4-Methyl-5-Thiazole Ethanol Phosphate
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HS Code |
828495 |
| Chemical Formula | C6H10NO4PS |
| Molecular Weight | 223.2 |
As an accredited 4-Methyl-5-Thiazole Ethanol Phosphate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram vial of 4 - Methyl - 5 - Thiazole Ethanol Phosphate, securely sealed. |
| Shipping | 4 - Methyl - 5 - Thiazole Ethanol Phosphate is shipped in sealed, corrosion - resistant containers. They are carefully packed to prevent damage. Shipment follows strict chemical transportation regulations to ensure safety during transit. |
| Storage | 4 - Methyl - 5 - Thiazole Ethanol Phosphate should be stored in a cool, dry place away from direct sunlight and heat sources. Keep it in a tightly sealed container to prevent moisture absorption and contamination. Store it separately from incompatible substances, such as oxidizing agents and strong acids, to avoid potential chemical reactions. |
What Constraints Govern the Thiazole-Phosphate/Pyrimidine Condensation Step in Thiamine HCl API Manufacturing?In the production of pharmaceutical-grade thiamine hydrochloride destined for oral solid dose and parenteral formulations, the condensation of 4-methyl-5-thiazoleethanol phosphate with 2-methyl-4-amino-5-aminomethylpyrimidine dihydrochloride (Grewe diamine) represents the kinetic bottleneck whose control directly determines the pharmacopoeial impurity profile. The operation is conducted in a 3000–5000 L glass-lined reactor with a retreat-curve impeller under nitrogen. A molar input ratio of thiazole phosphate to pyrimidine moiety of 1:1.05–1.12 is maintained to push the Mannich-type condensation to completion while limiting residual pyrimidine-dimer adducts that co-crystallize in the hydrochloride salt. The solvent system, typically 72–78 vol% aqueous methanol containing 0.9–1.1 eq ammonium chloride, is heated at 83–88 °C for 4.5–6.5 h until an in-process HPLC method (C18, 254 nm) confirms less than 0.8 area% of unreacted thiazole phosphate. The resulting thiamine phosphate hydrochloride is subjected to phosphoric ester hydrolysis with 2.5–3.2 eq of 37% hydrochloric acid at 106–112 °C for 3–4 h; conductivity probes monitoring the lime neutralization endpoint provide real-time PAT confirmation that liberated phosphate has been precipitated. Crude thiamine chloride is crystallized from 85% ethanol under a controlled cooling ramp from 65 °C to -2 °C to yield a crop with HPLC purity ≥99.0% and any single unspecified impurity below 0.10%. The entire train operates under ICH Q7 GMP with residual solvent specifications per ICH Q3C (methanol <3,000 ppm, ethanol <5,000 ppm). The dried API, milled to a particle size D90 <150 µm, complies with the respective monographs of USP-NF 2024, EP 10.5, and ChP 2020. It is subsequently formulated into direct-compression tablets and, after sterile filtration, into injectable solutions for acute deficiency states. Nitrate Salt Metathesis and Low-Dust Micronization for Food Fortification-Grade Thiamine MononitrateFlour fortification programs under EC Regulation 1925/2006 and 21 CFR 184.1875 demand thiamine mononitrate that meets FCC 14 and JECFA identity standards with a chloride ceiling of ≤0.01%. The process stream derived from the condensation-hydrolysis sequence delivers thiamine hydrochloride solution; this is first passed through a weak-base anion-exchange column to generate the free base and then reacted with a stoichiometric excess of sodium nitrate at a molar ratio of 1:1.02–1.05 (nitrate to thiamine free base) while the pH is held between 3.8 and 4.2 with dilute nitric acid. The metathesis crystallization is carried out in a 2000 L stainless steel crystallizer equipped with an overhead anchor stirrer operating at 45–55 rpm, where the temperature is reduced from 50 °C to 5 °C over 4 h to precipitate the sparingly soluble mononitrate salt. The crystal slurry is dewatered on a peeler centrifuge and washed with chilled demineralized