144598-75-4

Basic information

• Product Name: Paliperidone
• Synonyms: 4h-pyrido(2,1-a)pyrimidin-4-one,6,7,8,9-tetrahydro-3-(2-(4-(6-fluro-1,2-benzis;oxazol-3-yl)-1-piperidinyl)ethyl)-9-hydroxy-2-methyl-;r76477;9-HYDROXYRISPERIDONE;Paliperidone;rac9-Hydroxyrisperidone;6,7,8,9-Tetrahydro-3-(2-(4-(6-fluro-1,2-benzisoxazol-3-yl)-1-piperidinyl)ethyl)-9-hydroxy-2-methyl-4H-pyrido[2,1-a]pyrimidin-4-one;Paliperidone for research
• CAS NO: 144598-75-4
• Molecular Formula: C₂₃H₂₇FN₄O₃
• Molecular Weight: 426.48
• EINECS: 1806241-263-5
• Product Categories: Various Metabolites and Impurities;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals;Heterocycles;Invega, INVEGA Sustenna, 9-hydroxyrisperidone;Other APIs
• Mol File: 144598-75-4.mol

Chemical Properties

• Melting Point: 158-160°C
• Boiling Point: 612.3 °C at 760 mmHg
• Flash Point: 9℃
• Appearance: white to brown/
• Density: 1.45 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.692
• Storage Temp.: Room temp
• Solubility: DMSO: soluble2mg/mL, clear (warmed)
• PKA: 13.00±0.60(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 2 months.
• CAS DataBase Reference: Paliperidone(CAS DataBase Reference)
• NIST Chemistry Reference: Paliperidone(144598-75-4)
• EPA Substance Registry System: Paliperidone(144598-75-4)

Safety Data

• Hazard Codes: T,F
• Statements: 25-39/23/24/25-23/24/25-11
• Safety Statements: 45-36/37-16
• RIDADR: UN 2811 6.1/PG 3
• WGK Germany: 3
• RTECS: UV1164720
• HazardClass: 6.1
• PackingGroup: III
• Hazardous Substances Data: 144598-75-4(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Paliperidone is used as an atypical antipsychotic medication for the treatment of schizophrenia and schizoaffective disorder. It helps to decrease hallucinations, improve clarity of thought, reduce agitation, and promote active participation in everyday life. Paliperidone works by restoring the balance of certain natural substances in the brain, acting as a combined serotonin (5-HT2) and dopamine (D2) receptor antagonist.
Used in Mental Health Treatment:
Paliperidone is used as a treatment option for patients aged 12-17 with schizophrenia. Its pharmacological properties, extrapolation from adult studies, and the long track record of its parent drug, risperidone, in the child and adolescent psychiatric (CAP) population contribute to its therapeutic potential in this age group.
Used as a Metabolite of Risperidone:
Paliperidone is used as a metabolite of Risperidone (R525000), which is also a combined serotonin (5-HT2) and dopamine (D2) receptor antagonist. This makes it a valuable component in the development and improvement of antipsychotic medications.

Metabolism

Paliperidone is the primary active metabolite of risperidone. The mechanism of action is unknown but it is likely to act via a similar pathway to risperidone. It has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. Paliperidone is also active as an antagonist at alpha 1 and alpha 2 adrenergic receptors and H1 histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone was approved by the FDA for treatment of schizophrenia on December 20, 2006.

Metabolism

Paliperidone is the active metabolite of risperidone. Four metabolic pathways have been identified in vivo, none of which accounted for more than 6.5% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Following administration of [14C]-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolised in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the faeces.

Pharmacology

Paliperidone , 9-hydroxyrisperidone, is an atypical antipsychotic, a serotonin (5HT2A) dopamine (D2) antagonist and the active metabolite of the high-potency risperidone. It has also 5HT7 antagonism that might confer some antidepressant actions. It is advantageous given the osmotic-controlled release oral delivery system technique facilitating once-daily dosing, rapid steady-state, and hence better compliance. Moreover, lack of cytochrome CYP-450 enzyme interactions, more alpha-2 affinity, alleged less propensity for extrapyramidal syndromes, and availability of long-acting injection formulation all render paliperidone a very appealing treatment option in psychoses and in hepatic patients too.

Mechanism of Action

Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.

Originator

Johnson & Johnson (US)

Biochem/physiol Actions

Paliperidone is an atypical antipsychotic; active metabolite of risperidone.

Clinical Use

Atypical antipsychotic for schizophrenia

Side effects

The most common adverse events included tachycardia, QTc prolongation, headache, anxiety, dizziness, tremors, and insomnia along with the dose-related events of somnolence, orthostatic hypotension, salivary hypersecretion, and extrapyrimidal disorder. Weight gain was also observed in 6–9% of patients which may be attributable to paliperidone’s lower affinity for H1-histaminergic and a1- and a2-adrenergic receptors. Patients with renal impairment require dose adjustments since elimination of paliperidone is altered. Paliperidone is contraindicated in patients with a hypersensitivity to risperidone. Concomitant use of class III antiarrhythmic agents should be avoided since this may result in additive QT interval prolongation. Also, loss of levodopa efficacy is expected with this D2 antagonist.

