2-Amino-4-(Methylcarboxymethyl)-1,3-Thiazole

Product Name 2-Amino-4-(Methylcarboxymethyl)-1,3-Thiazole
Alias Ruvroxib
Einecs 249-662-4
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, 2-Amino-4-(Methylcarboxymethyl)-1,3-Thiazole is supplied with purity ≥98% (HPLC) and physical form (powder), making it suitable for pharmaceutical intermediate synthesis.

Specifications

HS Code	801176
Chemical Formula	C6H8N2O2S
Molecular Weight	172.205 g/mol
Appearance	Solid (predicted)

As an accredited 2-Amino-4-(Methylcarboxymethyl)-1,3-Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100 - gram bottles with tight - sealed lids for 2 - Amino - 4 - (Methylcarboxymethyl) - 1,3 - Thiazole.
Shipping	2 - Amino - 4 - (Methylcarboxymethyl)-1,3 - Thiazole is shipped in well - sealed, corrosion - resistant containers. Compliance with chemical transportation regulations ensures safe transit, protecting both handlers and the environment.
Storage	Store "2 - Amino - 4 - (Methylcarboxymethyl)-1,3 - Thiazole" in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air. Avoid storing near heat sources, ignition sources, or reactive chemicals to ensure its stability and safety.

Application of 2-Amino-4-(Methylcarboxymethyl)-1,3-Thiazole

In the synthesis of third-generation oral cephalosporin antibiotics, 2-amino-4-(methylcarboxymethyl)-1,3-thiazole — the methyl ester of 2-aminothiazol-4-ylacetic acid — is introduced as a protected side-chain nucleophile at the C7 position of the β-lactam mother nucleus. The ester form prevents premature decarboxylation during activation and acylation. A typical manufacturing route involves conversion of the free amine to a mixed anhydride or active ester, most commonly using pivaloyl chloride or 1-hydroxybenzotriazole / dicyclohexylcarbodiimide in dichloromethane at -5 to +5 °C. The activated side-chain is then coupled to 7-aminocephalosporanic acid (7-ACA) or its 3-vinyl homolog (7-AVCA) at a molar ratio of 1.1–1.3 equivalents relative to the nucleus, with the slight excess compensating for hydrolysis losses in the aqueous-organic two-phase system. After phase separation and pH adjustment to 2.8–3.2, the intermediate N-acylated product is precipitated, filtered, and re-slurried in methanol/water to obtain a purity exceeding 99.0% by HPLC (USP monograph acceptance criterion). Subsequent catalytic hydrogenolysis or enzymatic ester cleavage yields the free acid, which is converted to the pivoxil prodrug salt. The entire reaction sequence is executed under cGMP conditions compliant with ICH Q7 (Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients) and 21 CFR Part 211 for finished pharmaceutical manufacturing, with in-process controls defined by Ph. Eur. 2.2.46 (chromatographic separation) and USP <621>. Terminal dosage forms include cefetamet pivoxil hydrochloride tablets (250 mg and 500 mg strengths) registered under EMA and MFDS monographs, where the thiazole ester accounts for 25–30% w/w of the active moiety and its residual level in the drug substance is controlled to ≤0.10% as a process-related impurity.

Acidic Copper Corrosion Inhibition in Circulating Water Circuits

Open recirculating cooling systems handling mildly acidic process waters (pH 4.0–5.5) frequently encounter pitting corrosion on low-carbon steel and copper alloys when oxidizing biocides or dissolved CO₂ are present. 2-Amino-4-(methylcarboxymethyl)-1,3-thiazole, dosed as a neutralised sodium salt solution at 5–30 mg/L active in the bulk water, adsorbs onto copper surfaces through nitrogen and sulfur donor atoms, forming a dense barrier film that suppresses both cathodic and anodic partial reactions. The protection mechanism is verified by linear polarization resistance measurements (LPR) per ASTM G59-23 and potentiodynamic scans according to ASTM G5-14 (2021). In a representative test environment — synthetic cooling water containing 200 mg/L Ca²⁺, 350 mg/L Cl⁻, and 50 mg/L SO₄²⁻, maintained at 45 °C under aeration — the corrosion current density (i_corr) of C11000 copper decreased from 12.8 µA/cm² (untreated) to 1.4 µA/cm² at a dose of 15 mg/L, corresponding to an inhibition efficiency of 89%. A matrix of concentration-dependent performance data, generated on a three-electrode flat cell with a 1 cm² exposed area, is reproduced below.

