymethyl-1-methylpiperidine (37,5 g). The mixture was stirred and refluxed. After removal of the solvent in vacuo, the evaporation residue was poured into a mixture of ice (150 g), water (150 ml), and ether (200 ml). The ether layer was separated, and the aqueous layer was extracted with ether. The combined ether solutions were washed with water and dried with anhydrous magnesium sulphate, and the ether was evaporated. The residue was triturated with 200 ml of 99% ethanol and 11.5 ml of concentrated hydrochloric acid, yielding 30 g of (-)-b-4-(4-fluorophenyl-3-(1,3-benzdioxolyl(3)-oxymethyl)-1-methylpiperidine, hydrochloride were obtained. Melting point 202°C.
Brand name
Paxil[as hydrochloride] (SmithKline Beecham);Seroxat.
Therapeutic Function
Antidepressant
Biological Functions
Paroxetine (Paxil) has an elimination half-life of 21
hours and is also highly bound to plasma proteins, so it
requires special attention when administered with drugs
such as warfarin. Paroxetine is a potent inhibitor of the
cytochrome P450 2D6 isoenzyme and can raise the
plasma levels of drugs metabolized via this route. Of
particular concern are drugs with a narrow therapeutic
index, such as TCAs and the type 1C antiarrhythmics
flecainide, propafenone, and encainide. Additionally,
paroxetine itself is metabolized by this enzyme and inhibits
its own metabolism, leading to nonlinear kinetics.
Weight gain is higher with paroxetine than with the
other SSRIs, and it tends to be more sedating, presumably
because of its potential anticholinergic effects.
Additionally, patients have had difficulty with abrupt
discontinuation with this agent, reporting a flulike syndrome;
this symptom can be avoided by tapering the
medication.
General Description
In the structure of paroxetine (Paxil), an amino group, protonatedin vivo could H-bond with the–CH2–O– unshared electrons.A β-arylamine–like structure with an extra aryl groupresults. The compound is a very highly selective SERT. Asexpected, it is an effective antidepressant and anxiolytic.
Pharmacokinetics
Paroxetine appears to be slowly but well absorbed from the GItract following oral administration with an oral
bioavailability of approximately 50%, suggesting first-pass metabolism, reaching peak plasma
concentrations in 2 to 8 hours. Food does not substantially affect the absorption of paroxetine. Paroxetine is
distributed into breast milk. Approximately 80% of an oral dose of paroxetine is oxidized by CYP2D6 to a
catechol intermediate, which is then either O-methylated or O-glucuronidated. These conjugates are then
eliminated in the urine.
Paroxetine exhibits a preincubation-dependent increase in inhibitory potency of CYP2D6 consistent with a
mechanism-based inhibition of CYP2D6. The inactivation of CYP2D6 occurs via the formation of an
o-quinonoid reactive metabolite.
The methylenedioxy has been associated with mechanism-based inactivation of other CYP isoforms.
In contrast, fluoxetine, a potent inhibitor of CYP2D6 activity, did not exhibit a mechanism-based inhibition of
CYP2D6. As a result of mechanism-based inhibition, saturation of CYP2D6 at clinical doses appears to
account for its nonlinear pharmacokinetics observed with increasing dose and duration of paroxetine
treatment, which results in increased plasma concentrations of paroxetine at low doses. The elderly may be
more susceptible to changes in doses and, therefore, should be started off at lower doses. Following oral
administration, paroxetine and its metabolites are excreted in both urine and feces.
Oral administration of a single dose resulted in unmetabolized paroxetine accounting for 2% and metabolites
accounting for 62% of the excretion products. The effect of age on the elimination of paroxetine suggests that
hepatic clearance of paroxetine can be reduced, leading to an increase in elimination half-life (e.g., to ~36
hours) and increased plasma concentrations. The metabolites of paroxetine have been shown to possess no
more than 2% of the potency of the parent compound as inhibitors of 5-HT reuptake; therefore, they are
essentially inactive.
Because paroxetine is a potent mechanism-based inhibitor of CYP2D6, this type of inhibition yields nonlinear
and long-term effects on drug pharmacokinetics, because the inactivated or complexed CYP2D6 must be
replaced by newly synthesized CYP2D6 protein. Thus, coadministration of paroxetine with CYP2D6-
metabolized medications should be closely monitored or, in certain cases, avoided, as should upward dose
adjustment of paroxetine itself.
Clinical Use
In vitro binding studies suggest that paroxetine is a more
selective and potent inhibitor of 5-HT reuptake than fluoxetine. The drug essentially has no effect on NE or
dopamine reuptake, nor does it show affinity for other neuroreceptors. Its onset of action is 1 to 4 weeks.
Veterinary Drugs and Treatments
Paroxetine may be beneficial for the treatment of canine aggression,
and stereotypic or other obsessive-compulsive behaviors. It
has been used occasionally in cats as well.
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: increased risk of bleeding with aspirin
and NSAIDs; risk of CNS toxicity increased with
tramadol; concentration of methadone possibly
increased.
Anti-arrhythmics: possibly inhibits propafenone
metabolism (increased risk of toxicity).
Anticoagulants: effect of coumarins possibly
enhanced; possibly increased risk of bleeding with
dabigatran.
