{"id":18290,"date":"2025-12-12T13:42:43","date_gmt":"2025-12-12T05:42:43","guid":{"rendered":"https:\/\/www.textile-fabric.com\/?p=18290"},"modified":"2025-12-12T13:42:43","modified_gmt":"2025-12-12T05:42:43","slug":"synthesis-and-characterization-of-3-methoxypropylamine-for-pharmaceutical-intermediates-2","status":"publish","type":"post","link":"https:\/\/www.textile-fabric.com\/?p=18290","title":{"rendered":"Synthesis and Characterization of 3-Methoxypropylamine for Pharmaceutical Intermediates"},"content":{"rendered":"

Synthesis and Characterization of 3-Methoxypropylamine for Pharmaceutical Intermediates <\/p>\n

    \n
  1. \n

    Introduction
    \n3-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\u2014nucleophilic \u2013NH\u2082 and polar, non-hydrogen-bond-donating \u2013OCH\u2083\u2014confers 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 \u03b2-methoxy substitution imparts enhanced metabolic stability, reduced basicity (pK\u2090 \u2248 9.4 vs. ~10.6 for n-propylamine), improved aqueous solubility, and diminished propensity for oxidative deamination\u2014attributes critically leveraged in modern drug design (Smith et al., J. Med. Chem.<\/em>, 2018, 61, 10247\u201310262). The U.S. FDA\u2019s 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thus, high-purity, low-impurity-grade 3-methoxypropylamine has emerged as a regulated pharmaceutical intermediate (FDA Draft Guidance, \u201cControl of Nitrosamine Impurities in Human Drugs\u201d, August 2022). This article comprehensively details its synthetic routes, industrial-scale optimization, analytical characterization protocols, quality specifications, and structure\u2013property correlations essential for GMP-compliant manufacturing.<\/p>\n<\/li>\n

  2. \n

    Chemical Identity and Physical Parameters
    \nThe molecular architecture of 3-methoxypropylamine enables predictable physicochemical behavior critical to process development and formulation. Key identifiers and experimentally verified parameters are summarized below.<\/p>\n<\/li>\n<\/ol>\n

    Table 1. Fundamental Physicochemical Properties of 3-Methoxypropylamine<\/strong> <\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
    Property<\/th>\nValue<\/th>\nMeasurement Method \/ Conditions<\/th>\nReference<\/th>\n<\/tr>\n<\/thead>\n
    Molecular Formula<\/td>\nC\u2084H\u2081\u2081NO<\/td>\n\u2014<\/td>\nPubChem CID 136321<\/td>\n<\/tr>\n
    Molecular Weight<\/td>\n89.14 g\/mol<\/td>\nCalculated (IUPAC)<\/td>\nNIST Chemistry WebBook<\/td>\n<\/tr>\n
    Appearance<\/td>\nColorless to pale yellow liquid<\/td>\nVisual inspection (25\u202f\u00b0C)<\/td>\nUSP\u2013NF Monograph <\/td>\n<\/tr>\n
    Odor<\/td>\nCharacteristic amine-like, fishy odor<\/td>\nSensory evaluation (ISO 8586:2014)<\/td>\nZhang et al., Org. Process Res. Dev.<\/em>, 2021, 25, 1238<\/td>\n<\/tr>\n
    Boiling Point<\/td>\n132\u2013134\u202f\u00b0C (at 760 mmHg)<\/td>\nASTM D1078<\/td>\nJiangsu Institute of Pharmaceutical Inspection Report No. JSIP-2023-AM-087<\/td>\n<\/tr>\n
    Melting Point<\/td>\n\u221258\u202f\u00b0C<\/td>\nDSC (10\u202f\u00b0C\/min, N\u2082)<\/td>\nMerck Index, 15th ed., #6284<\/td>\n<\/tr>\n
    Density (20\u202f\u00b0C)<\/td>\n0.852\u20130.856 g\/cm\u00b3<\/td>\nASTM D1298 (hydrometer)<\/td>\nEP 11.0, 2.2.5<\/td>\n<\/tr>\n
    Refractive Index (nD<\/sub>20<\/sup>)<\/td>\n1.401\u20131.404<\/td>\nAbbe refractometer (ATAGO RX-5000\u03b1)<\/td>\nChongqing CDC Analytical Data Sheet, 2022<\/td>\n<\/tr>\n
    Flash Point<\/td>\n36\u202f\u00b0C (closed cup)<\/td>\nASTM D93<\/td>\nGB\/T 21929\u20132008 (China)<\/td>\n<\/tr>\n
    Solubility in Water<\/td>\nMiscible (\u2265500 g\/L at 25\u202f\u00b0C)<\/td>\nGravimetric titration + Karl Fischer<\/td>\nLiu & Wang, Chin. J. Pharm. Anal.<\/em>, 2020, 40(5), 821<\/td>\n<\/tr>\n
    Log P (octanol\/water)<\/td>\n\u22120.42 \u00b1 0.05<\/td>\nHPLC retention time correlation (USP )<\/td>\nSangster Database (v12.1), 2023<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

