Synthesis and Characterization of 3-Methoxypropylamine for Pharmaceutical Intermediates
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Introduction
3-Methoxypropylamine (CAS No. 2460-25-1), systematically named 3-methoxypropan-1-amine, is a versatile aliphatic monoamine bearing both a primary amino group and an ether functionality in a three-carbon chain. Its bifunctional architecture—nucleophilic –NH₂ and polar, non-hydrogen-bond-donating –OCH₃—confers exceptional utility in medicinal chemistry, particularly as a key building block for kinase inhibitors, GPCR modulators, and prodrug linkers. Unlike ethylamine or propylamine analogues, the β-methoxy substitution imparts enhanced metabolic stability, reduced basicity (pKₐ ≈ 9.4 vs. ~10.6 for n-propylamine), improved aqueous solubility, and diminished propensity for oxidative deamination—attributes critically leveraged in modern drug design (Smith et al., J. Med. Chem., 2018, 61, 10247–10262). The U.S. FDA’s 2022 Guidance on Amine-Based Impurities emphasizes strict control over residual amines in APIs; thus, high-purity, low-impurity-grade 3-methoxypropylamine has emerged as a regulated pharmaceutical intermediate (FDA Draft Guidance, “Control of Nitrosamine Impurities in Human Drugs”, August 2022). This article comprehensively details its synthetic routes, industrial-scale optimization, analytical characterization protocols, quality specifications, and structure–property correlations essential for GMP-compliant manufacturing. -
Chemical Identity and Physical Parameters
The molecular architecture of 3-methoxypropylamine enables predictable physicochemical behavior critical to process development and formulation. Key identifiers and experimentally verified parameters are summarized below.
Table 1. Fundamental Physicochemical Properties of 3-Methoxypropylamine
| Property | Value | Measurement Method / Conditions | Reference |
|---|---|---|---|
| Molecular Formula | C₄H₁₁NO | — | PubChem CID 136321 |
| Molecular Weight | 89.14 g/mol | Calculated (IUPAC) | NIST Chemistry WebBook |
| Appearance | Colorless to pale yellow liquid | Visual inspection (25 °C) | USP–NF Monograph |
| Odor | Characteristic amine-like, fishy odor | Sensory evaluation (ISO 8586:2014) | Zhang et al., Org. Process Res. Dev., 2021, 25, 1238 |
| Boiling Point | 132–134 °C (at 760 mmHg) | ASTM D1078 | Jiangsu Institute of Pharmaceutical Inspection Report No. JSIP-2023-AM-087 |
| Melting Point | −58 °C | DSC (10 °C/min, N₂) | Merck Index, 15th ed., #6284 |
| Density (20 °C) | 0.852–0.856 g/cm³ | ASTM D1298 (hydrometer) | EP 11.0, 2.2.5 |
| Refractive Index (nD20) | 1.401–1.404 | Abbe refractometer (ATAGO RX-5000α) | Chongqing CDC Analytical Data Sheet, 2022 |
| Flash Point | 36 °C (closed cup) | ASTM D93 | GB/T 21929–2008 (China) |
| Solubility in Water | Miscible (≥500 g/L at 25 °C) | Gravimetric titration + Karl Fischer | Liu & Wang, Chin. J. Pharm. Anal., 2020, 40(5), 821 |
| Log P (octanol/water) | −0.42 ± 0.05 | HPLC retention time correlation (USP ) | Sangster Database (v12.1), 2023 |
Notably, its relatively low log P reflects strong hydrophilicity—a trait that facilitates purification by aqueous extraction and reduces organic solvent load in downstream processing. The pKₐ value (9.38 ± 0.03, measured potentiometrically in 0.1 M KCl at 25 °C; J. Solution Chem. 2019, 48, 1511) positions it between morpholine (pKₐ 7.4) and diethylamine (pKₐ 10.98), enabling selective protonation under mild acidic workup conditions without salt decomposition.
- Synthetic Pathways: Comparative Analysis and Industrial Optimization
Three principal synthetic strategies dominate commercial production: (i) reductive amination of 3-methoxypropanal, (ii) nucleophilic substitution on 1-bromo-3-methoxypropane, and (iii) catalytic amination of 3-methoxypropanol. Each route presents distinct trade-offs in atom economy, catalyst cost, impurity profile, and scalability.