Antidepressants: avoid concomitant use with MAOIs
and moclobemide (increased risk of toxicity); avoid
with St John’s wort; possibly enhanced serotonergic
effects with duloxetine; can increase concentration of
tricyclics; possible increased risk of convulsions with
vortioxetine.
Antiepileptics: antagonism (lowered convulsive
threshold); concentration reduced by phenytoin and
phenobarbital.
Antimalarials: avoid with artemether/lumefantrine
and piperaquine with artenimol.
Antipsychotics: concentration of clozapine and
possibly risperidone increased; metabolism
of perphenazine inhibited, reduce dose of
perphenazine; possibly inhibits aripiprazole
metabolism, reduce aripiprazole dose; concentration
possibly increased by asenapine; increased risk of
ventricular arrhythmias with pimozide - avoid.
Antivirals: concentration possibly reduced by
darunavir and ritonavir.
Beta blockers: concentration of metoprolol possibly
increased - increased risk of AV block - avoid in
cardiac insufficiency.
Dapoxetine: possible increased risk of serotonergic
effects - avoid.
Dopaminergics: increased risk of hypertension and
CNS excitation with selegiline - avoid; increased
risk of CNS toxicity with rasagiline - avoid.
Hormone antagonists: metabolism of tamoxifen to
active metabolite possibly reduced - avoid.
5HT1 agonists: risk of CNS toxicity increased by
sumatriptan - avoid; possibly increased risk of
serotonergic effects with naratriptan.
Lithium: increased risk of CNS effects - monitor
levels.
Methylthioninium: risk of CNS toxicity - avoid if
possible.
Metabolism
Paroxetine is extensively metabolised in the liver to
pharmacologically inactive metabolites.
Urinary excretion of unchanged paroxetine is generally
less than 2% of dose whilst that of metabolites is about
64% of dose. About 36% of the dose is excreted in faeces,
probably via the bile, of which unchanged paroxetine
represents less than 1% of the dose. Thus paroxetine is
eliminated almost entirely by metabolism.
Check Digit Verification of cas no
The CAS Registry Mumber 61869-08-7 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 6,1,8,6 and 9 respectively; the second part has 2 digits, 0 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 61869-08:
(7*6)+(6*1)+(5*8)+(4*6)+(3*9)+(2*0)+(1*8)=147
147 % 10 = 7
So 61869-08-7 is a valid CAS Registry Number.
InChI:InChI=1/C19H20FNO3/c20-15-3-1-13(2-4-15)17-7-8-21-10-14(17)11-22-16-5-6-18-19(9-16)24-12-23-18/h1-6,9,14,17,21H,7-8,10-12H2/t14?,17-/m0/s1
61869-08-7Relevant articles and documents
Single point activation of pyridines enables reductive hydroxymethylation
Marinic, Bruno,Hepburn, Hamish B.,Grozavu, Alexandru,Dow, Mark,Donohoe, Timothy J.
, p. 742 - 746 (2021/01/28)
The single point activation of pyridines, using an electron-deficient benzyl group, facilitates the ruthenium-catalysed dearomative functionalisation of a range of electronically diverse pyridine derivatives. This transformation delivers hydroxymethylated piperidines in good yields, allowing rapid access to medicinally relevant small heterocycles. A noteworthy feature of this work is that paraformaldehyde acts as both a hydride donor and an electrophile in the reaction, enabling the use of cheap and readily available feedstock chemicals. Removal of the activating group can be achieved readily, furnishing the free NH compound in only 2 steps. The synthetic utility of the method was illustrated with a synthesis of (±)-Paroxetine.
Organocatalytic Hantzsch Type Reaction Using Aryl Hydrazines, Propiolic Acid Esters and Enals: Enantioselective Synthesis of Paroxetine
Chen, Lu,Zhang, Zhi,Zu, Liansuo
, p. 5385 - 5390 (2020/12/01)
Aryl hydrazines, propiolic acid esters and enals serve as a viable substrate combination for an organocatalytic enantioselective Hantzsch type reaction. The method converts readily available starting materials into important chiral heterocycles with good to excellent yields and enantioselectivities, and has addressed the longstanding scope limitation of the classic Hantzsch reaction in the asymmetric synthesis of 2,6-unsubstituted hydropyridines. The synthetic utility has been demonstrated by the concise enantioselective synthesis of paroxetine. (Figure presented.).
Diastereoconvergent Synthesis of (–)-Paroxetine
Chamorro-Arenas, Delfino,Fuentes, Lilia,Quintero, Leticia,Cruz-Gregorio, Silvano,H?pfl, Herbert,Sartillo-Piscil, Fernando
, p. 4104 - 4110 (2017/08/07)
A diastereoconvergent approach to (–)-paroxetine from diastereomeric 3,4-epoxy-2-piperidones is reported. For this synthesis, a regioselective and stereodivergent CuI-catalyzed epoxide-ring-opening reaction of epoxyamide precursors to give the 4-(4-fluorophenyl)-2-piperidone skeleton with the correct absolute configuration is crucial. Using CuBr·SMe2 as a catalyst, the epoxide-ring-opening reaction takes place with inversion of configuration; the configuration is retained when CuI is used.
