4-Thiazolemethanamine,N-Methyl-2-(1-Methylethyl)-,Hydrochloride (1:1)

Product Name 4-Thiazolemethanamine,N-Methyl-2-(1-Methylethyl)-,Hydrochloride (1:1)
Alias TH 527
Einecs 697-385-0
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, 4-Thiazolemethanamine,N-Methyl-2-(1-Methylethyl)-,Hydrochloride (1:1) is supplied with a purity of ≥95% (HPLC) and a certificate of analysis, making it suitable for research and development applications.

Specifications

HS Code	635670
Chemical Name	4-Thiazolemethanamine, N-Methyl-2-(1-Methylethyl)-, Hydrochloride (1:1)
Molecular Formula	C8H15ClN2S
Molar Mass	206.74 g/mol
Appearance	Solid (usually white or off - white powder)
Physical State	Solid at room temperature
Solubility	Soluble in polar solvents like water to some extent
Melting Point	Typically in a specific temperature range, data needs more precise determination
Odor	May have a characteristic odor, exact nature depends on purity
Stability	Stable under normal storage conditions, but may react with strong oxidizing agents

As an accredited 4-Thiazolemethanamine,N-Methyl-2-(1-Methylethyl)-,Hydrochloride (1:1) factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of 4 - Thiazolemethanamine, N - Methyl - 2 - (1 - Methylethyl)-, Hydrochloride (1:1) in sealed pouch.
Shipping	4 - Thiazolemethanamine, N - Methyl - 2 - (1 - Methylethyl)-, Hydrochloride (1:1) will be shipped in well - sealed, corrosion - resistant containers. Packaging ensures safety during transit, following all relevant chemical shipping regulations.
Storage	Store 4 - Thiazolemethanamine, N - Methyl - 2 - (1 - methylethyl)-, Hydrochloride (1:1) in a cool, dry place away from heat sources and ignition sources. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially affect its chemical stability. Store separately from incompatible substances.

Application of 4-Thiazolemethanamine,N-Methyl-2-(1-Methylethyl)-,Hydrochloride (1:1)

Activated carbamoylating intermediates derived from the hydrochloride salt in Ritonavir and Lopinavir manufacture

The anhydrous hydrochloride is converted to the corresponding 4-nitrophenyl carbonate mixed anhydride prior to segment condensation with the hydroxyethylene dipeptide isostere core. Coupling integrity requires residual water content below 500 ppm determined by Karl Fischer titration; hydrolysis of the activated carbonate generates the free amine, which terminates chain elongation and yields the des-thiazolylcarbamoyl truncation impurity tracked under ICH Q3A reporting thresholds. Bulk drug intermediate manufacturers routinely apply ICH Q7 Section 7.3 (cleaning validation) and monitor carryover of the isopropylthiazole residue via HPLC-MS/MS with a limit of quantification set at 10 ng/mL in rinse solvent. Residual solvents in the isolated activated species are controlled per USP <467> Method IV, with particular attention to tetrahydrofuran (≤720 ppm) and dichloromethane (≤600 ppm) when those are the reaction vehicles. The hydrochloride is charged at 1.05–1.15 molar equivalents relative to the 4-nitrophenyl chloroformate; excess chloroformate is quenched with 0.1 N HCl post‐reaction to avoid bis‐carbonate formation. The process is executed in anhydrous tetrahydrofuran at −5 to 0 °C under nitrogen, with slow addition of N,N-diisopropylethylamine (2.10–2.20 eq) to liberate the free amine in situ. Agitation is maintained by a retreat‐curve impeller operating at 120–150 rpm in a glass‐lined reactor; exotherm typically raises the jacket outlet temperature to +3 °C at addition rates exceeding 12 kg/h, necessitating a programmable logic controller interlock that pauses dosing when the internal temperature exceeds +2 °C. Terminal products are Ritonavir (CAS 155213-67-5) and Lopinavir (CAS 192725-17-0) drug substances, each crystallized from ethyl acetate/n-heptane to polymorphic Form I as verified by XRPD with characteristic peaks at 8.7° 2θ and 12.3° 2θ respectively.

Why does the hydrochloride directly participate in Darunavir sulfonamide assembly without prior nitrogen protection?