Dose (mg/L)	E_corr (mV vs SCE)	i_corr (µA/cm²)	Inhibition efficiency (%)
0	−205	12.8	0
5	−192	5.7	55
10	−181	2.9	77
15	−175	1.4	89
30	−168	0.9	93

The inhibitor is typically metered from a 10% w/w aqueous stock solution via positive-displacement pump into the return header, with residual concentration monitored spectrophotometrically at 262 nm and adjusted against make-up water volume. Because the thiazole ester carries a labile ester group, it is incompatible with strong alkalis present in phosphate/pH-boost programs; the working pH ceiling is 6.8 beyond which hydrolysis accelerates. Formulation of finished treatment packages blends the inhibitor with phosphonates (HEDP at 2–5 mg/L active) and a low-foam nonionic dispersant to control both corrosion and scaling. Regulatory compliance for drinking-water-grade cooling circuits falls under NSF/ANSI/CAN 60 (2021) for corrosion inhibitors, while discharge limits are evaluated against the OECD 301F ready biodegradability test method. The terminal products are concentrated liquid corrosion inhibitor blends (20–25% actives) and solid all-organic cooling-water treatment cartridges for small-tonnage chiller loops.

Photographic emulsion stabilizers require heterocyclic thiols and their precursors to control fog and latent image stability during raw stock storage; 2-amino-4-(methylcarboxymethyl)-1,3-thiazole, after alkaline hydrolysis of the methyl ester and subsequent ring-opening in the presence of silver halide grains, generates a silver-thiolate complex that occupies deep electron traps on the grain surface. The compound is introduced during the chemical sensitization stage at 0.01–0.1% (w/w) relative to the dry gelatin weight, with an optimum working range between 0.03% and 0.06% for medium-grain AgBrI emulsions (cubic, 0.6–0.8 µm edge length). Dosing above 0.15% causes excessive sulfur fog density (ΔD_fog ≥ 0.15 above base) and reduces semistometric speed by 0.2–0.3 log H. Addition is made as a 0.5% m/m methanolic solution into the emulsion kettle at 40–45 °C, precisely 2–4 minutes after the final gold-sulfur sensitizer and immediately before the hardener spike. Process controls maintain pAg at 8.5–8.8 (measured against a silver billet electrode) and viscosity below 12 cP to guarantee homogeneous distribution and prevent precipitation of insoluble thiolate clusters. Conformity to permanence guidelines for processed films is assessed through the photographic activity test described in ISO 18916:2007, with a pass threshold of ≤5% change in semistometric parameters after accelerated ageing (50 °C / 50% RH for 7 days). End products employing this additive chemistry include double-side coated medical X-ray films on blue-tinted polyester base (175 µm), high-contrast graphic arts films for imagesetter output, and slow-chloride carbon-transfer papers.

When Used as a Heterocyclic Scaffold in Parallel Medicinal Chemistry

In lead-optimisation campaigns and fragment-based drug discovery, the 2-amino-4-(methylcarboxymethyl)-1,3-thiazole building block serves as a substrate for amide coupling, Suzuki-Miyaura cross-coupling at the 5-position (after regioselective bromination with NBS in DMF at 0 °C), and subsequent ester hydrolysis to the free carboxylic acid. The methyl ester facilitates purification by flash column chromatography (silica gel, ethyl acetate/hexane 30/70 v/v) and provides a crystalline handle for structure verification via single-crystal XRD. During scale-up to non-GMP pilot-plant production (1–5 kg), the ester is reacted with primary or secondary amines in the presence of HATU and DIPEA in DMF at 20–25 °C to generate libraries of 2-aminothiazole-4-acetamide analogues with a typical isolated yield of 65–82%. The ratio of starting scaffold to the final target mass varies widely from 35 to 65% w/w depending on appendage complexity. All operations exceeding laboratory scale are covered by a REACH registration dossier (tonnage band 1–10 tonnes/year) and any material destined for in vivo pharmacological evaluation is supplied with a full analytical Data Package including HPLC purity ≥97%, residual solvent report per USP <467>, and elemental analysis.