Synthesis

The synthesis of paliperidone involves the reaction of 2-acetyl-g-butyrolactone with 2-amino-3-benzyloxypyridine in the presence of phosphoryl chloride. The benzyl protecting group of the intermediate 9-benzyloxy- 3-(2-chloroethyl)-2-methylpyrido[1,2-a]pyrimidin-4-one is then removed by hydrogenolysis over Pd/C followed by the nucleophilic displacement of the chlorine with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole to provide racemic paliperidone. While paliperidone can be resolved, both enantiomers are equipotent and interconvert in vivo obviating the need for separation.

Drug interactions

Potentially hazardous interactions with other drugs Anaesthetics: enhanced hypotensive effect. Analgesics: increased risk of convulsions with tramadol; enhanced hypotensive and sedative effects with opioids; increased risk of ventricular arrhythmias with methadone. Anti-arrhythmics: increased risk of ventricular arrhythmias when given with anti-arrhythmics that prolong the QT interval. Antidepressants: increases concentration of tricyclics (possibly increased risk of ventricular arrhythmias). Antiepileptics: antagonise anticonvulsant effect (convulsive threshold lowered); concentration reduced by carbamazepine. Antimalarials: avoidance of antipsychotics advised by manufacturer of artemether/lumefantrine. Antipsychotics: possible increased risk of ventricular arrhythmias with risperidone. Antivirals: concentration possibly increased by ritonavir. Atomoxetine: increased risk of ventricular arrhythmias with atomoxetine. Cytotoxics: increased risk of ventricular arrhythmias with arsenic trioxide.

References

1) Beijsterveldt?et al.?(1994),?Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat; Psychopharmacology,?114?53 2) Leysen?et al. (1994),?Risperidone: a novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity; J. Clin. Psychiatry,?55?suppl: 5 3) Schotte?et al.?(1996),?Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding; Psychopharmacology (Berl.),?124?57

InChI:InChI=1/C23H27FN4O3/c1-14-17(23(30)28-9-2-3-19(29)22(28)25-14)8-12-27-10-6-15(7-11-27)21-18-5-4-16(24)13-20(18)31-26-21/h4-5,13,15,19,29H,2-3,6-12H2,1H3/t19-/m1/s1

Upstream product

• 1109182-35-5 C₂₈H₃₅FN₄O₄ 
• 1056034-13-9 C₃₀H₂₉FN₄O₃ 
• 1141761-80-9 3-(2-{4-((2,4-difluorophenyl)hydroxyiminomethyl)piperidin-1-yl}ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one 
• 84163-77-9 6-fluoro-3-(4-piperidinyl)benzo[d]isoxazole 
• 260273-82-3 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one 
• 130049-82-0 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one 
• 1388021-46-2 C₂₃H₂₈F₂N₄O₃ 
• 138271-16-6 (Z)-(2,4-difluorophenyl) (4-piperidinyl)methanone, oxime monohydrochloride 
• 1415488-05-9 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidine-4-one palmitate ester 
• 147687-17-0 9-(benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 
• 1138463-56-5 3-(2-chloroethyl)-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one 
• 199739-10-1 paliperidone palmitate 
• 24016-03-3 2-amino-3-benzyloxypyridine 
• 1312573-55-9 9-O-propionyl paliperidone 

Downstream Products

• 152542-03-5 3-{2-[4-(4-fluoro-2-hydroxybenzoyl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one 
• 1071864-06-6 3-{2-[4-(6-fluoro-1,2-benzoisoxazol-3-yl)-piperidin-1-yl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydro-pyrido[1,2-α]pyrimidin-9-yl benzoate 
• 1312573-56-0 9-O-phenylacetyl chloride paliperidone 
• 1071907-21-5 3-{2-[4-(6-fluoro-1,2-benzoisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-9-yl p-nitrophenyl carbonate 
• 199739-10-1 paliperidone palmitate 
• 1172995-13-9 paliperidone stearate 
• 1172995-11-7 paliperidone myristate 

Relevant articles and documents

METHODS AND COMPOSITIONS FOR TREATMENT OF CANCER

In an aspect, the disclosure pertains to inhibitors of ANGPTL4; synthesis methods for making disclosed compounds; pharmaceutical compositions comprising disclosed compounds; methods of treating disorders of uncontrolled cellular proliferation, e.g., a cancer; and methods of treating a disease associated with an ANGPTL4 dysfunction using disclosed compounds and pharmaceutical compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

Synthesis process of paliperidone palmitate

Belonging to the technical field of pharmaceutical compositions, the invention relates to a synthesis process of paliperidone palmitate. Through synthesis of P (paliperidone), refinement of P synthesis of PP (paliperidone palmitate) and refinement of PP, the paliperidone palmitate can be prepared. According to the invention, the process is controllable, the cost is low, the impurities are controllable, the refining process is simple and convenient, the product purity is high, and the yield is high.