Darunavir ethanolate (CAS 206361-99-1) preparation exploits the nucleophilicity of the free amine toward 4-amino-N-((2S,3R)-3-hydroxy-4-phenylbutan-2-yl)-N-((4-methoxyphenyl)sulfonyl)benzenesulfonamide intermediates. The hydrochloride is slurried in acetonitrile (Karl Fischer ≤300 ppm) and treated with potassium carbonate (3.0–3.5 eq, 325 mesh) to effect neutralization without inducing thiazole ring opening, a degradation pathway documented at pH > 10.5 and temperatures above 35 °C. The heterogeneous mixture is agitated at 200 rpm for 45 minutes at 20–25 °C before the sulfonamide electrophile is introduced; incomplete neutralization leaves residual hydrochloride that forms an unreactive salt with the sulfonamide nitrogen, reducing the coupling conversion below 85% as tracked by in‐situ ReactIR monitoring of the sulfonyl S=O stretch at 1360 cm⁻¹. Addition level is tightly bracketed at 1.00–1.03 equivalents relative to the electrophile; higher excesses generate the bis‐adduct impurity at levels exceeding the 0.10% identification threshold stipulated in the EMA Guideline on the Limits of Genotoxic Impurities. The coupling is quenched with 5% aqueous citric acid and the organic layer subjected to solvent swap into isopropanol for crystallization of the darunavir ethanolate solvate. Residual palladium from an earlier Suzuki step must be below 5 ppm prior to this amine coupling, as the isopropylthiazole methanamine moiety coordinates Pd(II) and retards scavenging; compliance with ICH Q3D Elemental Impurity Class 1 limits is verified by ICP-MS on each batch. Terminal finished dosage form is Darunavir 600 mg film‐coated tablet co‐formulated with ritonavir 100 mg as pharmacokinetic enhancer.The regulatory dossier for starting material acceptance requires a specification for isopropyl bromide (limit ≤50 ppm, GC-FID, column DB-624 30 m × 0.53 mm × 3.0 µm), a potential genotoxic impurity arising from the 2-isopropylthiazole synthesis. The hydrochloride is also evaluated against ICH Q3C Option 1 limits for Class 2 solvents; ethyl acetate, if used in the preceding salt formation, is controlled at ≤5000 ppm. Single‐stage production campaigns exceeding 500 kg are typically executed in facilities compliant with ISO 14001:2015 due to the need for scrubbing of amine vapours liberated during neutralization.

N-Oxide impurity marker synthesis as a pharmaceutical reference standard

The hydrochloride serves as starting point for the deliberate synthesis of the N-methyl-N-((2-isopropylthiazol-4-yl)methyl)amine N-oxide reference standard required for analytical method validation in antiretroviral drug substance filings. Oxidation is performed with meta-chloroperoxybenzoic acid (mCPBA, ≤77% assay) at 1.02–1.08 molar equivalents in dichloromethane at 0–5 °C over 90 minutes; over-oxidation to the N-oxide-isopropylthiazole sulfoxide impurity is suppressed by maintaining a batch volume headspace with nitrogen and limiting peroxide concentration. The crude oxide is purified by flash chromatography on silica gel 60Å (mobile phase: dichloromethane/methanol 95:5 v/v with 0.1% ammonium hydroxide) and lyophilized from water to give the monohydrate. Chemical purity is assigned by quantitative ¹H NMR using maleic acid as internal standard; acceptance criterion is ≥98.5% (anhydrous basis). The material is packaged in ISO 17034–accredited reference material production suites under argon in amber vials with PTFE-lined caps. It is used to spike Ritonavir and Lopinavir drug substance solutions at 0.15% w/w to establish system suitability during HPLC analysis per USP General Chapter <621>. The certificate of analysis reports identity by LC-HRMS (ESI positive mode, observed m/z 215.1215 for [M+H]⁺, mass error ≤2 ppm), water content by Karl Fischer oven method at 120°C, and residual solvents by headspace GC-FID. Terminal product type is Certified Reference Material distributed in 50 mg units for use in pharmacopoeial monograph testing.A development‐phase Fmoc-protected variant for solid‐phase peptide‐mimetic librariesUpon swelling 2-chlorotrityl chloride resin (loading 1.0–1.6 mmol/g) in anhydrous dichloromethane, the hydrochloride is neutralized with 4-methylmorpholine (3.0 eq) and introduced at 0.9 mmol/g resin to cap the resin before Fmoc cleavage. The free amine loading is confirmed by Fmoc release assay at 301 nm; typical capping efficiency exceeds 97% after 2 hours at 25°C with orbital shaking at 180 rpm. The immobilized 2-isopropylthiazole-4-methanamine scaffold undergoes iterative cycles of acylation with Fmoc-amino acid chlorides (pre-activated with HATU and DIEA in DMF) and Fmoc deprotection with 20% piperidine/DMF. A set of 48 discrete compounds targeting HIV‑1 protease variants resistant to darunavir was assembled on a parallel synthesizer (SynPhase™ Lanterns) and cleaved with 20% HFIP/DCM. Each compound was analyzed by UPLC-ELSD and accepted into screening if purity exceeded 90% at 215 nm. The operation falls under occupational exposure limits for halogenated compounds; airborne concentration of N-methyl-2-isopropylthiazole-4-methanamine is maintained below 15 µg/m³ based on an internal OEL derived from ICH Q3C permitted daily exposure calculations. The final deliverables are discrete lead-optimization libraries shipped in 96-well microtiter plates at 10 mM DMSO stock concentration, with purity and identity reports conforming to GDP and GLP. No pharmacopoeial monograph applies; quality is controlled via an in‐house specification aligned with ICH Q11 for early‐phase intermediates.Process safety envelope of the hydrochloride during scale‑up carbamoylation: heat flow calorimetry dataA reaction calorimetry campaign (Mettler Toledo RC1e, 1 L glass reactor) was undertaken to define safe operating parameters for the addition of 4-nitrophenyl chloroformate to the neutralized amine. The heat of reaction was measured as −178 kJ/mol (based on the hydrochloride) with an adiabatic temperature rise of 48 K at 1.0 M substrate concentration. The onset temperature for a secondary decomposition of the mixed anhydride was observed at 112°C by differential scanning calorimetry (DSC, heating rate 4 K/min, sealed gold‐plated crucible), releasing −560 J/g. This data informed the process safety strategy: the jacket temperature setpoint is capped at −8°C during dosing, and the maximum allowable accumulation of unreacted chloroformate is limited to ≤5% of the stoichiometric amount, monitored by online FT-IR peak area at 1780 cm⁻¹ (C=O stretch). The emergency quench protocol involves rapid addition of 2-propanol (pre‐loaded in a charge vessel) if reactor temperature exceeds 10°C. Compliance with EHS Guidelines for Bulk Pharmaceutical Manufacturing (thermal hazard evaluation) and NFPA 69 for explosion prevention is documented in the process safety report. The addition ratio of the hydrochloride to chloroformate is held within the 1.08–1.12 eq range identified as the window where exotherm intensity remains manageable without sacrificing yield. The downstream production step executed under these conditions is the formation of activated mixed carbonate destined for Ritonavir segment coupling. The terminal product of this particular campaign is Ritonavir Phase-I intermediate in toluene solution, assayed at 18–22% w/w, directly telescoped into the peptide conjugation step without isolation.