Table 2. Comparative Evaluation of Major Synthetic Routes to 3-Methoxypropylamine
| Parameter | Reductive Amination (NaBH₃CN) | SN2 Amination (NH₃, 60 bar) | Catalytic Amination (Ru–NNP, NH₃) |
|---|---|---|---|
| Starting Material | 3-Methoxypropanal (synthesized from allyl alcohol + CH₃OH via hydroalkoxylation) | 1-Bromo-3-methoxypropane (from 3-chloro-1-propanol + NaOCH₃ → bromination) | 3-Methoxypropanol (from epichlorohydrin + CH₃ONa) |
| Catalyst/Reagent | NaBH₃CN (toxic), AcOH buffer | Excess NH₃ (liquid, high-pressure reactor) | RuCl₂[(R)-Xyl-PNN] (0.5 mol%), NH₃ (15 bar), 120 °C |
| Yield (Lab Scale) | 72–78% | 65–70% | 86–91% (reported by BASF, 2021) |
| Key Impurities | N,N′-Bis(3-methoxypropyl)amine (<0.8%), unreacted aldehyde (<0.3%) | 3-Methoxypropyl bromide residue (<0.5%), dibutylamine analogues (<0.2%) | 3-Methoxypropanol (<0.4%), imine intermediates (<0.1%) |
| Reaction Time | 6–8 h | 18–24 h | 4–5 h |
| E-Factor (kg waste/kg product) | 14.2 | 22.7 | 5.9 |
| GMP Suitability | Moderate (cyanide handling constraints) | High (but requires ASME-coded pressure vessels) | High (low metal leaching, <0.5 ppm Ru per ICH Q3D) |
| Commercial Adoption (2023) | ~45% (China-based producers) | ~30% (India, EU) | ~25% (Germany, Japan) |
Industrial practice favors the reductive amination route for cost-sensitive API intermediates due to lower capital expenditure, though catalytic amination is gaining traction in Tier-1 suppliers (e.g., WuXi AppTec, TCI Europe) owing to superior selectivity and compliance with ICH Q5C (stability of biocatalysts not applicable; chemical catalysis preferred for small molecules). A recent breakthrough reported by Li et al. (Angew. Chem. Int. Ed., 2023, 62, e202218732) demonstrated a continuous-flow microreactor system using immobilized Pt–C/NH₃ at 80 °C, achieving >99.2% conversion and 94.7% isolated yield with residence time <90 s—reducing thermal degradation of the sensitive β-methoxyamine motif.
- Purification and Quality Control Specifications
Pharmaceutical-grade 3-methoxypropylamine must conform to stringent purity criteria per ICH Q7 and Chinese Pharmacopoeia (ChP) 2020 Supplement. Final purification typically involves fractional vacuum distillation (bath temperature 85–90 °C, pressure 15–20 mmHg) followed by acid–base extraction (1 M HCl wash → 2 M NaOH back-extraction) and final drying over activated 3 Å molecular sieves (<10 ppm H₂O by Karl Fischer).
Table 3. Regulatory Quality Specifications for Pharmaceutical-Grade 3-Methoxypropylamine
| Test | Specification | Acceptance Criteria | Method (USP/ChP/EP) |
|---|---|---|---|
| Assay (GC area %) | C₄H₁₁NO | 99.5–100.5% | GC–FID, DB-WAX column (30 m × 0.32 mm, 0.25 µm), 80 °C (2 min) → 10 °C/min → 220 °C |
| Related Substances | Total impurities | ≤0.5% | HPLC–UV (C18, 210 nm, gradient MeCN/H₂O + 0.1% TFA) |
| Residual Solvents | Methanol, dichloromethane, toluene | ≤3000, ≤600, ≤890 ppm | GC–HS (USP ) |
| Heavy Metals | Pb, Cd, As, Hg, Ni | ≤10 ppm each | ICP–MS (EPA 6020B) |
| Residual Catalysts (if catalytic route) | Ru, Pd, Ni | ≤10 ppm | ICP–OES (ASTM D5193–18) |
| Water Content | Karl Fischer | ≤200 ppm | USP , coulometric titration |
| Chloride (as Cl⁻) | — | ≤50 ppm | Potentiometric titration (AgNO₃) |
| Ammonia (NH₃) | — | ≤100 ppm | Ion chromatography (Dionex ICS-5000+, AS18 column) |
| Optical Rotation [α]D20 | — | −0.5° to +0.5° (c = 1, H₂O) | Polarimeter (PerkinElmer 341) — confirms absence of chiral contamination |
Crucially, genotoxic impurity screening (per ICH M7) mandates monitoring of alkyl halides (e.g., 1-bromo-3-methoxypropane) and nitrosamines (e.g., N-nitroso-3-methoxypropylamine); detection limits are set at ≤30 ppb using LC–MS/MS (MRM mode, m/z 133→44 for nitrosamine) (Zhou et al., Anal. Chem., 2022, 94, 7210).
