Friedel-Crafts Condensation Pathway

The classical synthesis involves a multi-step sequence starting with Friedel-Crafts acylation. 1,3-Difluorobenzene (I) reacts with 1-acetylpiperidine-4-carbonyl chloride (II) in dichloromethane catalyzed by AlCl₃, yielding 1-acetyl-4-(2,4-difluorobenzoyl)piperidine (III). Hydrolysis of III with 6N HCl under reflux produces 4-(2,4-difluorobenzoyl)piperidine (IV), which is subsequently converted to an oxime (V) via hydroxylamine in ethanol. Cyclization of V with KOH in boiling water generates 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (VI), which is finally condensed with 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (VII) using K₂CO₃ and KI.

Alkylation-Based Synthesis

An alternative method involves reacting 4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidine with 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one in aqueous Na₂CO₃ at 85–90°C for 4 hours. Post-reaction processing includes dissolution in dimethylformamide (DMF) at 80°C, followed by cooling and filtration to yield this compound with 73% efficiency.

Polymorphic Form Preparation

This compound exhibits multiple polymorphic forms (A, B, E), each requiring distinct crystallization conditions.

Form A Crystallization

Solvent-Based Methods :

• Dissolution in organic solvents (e.g., acetone, toluene, methanol) at reflux, followed by cooling to 25°C and ice-bath precipitation. Optimal solvent ratios include 1:28–1:32 (this compound:acetone) for 99.7–99.8% purity.

• Dichloromethane/cyclohexane systems: this compound dissolved in dichloromethane (1:9 ratio) precipitates Form A upon hexane addition.

Thermal Conversion :

• Heating Form B at 80°C under reduced pressure for 16–20 hours induces conversion to Form A.

Form B Crystallization

• Alcohol/Water Systems : this compound dissolved in C₁–C₄ alcohols (1:7.5–1:9 ratio) precipitates Form B upon water addition. Methanol (45 mL/g) with 70 mL water yields Form B, convertible to A via heating.

• Acid/Base Precipitation : Dissolution in 0.5N HCl followed by Na₂CO₃ addition at pH 8 produces Form B mixtures.

Form E Crystallization

• Isopropanol/water mixtures (1:12 this compound:isopropanol) facilitate Form E precipitation.

Recrystallization and Purification

Solvent Selection for Purity Enhancement

Recrystallization in acetone eliminates residual DMF, addressing toxicity concerns. Hot filtration at reflux ensures impurity removal, with cooling rates affecting crystal size and form stability.

Process Optimization and Yield Analysis

Temperature and Time Dependence

• Reflux Duration :

  • Isopropanol: 9 hours

  • Methyl ethyl ketone: Overnight

  • Acetonitrile: 17 hours

• Thermal Stability : Form A remains stable ≤80°C, while Form B converts above 25°C.

Catalytic and Solvent Effects

• AlCl₃ in Friedel-Crafts : Critical for acylation efficiency but requires stringent moisture control.

• K₂CO₃ vs. NaOH : K₂CO₃ in alkylation reduces side reactions, improving yield to 73% vs. 50–60% with NaOH.

Comparative Analysis of Methods

Table 1: Olanzapine vs. This compound in BPSD

Lurasidone

Efficacy: A 6-week randomized trial demonstrated non-inferiority of lurasidone to this compound in schizophrenia, with a pre-specified margin of 7 points on the PANSS scale . Safety: Lurasidone has a lower EPS risk and minimal metabolic impact compared to this compound, making it preferable for patients with obesity or diabetes .

Paliperidone (9-Hydroxythis compound)

Pharmacodynamics: Paliperidone, the primary metabolite of this compound, has lower 5-HT2A affinity (5-HT2A/D2 ratio = 1.0 vs. Pharmacokinetics: As a long-acting injectable, paliperidone palmitate achieves steadier plasma concentrations than oral this compound, improving adherence . Tolerability: this compound ISM (in situ microsuspension) required anticholinergic agents in 2.3% of patients vs. 4.1% for paliperidone palmitate .

Table 2: Receptor Binding Affinities

Haloperidol

Efficacy : this compound ≤8 mg/day showed comparable efficacy to haloperidol in schizophrenia but with superior tolerability .
Safety : EPS incidence with this compound (22%) was half that of haloperidol (45%), and this compound required fewer anticholinergic adjuncts (15% vs. 38%) .

Other SGAs

• Clozapine : Superior efficacy in treatment-resistant schizophrenia but carries a risk of agranulocytosis, unlike this compound .
• Amisulpride : Similar EPS rates to this compound but less effective against negative symptoms .
• Ziprasidone : Both inhibit CYP2D6 (Ki = 6.9 μM for this compound vs. 11 μM for ziprasidone), increasing drug interaction risks .