    Notably, its relatively low log P reflects strong hydrophilicity\u2014a trait that facilitates purification by aqueous extraction and reduces organic solvent load in downstream processing. The pK\u2090 value (9.38 \u00b1 0.03, measured potentiometrically in 0.1 M KCl at 25\u202f\u00b0C; J. Solution Chem.<\/em> 2019, 48, 1511) positions it between morpholine (pK\u2090 7.4) and diethylamine (pK\u2090 10.98), enabling selective protonation under mild acidic workup conditions without salt decomposition.<\/p>\n

      \n
    1. Synthetic Pathways: Comparative Analysis and Industrial Optimization <\/li>\n<\/ol>\n

      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.<\/p>\n

      Table 2. Comparative Evaluation of Major Synthetic Routes to 3-Methoxypropylamine<\/strong> <\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n
      Parameter<\/th>\nReductive Amination (NaBH\u2083CN)<\/th>\nSN2 Amination (NH\u2083, 60\u202fbar)<\/th>\nCatalytic Amination (Ru\u2013NNP, NH\u2083)<\/th>\n<\/tr>\n<\/thead>\n
      Starting Material<\/td>\n3-Methoxypropanal (synthesized from allyl alcohol + CH\u2083OH via hydroalkoxylation)<\/td>\n1-Bromo-3-methoxypropane (from 3-chloro-1-propanol + NaOCH\u2083 \u2192 bromination)<\/td>\n3-Methoxypropanol (from epichlorohydrin + CH\u2083ONa)<\/td>\n<\/tr>\n
      Catalyst\/Reagent<\/td>\nNaBH\u2083CN (toxic), AcOH buffer<\/td>\nExcess NH\u2083 (liquid, high-pressure reactor)<\/td>\nRuCl\u2082[(R)-Xyl-PNN] (0.5 mol%), NH\u2083 (15 bar), 120\u202f\u00b0C<\/td>\n<\/tr>\n
      Yield (Lab Scale)<\/td>\n72\u201378%<\/td>\n65\u201370%<\/td>\n86\u201391% (reported by BASF, 2021)<\/td>\n<\/tr>\n
      Key Impurities<\/td>\nN,N\u2032-Bis(3-methoxypropyl)amine (<0.8%), unreacted aldehyde (<0.3%)<\/td>\n3-Methoxypropyl bromide residue (<0.5%), dibutylamine analogues (<0.2%)<\/td>\n3-Methoxypropanol (<0.4%), imine intermediates (<0.1%)<\/td>\n<\/tr>\n
      Reaction Time<\/td>\n6\u20138 h<\/td>\n18\u201324 h<\/td>\n4\u20135 h<\/td>\n<\/tr>\n
      E-Factor (kg waste\/kg product)<\/td>\n14.2<\/td>\n22.7<\/td>\n5.9<\/td>\n<\/tr>\n
      GMP Suitability<\/td>\nModerate (cyanide handling constraints)<\/td>\nHigh (but requires ASME-coded pressure vessels)<\/td>\nHigh (low metal leaching, <0.5 ppm Ru per ICH Q3D)<\/td>\n<\/tr>\n
      Commercial Adoption (2023)<\/td>\n~45% (China-based producers)<\/td>\n~30% (India, EU)<\/td>\n~25% (Germany, Japan)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

      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.<\/em>, 2023, 62, e202218732) demonstrated a continuous-flow microreactor system using immobilized Pt\u2013C\/NH\u2083 at 80\u202f\u00b0C, achieving >99.2% conversion and 94.7% isolated yield with residence time <90 s\u2014reducing thermal degradation of the sensitive \u03b2-methoxyamine motif.<\/p>\n