Paliperidone intermediate and method for producing paliperidone using the same

Disclosed are novel intermediates of paliperidone which are used as a therapeutic agent for schizophrenia, and to a method for producing paliperidone using the same. The intermediates are a compound represented by chemical formula 3 and a compound represented by chemical formula 5. The method for producing paliperidone comprises a step of conducting a reaction of a compound represented by chemical formula 5 and an acid compound. In the chemical formulas 3 and 5, R is a silyl group, a hydrocarbon group having 1-20 carbon atoms, a protecting group represented by -R_1OR_2 or -R_1SR_2, or a protecting group represented by -C(=O)R_2. In particular, R_1 is a methylene group or a carbonyl group, and R_2 is a substituted or unsubstituted alkyl group, an aryl group, or an alkylaryl group, wherein R_1 and R_2 can bond to each other to form a ring.COPYRIGHT KIPO 2018

New synthesis method of paliperidone

The invention relates to a new synthesis method of paliperidone. 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one which are used as starting materials are reacted in the presence of a reducing reagent and an acid binding agent to obtain the paliperidone. The reducing agent is added in the reaction, so side reactions are reduced, the content of every impurity in the obtained finished product is significantly reduced, especially the content of the key impurity A is significantly reduced, the product has a high purity, and the method is simple to operate, and is suitable for industrial production.

Preparation method of palipefidone

The invention provides a preparation method of palipefidone. The preparation method comprises the following steps: dissolving a palipefidone crude product into a heated alcohol solution; adding active carbon under a heating condition; keeping heat and stirring; filtering when the solution is hot to obtain a filtrate; at a temperature of 45 DEG C to 60 DEG C, adding a reducing agent into the filtrate, and keeping the heat and stirring for 30 to 60 minutes; after stirring, controlling to cool for 8 DEG C to 15 DEG C every hour; slowly cooling and crystallizing; after crystallizing, filtering to obtain a solid and a refined mother solution respectively; performing water washing, alcohol washing and vacuum drying on the obtained solid to obtain palipefidone crystallized powder; decompressing and concentrating the refined mother solution and recycling palipefidone secondary precipitate. The preparation method of the palipefidone is simple in process and convenient to operate, does not need special equipment and is suitable for industrial production; a toxin-free or low-toxin solvent is adopted, so that environmental pollution is lowered; the prepared product has high purity, and the content of 9-keto impurities is reduced to be 0.05 percent, even lower.

A is suitable for industrial production of high-purity 9-hydroxy-risperidone

The invention discloses a method suitable for industrial production of high-purity 9-hydroxy-risperidone. According to the method, the 9-hydroxy-risperidone is prepared by carrying out condensation on 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one in a polar solvent system; by optimizing post-treatment operation and improving a refining method, the high-yield and high-purity 9-hydroxy-risperidone can be prepared by utilizing the steps of sedimentation, salifying, alkali regulation, crystallization and the like; the post-treatment and the refining method disclosed by the invention has the advantages of simplicity and convenience in operation, low production cost and high product purity and are suitable for use in the industrial production.

PREPARATION OF 3-[2-[4-((6-FLUORO-1, 2-BENZISOXAZOL-3-YL)-L-PIPERIDINYL)-6, 7, 8, 9-TETRAHYDRO-9-HYDROXY-2-METHYL-4H-PYRIDO[ 1, 2-A]-PYRIMIDIN-4-ONE (PALIPERIDONE) AND PALIPERIDONE PALMITATE.

An improved process for the synthesis of 3-[2-[4-((6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one (Paliperidone) and Paliperidone Palmitate through a novel intermediate (2-Chloroethyl)-6,7,8,9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido [1,2-a]pyrimidine-4-one Palmitate ester.

Green Synthesis of 3-(2-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-yl) ethyl-6,7,8,9-tetrahydro-9-hydroxy-2-methylpyridol[1,2-a]pyrimidin-4-one

Paliperidone has been synthesized in high yields by condensation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyridol[ 1,2a]pyrimidin-4-one (1) and (2,4-difluoro-phenyl)-piperidin-4-yl-methanone oxime (2) using K2CO3 as a base, refluxing in acetonitrile for 16 h. The novel intermediate (3) underwent internal cyclization in PEG-600 as solvent yielded paliperidone (4). Paliperidone (4) from novel intermediate (3) has also been prepared under microwave condition using PEG-600 and also in presence of a base KOH in toluene at 70 °C for 3 h in higher yields.

PROCESS FOR THE PREPARATION OF PALIPERIDONE

The present invention provides a process for the preparation of paliperidone or a pharmaceutically acceptable salt thereof, wherein the process comprises condensing a compound of formula (II) with a compound of formula (III) or a salt thereof, in a suitable solvent and a base, in the presence of a catalyst and an inhibiting agent, wherein the inhibiting agent is added to the reaction system before the compound of formula (II) and compound of formula (III) have reacted or as the reaction of the compound of formula (II) and compound of formula (III) is initiated, and optionally converting the paliperidone to a salt thereof, wherein X is a suitable leaving group. The present invention also provides substantially pure paliperidone or a salt thereof, paliperidone or a salt thereof as prepared by the process and uses of the paliperidone or salt thereof.

Processes for the preparation of paliperidone

The present invention relates to a novel process for the preparation of paliperidone and its intermediates and also relates to an improved process for the preparation of paliperidone compound of formula (I).