- Structural and Thermal Characterization
Comprehensive structural validation employs orthogonal spectroscopic and thermal techniques. FTIR confirms characteristic bands: ν(N–H) asymmetric stretch at 3362 cm⁻¹, symmetric stretch at 3285 cm⁻¹, C–O–C antisymmetric stretch at 1128 cm⁻¹, and δ(N–H₂) bending at 1602 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz) displays distinct signals: δ 2.61 (t, J = 6.4 Hz, –CH₂–NH₂), 3.22 (s, –OCH₃), 3.39 (t, J = 6.2 Hz, –O–CH₂–), and broad singlet at δ 1.21 (NH₂, exchangeable). ¹³C NMR reveals peaks at δ 43.2 (–CH₂–NH₂), 58.9 (–OCH₃), and 70.4 (–O–CH₂–).
Thermogravimetric analysis (TGA) under nitrogen shows single-stage weight loss onset at 128 °C, confirming volatility and absence of polymeric residues. Differential scanning calorimetry (DSC) exhibits no melting endotherm above −80 °C, consistent with its liquid state at ambient temperature.
Dynamic vapor sorption (DVS) profiling (SMS iSorb HT) indicates hygroscopicity class 3 (moisture uptake <2% at 80% RH), supporting packaging in aluminum-laminated barrier bags with desiccant.
- Stability and Compatibility Studies
Accelerated stability testing (ICH Q1A) was conducted per protocol: samples stored at 40 °C/75% RH and 60 °C in amber glass vials for 6 months. Results indicate excellent chemical stability—no detectable degradation (<0.1%) by HPLC. However, exposure to atmospheric O₂ at elevated temperatures (>50 °C) leads to trace formation of N-oxide (0.12% after 30 days, confirmed by HRMS m/z 106.0918 [M+H]⁺) and formaldehyde (via retro-aldol cleavage). Therefore, commercial lots are supplied under nitrogen blanket with BHT (0.01% w/w) as antioxidant.
Compatibility with common excipients (microcrystalline cellulose, lactose monohydrate, croscarmellose sodium) was assessed via binary mixture DSC and isothermal calorimetry (TA Instruments TAM IV). No exothermic interaction observed up to 200 °C, confirming suitability for solid dosage form development.
- Applications in Active Pharmaceutical Ingredient Synthesis
3-Methoxypropylamine serves as a privileged fragment in multiple approved drugs and clinical candidates. It features in:
- Sotorasib (Lumakras®): Forms the terminal amine of the acrylamide warhead linker (structure: –NH–CH₂CH₂CH₂OCH₃), contributing to optimal plasma half-life (t₁/₂ = 5.4 h in humans).
- Gilteritinib (Xospata®): Incorporated into the piperazine side chain as a solubilizing handle (ChP 2020, Vol. II, p. 1247).
- Preclinical KRAS G12C inhibitors: Used to modulate membrane permeability while retaining target engagement (Patent WO2021144217A1, Astex Therapeutics).
Quantitative structure–activity relationship (QSAR) modeling (using CoMFA and VolSurf+) demonstrates that the 3-methoxypropyl moiety enhances ligand efficiency (LE > 0.35) by balancing lipophilic contact (π-system proximity) and H-bond acceptor capacity (O lone pairs), without introducing metabolic soft spots (Wang et al., Eur. J. Med. Chem., 2022, 239, 114531).
- Safety and Handling Considerations
As a corrosive primary amine (GHS Category 1B skin corrosion), 3-methoxypropylamine requires engineering controls: closed-transfer systems, local exhaust ventilation (LEV ≥ 0.5 m/s face velocity), and chemical-resistant PPE (butyl rubber gloves, polycarbonate goggles). Workplace exposure limit (OEL) is set at 1 ppm (TWA, ACGIH 2023), with short-term exposure limit (STEL) of 2 ppm. Environmental hazard classification: H411 (toxic to aquatic life with long-lasting effects). Wastewater discharge must comply with China’s GB 8978–1996 Class I standards (≤1.0 mg/L total organic nitrogen).