Pharmacokinetic and Metabolic Considerations

• Formulation Impact : A lipid-based this compound formulation (VAL401) showed similar AUC and C_max to oral this compound but a shorter half-life (15 vs. 20 hours), possibly due to altered distribution .
• CYP Interactions : this compound’s metabolism via CYP2D6 makes it susceptible to interactions with inhibitors (e.g., terbinafine), elevating this compound:9-OHR ratios and EPS risk .

Table 3: CYP Enzyme Inhibition Profiles

Table 4: EPS Incidence Across Antipsychotics

Q. How do standardized psychiatric rating scales (e.g., PANSS) address variability in assessing risperidone’s efficacy for schizophrenia?

The Positive and Negative Syndrome Scale (PANSS) operationalizes symptom severity through 30 items, balancing positive, negative, and general psychopathology domains. Its reliability stems from standardized scoring protocols and statistical validation (e.g., inverse correlation between positive/negative symptoms after controlling for global severity). Researchers must ensure inter-rater reliability by training evaluators and applying correction factors for baseline symptom heterogeneity .

Q. What methodological challenges arise in designing pediatric formulations of this compound, and how are they addressed?

Pediatric formulations require overcoming poor drug flowability, compaction, and dosing precision. A Box-Behnken experimental design optimizes excipient combinations (e.g., mannitol, microcrystalline cellulose) to improve mechanical properties and disintegration times. Critical parameters include superdisintegrant swelling pressure and glidant surface area, validated via FTIR compatibility studies and in vitro disintegration testing .

Q. How are physicochemical properties (e.g., pKa, log P) of this compound determined to inform formulation and pharmacokinetic studies?

The dissociation constant (pKa) is measured via UV-spectrophotometric titration across pH gradients, while the partition coefficient (log P) is quantified using the shake-flask method with octanol/water phases. These parameters guide solubility enhancement strategies and predict bioavailability in preclinical models .

Advanced Research Questions

Q. How can researchers reconcile contradictory findings in this compound’s osteoblast toxicity across preclinical models?

Dose-dependent inhibition of MC3T3-E1 cell proliferation (e.g., 48-hour IC50) must be contextualized with in vivo pharmacokinetics. Confounding factors include species-specific metabolic pathways and exposure duration. Researchers should employ longitudinal studies with bone turnover biomarkers (e.g., ALP, TRAP) and adjust dosing regimens to mirror human therapeutic indices .

Q. What statistical approaches mitigate bias in retrospective analyses of this compound-associated adverse events (AEs) in EHR datasets?

Multivariate regression models adjust for covariates like comorbidities, polypharmacy, and dose escalation patterns. Time-to-event analyses (e.g., Kaplan-Meier) account for censored data, while MedEx NLP tools standardize AE extraction from unstructured clinical notes. Sensitivity analyses validate robustness against missing data assumptions .

Q. How does the Box-Behnken design optimize this compound OD-mini-tablets while minimizing production variability?

This response surface methodology evaluates interactions between excipient ratios (X1: mannitol-Avicel), superdisintegrant swelling (X2), and glidant surface area (X3). Outputs (crushing strength, friability) are modeled via polynomial equations to identify robust design spaces. Process validation includes content uniformity testing per USP <905> .

Q. What mechanistic insights link this compound’s receptor affinity to differential outcomes in autism-related irritability vs. schizophrenia?

Comparative receptor binding assays (e.g., D2/5-HT2A ratios) and fMRI studies correlate occupancy thresholds with behavioral outcomes. In autism, lower D2 affinity may reduce extrapyramidal symptoms, while 5-HT2A antagonism modulates irritability. Mechanistic studies should integrate PET imaging with longitudinal PANSS-A (Autism) subscales .

Q. How do HPLC method validation protocols ensure specificity in quantifying this compound and its metabolites?

A 32-mixture design optimizes mobile phase composition (methanol-acetonitrile-phosphate buffer) for baseline separation. Validation includes linearity (1–50 µg/mL), precision (RSD <2%), and robustness testing per ICH Q2(R1). Forced degradation studies (acid/alkaline hydrolysis) confirm stability-indicating capability .

Methodological Guidelines

What criteria define a well-structured research question for this compound clinical trials?

Apply the PICOT framework: P opulation (e.g., children with autism), I ntervention (this compound dose range), C omparator (placebo/alternative antipsychotic), O utcome (e.g., ABC-Irritability score), and T imeframe (8-week RCT). Avoid vague terms like “evaluate efficacy” in favor of operationalized endpoints .

Q. How should systematic reviews address heterogeneity in this compound pharmacovigilance studies?

Use SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type) to filter studies by AE type, dosing regimen, and patient demographics. Meta-regression models quantify heterogeneity sources (e.g., age, CYP2D6 polymorphisms), while GRADE criteria assess evidence quality .