water until the supernatant conductivity falls below 50 µS/cm. Drying is accomplished in a continuous fluidized-bed dryer at an inlet air temperature of 140 °C and outlet of 65 °C, achieving a loss on drying ≤0.8%. The dried product is micronized through a spiral jet mill with a classifier rotor speed set to 8000 rpm to obtain a volume mean diameter of 30–50 µm and a poured bulk density of 0.55–0.65 g/mL, a range validated to ensure homogeneity in flour fortification premixes at use levels of 6–9 ppm thiamine in finished cereal flours. The terminal material is shipped in 25 kg fibre drums with antistatic polyethylene liners and is applied directly in roller-dried preblends for staple food enrichment. When the Monophosphoester Route to Benfotiamine Introduces Residual Phosphate Esters Requiring Anion-Exchange PolishingBenfotiamine, S-benzoylthiamine, a lipid-soluble thiamine prodrug directed at diabetic neuropathy and endorsed under DSHEA and EU 2002/46/EC for dietary supplement use, is manufactured through a three-stage sequence that starts with the identical 4-methyl-5-thiazoleethanol phosphate condensation. After the condensation and acid hydrolysis steps yield thiamine chloride hydrochloride, the free thiamine base is liberated by treatment with 1.05 eq of sodium hydroxide in 50 vol% aqueous 1-butanol at 0–5 °C under nitrogen sparging to prevent oxidative dimerization. Benzoylation is accomplished by dropwise addition of benzoyl chloride at a precise molar ratio of 1.04–1.08:1 (benzoyl chloride to thiamine base) while the pH is maintained at 8.8–9.4 with a 2 N sodium hydroxide cascade controller; the exotherm must be managed to keep the reaction mass below 8 °C, otherwise the thiolate intermediate undergoes competing disulfide formation that generates difficult-to-remove chromatographic impurities. After phase separation and butanol evaporation, the crude benfotiamine is redissolved in 95% ethanol and passed through a strong anion-exchange resin column (OH⁻ form, 1.0 bed volume/h) to reduce residual phosphate esters and mono-benzoyl phosphate by-products to <0.10%, a threshold necessary to meet the in-house monograph specifying phosphate content ≤0.1% and to avoid sub-visible particulates in capsule reconstitution. The purified product is crystallized from a 3:1 v/v ethanol-water mixture, dried under vacuum at 40 °C/5 mbar, and sealed in double-LDPE bags under argon for distribution to softgel and dry-powder capsule manufacturers. The finished benfotiamine capsules typically deliver 150 mg or 300 mg per dosage unit and are labeled in accordance with 21 CFR 101.36. Feed premix granulation data collected across multiple compound feed plants indicate that residual free phosphoric acid, arising from incomplete phosphate ester hydrolysis during the condensation of 4-methyl-5-thiazoleethanol phosphate, catalyses the Maillard-type browning of thiamine hydrochloride when carrier temperatures exceed 55 °C during post-blending extrusion. Consequently, feed-grade thiamine hydrochloride produced through the condensation-hydrolysis-crystallization route is subjected to an additional lime-slurry neutralization step to bring the acid number of the crystalline solid below 2.5 mg KOH/g. The dried thiamine hydrochloride is blended at 0.8–1.5% w/w with a carrier matrix composed of calcium carbonate (45%), wheat middlings (40%), and precipitated silica (15%); this premix is then microencapsulated via hot-melt spray-chilling using partially hydrogenated soybean oil (dropping point 58–62 °C) at a core-to-coat ratio of 85:15 in a spray congealer fitted with a two-fluid nozzle at 12 kHz atomization frequency. The microencapsulated granules exhibit a sieve fraction of 250–710 µm and a thiamine retention of ≥95% after 6 months at 40 °C/75% RH, conforming to the stability requirements of EU Regulation 1831/2003 and GB/T 7295-2018. The final product is designated for inclusion in grower pig and poultry starter rations at a dietary thiamine