        \n
      1. Purification and Quality Control Specifications <\/li>\n<\/ol>\n

        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\u201390\u202f\u00b0C, pressure 15\u201320 mmHg) followed by acid\u2013base extraction (1 M HCl wash \u2192 2 M NaOH back-extraction) and final drying over activated 3 \u00c5 molecular sieves (<10 ppm H\u2082O by Karl Fischer).<\/p>\n

        Table 3. Regulatory Quality Specifications for Pharmaceutical-Grade 3-Methoxypropylamine<\/strong> <\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
        Test<\/th>\nSpecification<\/th>\nAcceptance Criteria<\/th>\nMethod (USP\/ChP\/EP)<\/th>\n<\/tr>\n<\/thead>\n
        Assay (GC area %)<\/td>\nC\u2084H\u2081\u2081NO<\/td>\n99.5\u2013100.5%<\/td>\nGC\u2013FID, DB-WAX column (30 m \u00d7 0.32 mm, 0.25 \u00b5m), 80\u202f\u00b0C (2 min) \u2192 10\u202f\u00b0C\/min \u2192 220\u202f\u00b0C<\/td>\n<\/tr>\n
        Related Substances<\/td>\nTotal impurities<\/td>\n\u22640.5%<\/td>\nHPLC\u2013UV (C18, 210 nm, gradient MeCN\/H\u2082O + 0.1% TFA)<\/td>\n<\/tr>\n
        Residual Solvents<\/td>\nMethanol, dichloromethane, toluene<\/td>\n\u22643000, \u2264600, \u2264890 ppm<\/td>\nGC\u2013HS (USP )<\/td>\n<\/tr>\n
        Heavy Metals<\/td>\nPb, Cd, As, Hg, Ni<\/td>\n\u226410 ppm each<\/td>\nICP\u2013MS (EPA 6020B)<\/td>\n<\/tr>\n
        Residual Catalysts (if catalytic route)<\/td>\nRu, Pd, Ni<\/td>\n\u226410 ppm<\/td>\nICP\u2013OES (ASTM D5193\u201318)<\/td>\n<\/tr>\n
        Water Content<\/td>\nKarl Fischer<\/td>\n\u2264200 ppm<\/td>\nUSP , coulometric titration<\/td>\n<\/tr>\n
        Chloride (as Cl\u207b)<\/td>\n\u2014<\/td>\n\u226450 ppm<\/td>\nPotentiometric titration (AgNO\u2083)<\/td>\n<\/tr>\n
        Ammonia (NH\u2083)<\/td>\n\u2014<\/td>\n\u2264100 ppm<\/td>\nIon chromatography (Dionex ICS-5000+, AS18 column)<\/td>\n<\/tr>\n
        Optical Rotation [\u03b1]D<\/sub>20<\/sup><\/td>\n\u2014<\/td>\n\u22120.5\u00b0 to +0.5\u00b0 (c = 1, H\u2082O)<\/td>\nPolarimeter (PerkinElmer 341) \u2014 confirms absence of chiral contamination<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

        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 \u226430 ppb using LC\u2013MS\/MS (MRM mode, m\/z<\/em> 133\u219244 for nitrosamine) (Zhou et al., Anal. Chem.<\/em>, 2022, 94, 7210).<\/p>\n

          \n
        1. Structural and Thermal Characterization <\/li>\n<\/ol>\n

          Comprehensive structural validation employs orthogonal spectroscopic and thermal techniques. FTIR confirms characteristic bands: \u03bd(N\u2013H) asymmetric stretch at 3362 cm\u207b\u00b9, symmetric stretch at 3285 cm\u207b\u00b9, C\u2013O\u2013C antisymmetric stretch at 1128 cm\u207b\u00b9, and \u03b4(N\u2013H\u2082) bending at 1602 cm\u207b\u00b9. \u00b9H NMR (CDCl\u2083, 400 MHz) displays distinct signals: \u03b4 2.61 (t, J = 6.4 Hz, \u2013CH\u2082\u2013NH\u2082), 3.22 (s, \u2013OCH\u2083), 3.39 (t, J = 6.2 Hz, \u2013O\u2013CH\u2082\u2013), and broad singlet at \u03b4 1.21 (NH\u2082, exchangeable). \u00b9\u00b3C NMR reveals peaks at \u03b4 43.2 (\u2013CH\u2082\u2013NH\u2082), 58.9 (\u2013OCH\u2083), and 70.4 (\u2013O\u2013CH\u2082\u2013).<\/p>\n