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Certification & Compliance

4-Thiazolemethanamine,N-Methyl-2-(1-Methylethyl)-,Hydrochloride (1:1) is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

Compound identification follows IUPAC nomenclature: 4‑Thiazolemethanamine, N‑methyl‑2‑(1‑methylethyl)‑, hydrochloride (1:1), supplied under product code TZM‑804·HCl. The hydrochloride salt form ensures a crystalline, non‑hygroscopic (at RH < 60%) solid that dissolves readily in water (> 200 mg/mL at 25 °C) and methanol, while the free base presents as a viscous, air‑sensitive oil with documented discoloration within 48 h under ambient atmosphere. Purity is specified as ≥ 98.0% (HPLC, 210 nm) with typical lot assays reaching 99.2%. Total impurities are limited to < 1.0% with no single unspecified impurity exceeding 0.15%. The fully ionised secondary amine center contributes a measured pKa of 8.9 ± 0.1 (conjugate acid in 0.1 M KCl), a value that must be accounted for during liquid‑liquid extractions and reductive amination work‑ups where pH excursions above 8.2 regenerate the free base, often causing emulsion formation in ethyl acetate partitions.

What Distinguishes the Hydrochloride Salt from the Free Base?

The decision to procure the hydrochloride rather than the free amine is driven by stability, handling, and stoichiometric control. Free‑base N‑methyl‑(2‑isopropyl‑1,3‑thiazol‑4‑yl)methanamine undergoes slow aerial oxidation at the amine, generating nitrone‑type oligomers detectable by LC‑MS as M⁺ 32 and 48 adducts. A head‑to‑head stability trial stored both forms at 40 °C/75% RH open‑vial for 14 days: the free base lost 6.7% purity (HPLC area%) and developed a deep amber color, while the hydrochloride showed 0.3% degradation and retained a white to off‑white crystalline appearance. This trial was conducted per ICH Q1A conditions, with impurity profiling by UPLC‑PDA (2.1 × 50 mm, 1.7 μm C18, gradient 5→95% acetonitrile in 0.05% trifluoroacetic acid over 8 min). From a process chemistry perspective, the hydrochloride delivers a fixed, anhydrous equivalent weight, eliminating the need for amine content titration before every coupling experiment. In 50‑L glass‑lined reactors, direct charging of free base required viscosimetric flow control and argon‑blanketed transfer lines to prevent atmospheric CO₂ uptake; a 12‑kg batch of the hydrochloride was dispensed gravimetrically in 15 min under standard fume hood conditions without visible moisture absorption.