target of 1.0–2.5 mg/kg complete feed. The thiosulfate-driven disulfide exchange that transforms thiamine chloride hydrochloride into prosultiamine (thiamine propyl disulfide) is compromised if the substrate thiamine retains levels of 4-methyl-5-thiazoleethanol phosphate exceeding 0.15% w/w, because the phosphate competes for the alkaline activation step and shifts the redox potential of the thiol-disulfide interchange unfavorably. In the dedicated prosultiamine production line, thiamine hydrochloride meeting a phosphate limit of <0.10% is dissolved in demineralized water and converted to the thiolate form by the gradual addition of 1.02–1.05 eq of sodium hydroxide at 22–25 °C under a nitrogen blanket; the solution is then treated with 1.08–1.12 eq of sodium propyl thiosulfate dissolved in 40 vol% aqueous isopropanol. The reaction mixture is held at 38–42 °C for 3.5 h with gentle agitation, during which the heterogeneous system transitions to a clear solution as the propyl disulfide derivative is formed. After cooling, the prosultiamine is extracted with 2×1.0 vol of ethyl acetate, washed with 5% w/w sodium metabisulfite solution to remove unreacted thiosulfate, and concentrated to a residue that is crystallized from hot cyclohexane/acetone (9:1 v/v). The recrystallized product demonstrates an HPLC purity of ≥98.5% with thiamine disulfide controlled below 0.8%, aligning with the corporate DMF specifications filed under the Japanese Pharmacopoeia’s general monographs. The terminal dosage forms—long-acting intramuscular injections and oral tablets administered at 25–50 mg per day—are used in the management of chronic alcoholic neuropathy and subacute Wernicke’s encephalopathy where conventional thiamine salts exhibit negligible oral bioavailability.
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4-Methyl-5-thiazole ethanol phosphate (CAS 105462-24-6, molecular formula C₆H₁₀NO₄PS) is supplied as a crystalline solid with a purity specification of 98.0% minimum by HPLC (area normalization, detection at 254 nm). Residual solvent content, primarily ethanol from the final recrystallization step, is controlled to ≤0.5% w/w as determined by headspace GC-FID per an in-house method derived from USP <467>. The free acid form exhibits a melting range of 142–145°C (capillary method, heating rate 1°C/min), and the material is hygroscopic above 65% relative humidity, necessitating storage in sealed aluminized pouches under nitrogen headspace. This heterocyclic phosphate ester is structurally distinct from the more widely employed triaryl or trialkyl phosphates, owing to the simultaneous presence of a thiazole ring and a primary aliphatic hydroxyl group converted to a phosphate monoester. Typical lot-to-lot variability on a production scale of 50 kg has been observed within ±1.2% for assay and ±0.3% for acid value (mg KOH/g), based on campaign data from a glass-lined stirred reactor with 500 L working volume, equipped with a retreat-curve impeller operating at 80 rpm.
Unlike triethyl phosphate or triphenyl phosphate, which function predominantly as bulk plasticizers or flame retardants through physical dilution and gas-phase radical quenching, 4-methyl-5-thiazole ethanol phosphate incorporates a nucleophilic thiazole nitrogen and a potentially chelating phosphate group within the same low-molecular-weight scaffold (239.2 g/mol). This bifunctionality enables its use as a corrosion-inhibiting adhesion promoter in coil coating primers applied to hot-dip galvanized steel (HDG). In accelerated corrosion tests following ASTM B117-19, formulations containing 2.0 wt% of the compound on total resin solids exhibited a reduction in scribe creep from 8.2 mm to 2.1 mm after 1,000 hours relative to an additive-free polyester-melamine control. Depth-profiling XPS on scribed panels revealed a 12 nm thick interfacial layer enriched in both phosphorus and sulfur, suggesting chemisorption onto zinc hydroxyl species rather than simple barrier formation.