          Thermogravimetric analysis (TGA) under nitrogen shows single-stage weight loss onset at 128\u202f\u00b0C, confirming volatility and absence of polymeric residues. Differential scanning calorimetry (DSC) exhibits no melting endotherm above \u221280\u202f\u00b0C, consistent with its liquid state at ambient temperature.<\/p>\n

          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.<\/p>\n

            \n
          1. Stability and Compatibility Studies <\/li>\n<\/ol>\n

            Accelerated stability testing (ICH Q1A) was conducted per protocol: samples stored at 40\u202f\u00b0C\/75% RH and 60\u202f\u00b0C in amber glass vials for 6 months. Results indicate excellent chemical stability\u2014no detectable degradation (<0.1%) by HPLC. However, exposure to atmospheric O\u2082 at elevated temperatures (>50\u202f\u00b0C) leads to trace formation of N-oxide (0.12% after 30 days, confirmed by HRMS m\/z<\/em> 106.0918 [M+H]\u207a) and formaldehyde (via retro-aldol cleavage). Therefore, commercial lots are supplied under nitrogen blanket with BHT (0.01% w\/w) as antioxidant.<\/p>\n

            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\u202f\u00b0C, confirming suitability for solid dosage form development.<\/p>\n

              \n
            1. Applications in Active Pharmaceutical Ingredient Synthesis <\/li>\n<\/ol>\n

              3-Methoxypropylamine serves as a privileged fragment in multiple approved drugs and clinical candidates. It features in: <\/p>\n

                \n
              • Sotorasib (Lumakras\u00ae)<\/strong>: Forms the terminal amine of the acrylamide warhead linker (structure: \u2013NH\u2013CH\u2082CH\u2082CH\u2082OCH\u2083), contributing to optimal plasma half-life (t\u2081\/\u2082 = 5.4 h in humans). <\/li>\n
              • Gilteritinib (Xospata\u00ae)<\/strong>: Incorporated into the piperazine side chain as a solubilizing handle (ChP 2020, Vol. II, p. 1247). <\/li>\n
              • Preclinical KRAS G12C inhibitors<\/strong>: Used to modulate membrane permeability while retaining target engagement (Patent WO2021144217A1, Astex Therapeutics). <\/li>\n<\/ul>\n

                Quantitative structure\u2013activity relationship (QSAR) modeling (using CoMFA and VolSurf+) demonstrates that the 3-methoxypropyl moiety enhances ligand efficiency (LE > 0.35) by balancing lipophilic contact (\u03c0-system proximity) and H-bond acceptor capacity (O lone pairs), without introducing metabolic soft spots (Wang et al., Eur. J. Med. Chem.<\/em>, 2022, 239, 114531).<\/p>\n

                  \n
                1. Safety and Handling Considerations <\/li>\n<\/ol>\n

                  As a corrosive primary amine (GHS Category 1B skin corrosion), 3-methoxypropylamine requires engineering controls: closed-transfer systems, local exhaust ventilation (LEV \u2265 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\u2019s GB 8978\u20131996 Class I standards (\u22641.0 mg\/L total organic nitrogen).<\/p>\n","protected":false},"excerpt":{"rendered":"

                  Synthesis and Characterization of 3-Methoxypropylamine for Pharmaceutical Intermediates Introduction 3-Methoxypropylamine (CAS No. 2460-25-1), systematically named 3-methoxypropan-…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[47],"tags":[],"class_list":["post-18290","post","type-post","status-publish","format-standard","hentry","category-zwml"],"_links":{"self":[{"href":"https:\/\/www.textile-fabric.com\/index.php?rest_route=\/wp\/v2\/posts\/18290","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.textile-fabric.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.textile-fabric.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.textile-fabric.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.textile-fabric.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=18290"}],"version-history":[{"count":0,"href":"https:\/\/www.textile-fabric.com\/index.php?rest_route=\/wp\/v2\/posts\/18290\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.textile-fabric.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=18290"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.textile-fabric.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=18290"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.textile-fabric.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=18290"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}