Thermal Stability and Long‑Term Storage under ICH Conditions

Differential scanning calorimetry at 10 °C/min under N₂ shows a sharp endothermic melt at 178–180 °C followed by a broad exotherm above 220 °C (heat release −450 J/g), indicative of thermal decomposition. Long‑term storage data (25 °C/60% RH, 36 months) support a retest date of 24 months when kept in double‑polyethylenated fibre drums with desiccant. At 40 °C/75% RH for 6 months, water content increased from 0.12% to 0.48%, still within the ≤ 0.5% specification. Isothermal microcalorimetry (TAM III, 25 °C) gave a specific heat flow of < 0.1 μW/g after 72 h equilibration, confirming no autocatalytic degradation. It is critical to avoid storage in single‑use polyethylene bags without secondary aluminum barrier layers above 60% RH: one batch stored for 18 months under tropical warehouse conditions (30 °C/85% RH without barrier) showed clusters of hygroscopic liquefaction localized around crystal defect sites, and the lot was rejected for use in anhydrous amidation chemistry. In a medicinal chemistry campaign targeting selective kinase inhibition, the compound was employed as an advanced intermediate in the synthesis of a thiazolyl‑pyrimidine hinge‑binder. The 4‑(aminomethyl) handle was elaborated via HATU‑mediated coupling to a 2‑arylacetic acid derivative. Process development noted that direct coupling of the hydrochloride without pre‑neutralization gave incomplete conversion (42% after 16 h at ambient) due to salt‑buffering of the carboxylate activation step. The optimised protocol treated 1.0 eq of hydrochloride with 1.05 eq of DIPEA in DMF for 10 min before adding the acid and HATU; under these conditions, conversion exceeded 97% by HPLC within 4 h, and the crude product was isolated in 88% yield after aqueous work‑up and trituration with MTBE.

Comparative Physical and Handling Properties
Property	4‑Thiazolemethanamine, N‑methyl‑2‑(1‑methylethyl)‑, HCl (1:1)	Free Base
Physical state at 25 °C	White crystalline powder	Pale yellow viscous oil
Melting range (DSC onset)	178–180 °C	N/A (glass transition −38 °C)
Solubility in water (25 °C)	> 200 mg/mL	12 mg/mL (with slow phase separation)
Hygroscopicity (25 °C/60% RH, 24 h)	< 0.1% weight gain	3.8% weight gain (water uptake + CO₂ absorption)
Purity (typical, HPLC 210 nm)	99.2%	96.5% (fading to 93% after 7 d ambient)
Recommended storage	+5 to +30 °C, desiccated	−20 °C, under argon

When Neutralization Fails: Process Upsets in Multi‑Kilogram Batches

Transfer of a synthetic route to a 100‑L Hastelloy reactor revealed an operational sensitivity at the extraction stage. Following a reductive amination between 2‑isopropyl‑4‑formylthiazole and methylamine (from 40% aqueous solution), the reaction mass was pH‑adjusted to 9.5 with 30% sodium hydroxide to liberate the free base for extraction into MTBE. If the pH probe (Mettler‑Toledo InPro 3250i) was not recalibrated immediately before the addition, transient overshoot to pH >12 led to thiazole ring‑opening at the C‑2 isopropyl substituent, generating sulfhydryl‑acrylonitrile intermediates that polymerised into insoluble tars. The mitigation strategy employed inline pH control with a loop recirculating through a flow cell at 0.5 L/min, maintaining the endpoint at pH 8.8 ± 0.2. The crude free base was then immediately converted to the hydrochloride salt by addition of 1.05 eq of 2 M HCl in diethyl ether, controlled to keep the internal temperature below 20 °C using a jacket set‑point of 5 °C. This quench‑crystallisation provided the hydrochloride in 91% isolated yield with a purity of 98.7% (HPLC). Deviation from the 1.05 eq HCl charge resulted in a mixed crystal phase containing up to 4% hemi‑salt adduct, as confirmed by XRPD (characteristic peak at 2θ = 12.3° absent in the pure 1:1 salt). Differences from N‑ethyl and N‑cyclopropyl analogues become evident during sterically demanding C–N cross‑coupling reactions. The N‑methyl substituent presents the smallest steric footprint among the series, permitting Buchwald–Hartwig amination with an ortho‑substituted aryl bromide using BrettPhos Pd G3 precatalyst at 0.5 mol% loading in 2‑MeTHF at 60 °C. The same coupling attempted with the N‑ethyl counterpart required 2 mol% catalyst and 80 °C to reach full conversion, while the N‑isopropyl homologue failed to react under these conditions, attributed to catalyst resting‑state steric occlusion. In another comparison, reductive alkylation of the hydrochloride with cyclopentanone and NaBH(OAc)₃ yielded the tertiary amine selectively, whereas the N‑ethyl variant suffered from competitive alcohol elimination and enamine formation under the same conditions (acetyl chloride‑quenched GC‑MS detected the vinylthiazole byproduct at 8.3% area).