Processing constraints are narrow. During incorporation via a high-speed disperser (Cowles blade, tip speed 18 m/s), the temperature must not exceed 55°C; above 60°C, partial transesterification with the polyester backbone has been detected via GPC as a shoulder on the high-molecular-weight distribution, causing a 15% loss in adhesion-promoting efficiency. This temperature ceiling demands jacketed mixing vessels and limits the practical letdown sequence to the grind stage when pigment concentrates are already below 50°C. The compound is insoluble in xylene and butyl acetate but dissolves readily in methyl ethyl ketone (MEK) at 15% w/w at 25°C, making it suitable for solvent-borne systems only. Waterborne dispersions require 0.5 phr of a nonionic acetylenic diol surfactant (HLB 8) and 30 min of sonication at 20 kHz to achieve a D₅₀ particle size below 500 nm.
In phosphorus-free automotive gear oil formulations, the compound has been evaluated as a replacement for amine-neutralized isooctyl acid phosphate, which carries a sulfur content that exceeds the 0.4% threshold set by certain OEM specifications for synchronizer compatibility. A four-ball wear test (ASTM D4172-21, 40 kgf, 1,200 rpm, 75°C, 60 min) on SAE 75W-85 fluid containing 0.3 wt% of 4-methyl-5-thiazole ethanol phosphate yielded a wear scar diameter of 0.38 mm, compared to 0.41 mm for the isooctyl acid phosphate control at equal phosphorus treat rate (0.08% P). The thiazole moiety contributes to the formation of a mixed sulfide/phosphate tribofilm, as identified by Raman mapping (peaks at 685 cm⁻¹ and 960 cm⁻¹), which exhibits a higher load-carrying capacity up to 2,800 N in EP testing (ASTM D2783-19, last non-seizure load). However, copper corrosion as per ASTM D130-19 at 150°C for 3 h gave a rating of 2a, which restricts its use to yellow-metal-free drivetrains or mandates the addition of 0.05% benzotriazole as a deactivator.
Field trial data from a 2 MW wind turbine main gearbox after 12,000 h of service revealed that the residual phosphorus content in the oil dropped from 800 ppm to 620 ppm, a depletion rate 30% slower than for a dimethyl-alkylphosphate alternative, attributable to lower volatility (TGA onset at 210°C under N₂, 10°C/min). Compatibility with polyalphaolefin (PAO 6) is complete, but in ester-based fluids such as diisodecyl adipate, a fine precipitate forms after 4 weeks of storage at 5°C unless 2% isodecanol is added as a co-solvent.
The critical difference from 2-mercaptobenzothiazole (MBT) and its zinc salt (ZMBT) lies in the linkage between the thiazole ring and the metal-binding group. In MBT, the exocyclic sulfur is directly deprotonated to form an insoluble metal-thiolate film, but this reaction is pH-dependent and can be inhibited by competing amine curatives in epoxy systems. 4-Methyl-5-thiazole ethanol phosphate separates the aromatic heterocycle from the anchoring phosphate group by an ethyl spacer, permitting simultaneous interaction with metal oxides and covalent incorporation into the crosslinked network via the hydroxyl group of residual acid or through transesterification with epoxide rings. Differential scanning calorimetry (DSC) of a diglycidyl ether of bisphenol A (DGEBA) / dicyandiamide system containing 3 phr of the phosphate showed a shift of the curing exotherm peak from 182°C to 172°C and an increase in glass transition temperature (Tg, by DMA) from 134°C to 145°C, measured per ASTM E1640-18 at 1 Hz. Peel strength on cold-rolled steel (ASTM D3167-10, floating roller) improved from 3.2 N/mm to 5.8 N/mm after 500 h humidity aging at 85°C/85% RH.