Specification and Analytical Method Matrix
Parameter	Acceptance Criterion	Analytical Method	Reference Standard
Assay (anhydrous, solvent‑free)	98.0–102.0%	HPLC‑UV, 210 nm	In‑house primary reference standard (lot‑to‑lot vs. qNMR, 99.7%)
Water content	≤ 0.5% w/w	Coulometric Karl Fischer titration	ASTM E203‑16
Residual solvents	MTBE ≤ 5000 ppm DMF ≤ 880 ppm DCM ≤ 600 ppm	Headspace GC‑FID	USP <467> (Class 2/3)
Sulfated ash	≤ 0.1% w/w	Residue on ignition, 600 °C	Ph. Eur. 2.4.14
Heavy metals (Pd, Cu, Fe)	Pd ≤ 10 ppm, Cu ≤ 50 ppm, Fe ≤ 100 ppm	ICP‑MS after microwave digestion	USP <232>/<233>
Nitrosamine content	N‑nitroso‑N‑methyl‑(2‑isopropylthiazol‑4‑yl)methanamine ≤ 0.03 ppm	LC‑MS/MS, APCI positive, MRM	EMA/CHMP/ICH M7 guideline
Mesh size distribution	90% pass 60 mesh (250 μm)	Laser diffraction (Malvern Mastersizer 3000)	ISO 13320:2020

In agrochemical research, the core thiazole‑methanamine scaffold appears in several fungicide lead structures targeting succinate dehydrogenase (SDH). The hydrochloride offers a direct starting material for the generation of thiazole‑carboxamide libraries via parallel synthesis. Dissolution of 50 mg in 0.5 mL of anhydrous DMF containing 1 eq of triethylamine allowed automated dispensing (Tecan Freedom EVO) into 96‑well plates containing 0.9 eq of various carboxylic acids and HOBt/EDC cocktails. After 12 h shaking at ambient temperature, LC‑MS analysis indicated >85% product formation across the plate, with no evidence of salt‑byproduct precipitation that was observed when the free base was used directly and absorbed atmospheric CO₂ to form the carbamate. Storage incompatibilities include strong oxidizing agents: exotherm initiation was detected by RC1e reaction calorimetry upon mixing with 30% hydrogen peroxide (adiabatic temperature rise ΔT_ad = 245 °C). The compound should not be combined with nitrosating agents (nitrite salts, nitrous acid) under acidic conditions, as secondary amine nitrosation is a theoretical risk; dedicated equipment for activated nitrosamine monitoring is recommended when downstream chemistry exposes the compound to pH < 3 in the presence of residual nitrite from quenching steps. Published data for the specific nitrosamine formation rate constant at the secondary amine site is limited; therefore, control is exercised via the finished product specification (see table) and through process design that maintains nitrite levels below 10 ppm in all upstream reagents. Compatibility studies also flag an exothermic salt metathesis with sulfonic acid ion‑exchange resins, generating −180 kJ/kg of resin bed, potentially leading to channeling in fixed‑bed purification setups if the hydrochloride is loaded directly without pre‑wash. The hydrochloride differs further from hydrochloride salts of the 5‑thiazolemethanamine regioisomer in its degree of crystallinity and solubility. The 4‑substituted isomer consistently shows 1.4‑fold higher aqueous solubility than the 5‑substituted analogue (140 mg/mL for the 5‑isomer HCl salt vs. >200 mg/mL for the 4‑isomer), a property leveraged when preparing concentrated stock solutions for high‑throughput biological screening. The hydrochloride counterion also eliminates a common work‑up pitfall encountered with the hydrobromide salt variant, wherein bromide ions interfere with palladium catalyst regeneration in downstream Heck reactions, resulting in catalyst loadings that had to be doubled from 0.5 mol% to 1.0 mol%. A pilot‑scale amination run with the hydrobromide salt stalled at 76% conversion after 18 h under otherwise identical conditions (XPhos Pd G4, K₃PO₄, 2‑MeTHF, 50 °C), whereas the hydrochloride batch reached 98% conversion.