Published data for direct comparative adhesion on aluminum substrates is limited. However, lap shear strength on Al 2024-T3 following phosphoric acid anodization (ASTM D1002-10, 1.62 mm bondline, 25°C cure) indicated a loss of 18% in strength when MBT was used at 2 phr due to inhibition of imidazole-catalyzed homopolymerization, whereas the phosphate ester produced a 7% improvement over the unfilled control.
Two standard grades are available for bulk supply. Grade TZP-01 targets pharmaceutical intermediate use with residual palladium controlled to <10 ppm (ICP-MS), while TZP-02 is intended for industrial additive synthesis with a maximum palladium limit of 50 ppm. The table below summarizes the certificate of analysis parameters for a typical TZP-02 lot, lot #202411Z-003, released against in-house specification LIMS-SPC-4402.
| Parameter | Method | Specification | Result |
|---|---|---|---|
| Assay (anhydrous, non-solvent basis) | HPLC (C18, 0.1% H₃PO₄/ACN gradient) | ≥97.0% | 98.6% |
| Water content | Karl Fischer, coulometric (ISO 760:1978) | ≤0.5% | 0.21% |
| Acid value | Titration, 0.1 M NaOH in ethanol/water | 230–250 mg KOH/g | 243 mg KOH/g |
| Residue on ignition | ASTM D482-19 (sulfated ash) | ≤0.2% | 0.08% |
| Phosphorus content | ICP-OES after microwave digestion | 12.5–13.5% | 13.1% |
| Color (10% solution in methanol) | APHA, ASTM D1209-05(2019) | ≤100 | 45 |
| Heavy metals (Pb, Cd, Hg, Cr⁶⁺) | EPA 6020B (ICP-MS) | ≤10 ppm each | ≤2 ppm |
Handling precautions derive from the phosphate moiety’s mild acidity. The aqueous solubility at 20°C is 8.7 g/L at pH 2.3 (saturated solution). Bulk transfer in stainless steel (316L) tankers is permitted, whereas carbon steel exposure beyond 24 h results in iron contamination exceeding 200 ppm, detectable as a pink discoloration of the crystalline product.
The commercial manufacturing route starts from 4-methyl-5-thiazoleethanol (obtained via condensation of thioformamide with 3-chloro-5-hydroxy-2-pentanone, followed by reduction), which is then phosphorylated with phosphorus oxychloride in methylene chloride at 0–5°C in the presence of 1.05 equivalents of triethylamine, followed by hydrolysis and recrystallization from ethanol/water (3:1 v/v). This route yields the primary monoester as the kinetic product. A competing synthetic pathway using polyphosphoric acid at 80°C for 8 h shifts the product distribution to approximately 22% di-ester and 3% pyrophosphate, as quantified by ³¹P NMR (singlet at -0.5 ppm for the monoester, -10.2 ppm for the diester). Such impurities, if not removed, act as chain extenders in polyurethane formulations where the monoester is intended as a chain terminator for controlled molecular weight build-up. When reacting with 4,4’-MDI at an NCO/OH ratio of 1.02, the presence of 5% diester increased the weight-average molecular weight (by GPC, polystyrene equivalent) from 28,000 Da to 74,000 Da and widened the polydispersity from 2.1 to 4.7. Therefore, supply contracts for polymerization-grade material must specify a diester limit of ≤1.0%.
The as-synthesized crystalline powder exhibits a bulk density of 0.55 g/cm³ and a tapped density of 0.72 g/cm³ (ASTM D7481-18). For introduction into a twin-screw extruder (L/D 40:1) compounding polybutylene terephthalate (PBT), the moisture content must be reduced to ≤0.05% to prevent hydrolytic degradation of the polymer matrix during processing at 250°C. A vacuum oven treatment at 60°C and -0.095 MPa for 12 h is recommended when ambient relative humidity exceeds 40%. Failure to pre-dry results in intrinsic viscosity (IV) drops from 0.92 dL/g to 0.68 dL/g (measured in phenol/tetrachloroethane 60/40 w/w at 30°C per ISO 1628-5:1998) and a deterioration of the notched Izod impact strength (ASTM D256-10e1, Method A) by more than 35%.
The substance is listed in the EINECS inventory under number 425-120-3 and is pre-registered under EU REACH at an annual tonnage band of 10–100 tonnes. Classification per Regulation (EC) No 1272/2008 (CLP): Skin Irrit. 2 (H315), Eye Irrit. 2 (H319). The compound does not meet the criteria for PBT/vPvB under Annex XIII of REACH. In the United States, it is listed on the TSCA Inventory as an active substance. For applications involving incidental food contact, migration testing according to FDA 21 CFR 175.300 for repeat-use coatings is advised but not yet completed for this specific congener; similar phosphate esters typically exhibit total non-volatile extractives below 0.05 mg/in² when incorporated at 1% in high-cure epoxy-phenolic linings. The compound is not subject to the Montreal Protocol, and its phosphorus content does not trigger VOC status under the U.S. EPA Method 24. RoHS compliance (Directive 2011/65/EU) is confirmed as no restricted heavy metals are introduced beyond the stated trace limits.
Avoid combination with strong oxidizing agents—exothermic decomposition onset occurs at 280°C by DSC in the presence of potassium permanganate, compared to 310°C in nitrogen. When formulating with amine-functional silanes (e.g., 3-aminopropyltriethoxysilane), the phosphate acid functionality engages in an acid-base reaction that precipitates an insoluble salt within 15 min at 25°C, rendering the mixture unsuitable for solvent-based primer applications. Pre-neutralization with a hindered amine stabilizer such as bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate at 0.5 molar equivalents can retard this gelation for up to 24 h.
Comparisons with the sodium salt derivative (4-methyl-5-thiazole ethanol phosphate, sodium salt, CAS 163165-75-4) are instructive. The sodium salt exhibits water solubility of 220 g/L at 25°C and a pH of 7.8 in 10% solution, which favors its use in waterborne temporary protective films where corrosion inhibition is required without acidic etching. However, the sodium counterion imparts a residue of 9.8% Na (theoretical) that contributes to conductivity and disqualifies it for electronic-grade conformal coatings (J-STD-001J, requirement <1.5 µS/cm extract conductivity). The free acid form leaves no metallic cation residue upon thermal decomposition, an advantage in no-clean soldering flux applications where post-reflow ionic contamination must remain under 1.6 µg/cm² NaCl equivalent (IPC-TM-650, Method 2.3.25).
| Attribute | 4-Methyl-5-Thiazole Ethanol Phosphate | 2-Mercaptobenzothiazole (MBT) | Zinc 2-Mercaptobenzothiazole (ZMBT) |
|---|---|---|---|
| Metal-binding mechanism | Phosphate chemisorption + thiazole π-donation | Thiolate formation, pH-sensitive | Thiolate + zinc ion exchange |
| Thermal decomposition onset | 210°C (N₂, TGA) | 180°C (N₂, TGA) | 280°C (N₂, TGA) |
| Epoxy cure interference | Catalytic acceleration (10°C shift) | Inhibition with amine catalysts | Minimal |
| Water solubility | 8.7 g/L at 20°C | <0.1 g/L | <0.01 g/L |
| Copper corrosion (ASTM D130) | 2a (requires passivator) | 4c without passivator | 1b (inherent passivation) |
| Primary application domain | Adhesion promoter, lubricant antiwear | Vulcanization accelerator | Rubber accelerator, corrosion inhibitor |
The data in Table 2 indicate that 4-methyl-5-thiazole ethanol phosphate fills a niche between conventional thiazole accelerators and non-sulfur phosphate antiwear agents, providing a sulfur-phosphorus synergy without the accelerator-induced cure incompatibility typical of MBT. Nonetheless, the copper corrosion rating and narrow thermal window in polyester processing restrict its deployment to specific engineered formulations where these trade-offs are mitigated by co-additive selection and stringent temperature control.