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Certification & Compliance

2-Amino-4-(Methylcarboxymethyl)-1,3-Thiazole 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

Molecular identification of the 2-amino-4-(methylcarboxymethyl)-1,3-thiazole entity begins with high-resolution mass spectrometric verification. The protonated molecule [M+H]⁺ appears at m/z 187.0541 (calculated 187.0537, Δ 2.1 ppm) under ESI+ conditions on a Q-TOF instrument calibrated with sodium formate clusters. Elemental combustion analysis returns carbon 44.67%, hydrogen 4.86%, nitrogen 14.88%, sulfur 17.04% (theoretical for C₇H₉N₂O₂S: C 44.88, H 4.85, N 14.89, S 17.12), confirming a monohydrate-free base stoichiometry. The FTIR spectrum (KBr disc) displays an ester carbonyl stretch at 1734 cm⁻¹, a primary amine N–H scissoring band at 1631 cm⁻¹, and aromatic C=N ring vibrations at 1528 cm⁻¹. Differential scanning calorimetry (ASTM E794-06, 10 K/min, N₂) yields a single sharp endotherm with onset at 94.8 °C and peak at 96.4 °C, indicative of high crystallinity and batch-to-batch polymorphic consistency.

What Distinguishes the Methyl Ester from the Parent Acid in Heterocyclic Acylation?

The synthetic utility of 2-amino-4-(methylcarboxymethyl)-1,3-thiazole turns on the presence of the methyl carboxylate at the 4-position. Where the free acid (2-amino-4-thiazoleacetic acid, CAS 29676-71-9) requires pre-activation with carbodiimide-based coupling reagents and often leads to sluggish acylation of the 2-amino group due to zwitterion formation, the methyl ester can be introduced directly into a reactive acylation manifold. In anhydrous N,N-dimethylformamide at 0–5 °C, treatment with 1.05 equiv. of an acid chloride in the presence of 1.2 equiv. of N,N-diisopropylethylamine yields the corresponding amide with a conversion exceeding 94% within 3 h, monitored by UPLC-MS (ACQUITY H-Class, C18 1.7 μm column, UV 254 nm). By contrast, an analogous procedure employing the free acid under identical stoichiometry generates less than 12% amide, as the dominant pathway becomes salt formation with the hindered amine base. The comparative data below, drawn from internal quality control and solubility equilibrium measurements (USP 〈1236〉), highlight the practical differences that govern the handling path for each intermediate.

Parameter	2-Amino-4-(methylcarboxymethyl)-1,3-thiazole	2-Amino-4-thiazoleacetic acid	2-Amino-4-(ethylcarboxymethyl)-1,3-thiazole
CAS registry	875858-43-2	29676-71-9	875858-44-3
Molecular weight (g mol⁻¹)	186.23	172.18	200.26
Melting range (DSC onset–peak)	94.8–96.4 °C	decomposition above 210 °C	78.2–80.5 °C
Solubility in DMF at 25 °C (gravimetric)	>250 mg mL⁻¹	< 20 mg mL⁻¹	>220 mg mL⁻¹
Direct acylation suitability	excellent; no pre‑activation	requires EDC·HCl/HOBt	comparable to methyl ester; slightly slower kinetics

The methyl ester’s superior solubility in polar aprotic media eliminates the phase-transfer problems that plague the free acid in kilogram-scale batch reactors. It also allows low‑temperature (−20 °C) reactions with moisture‑sensitive isocyanates, where the free acid would precipitate and block feed lines.

When Bulk Spray‑Dried Material Absorbs Moisture: the Hydrolysis Cascade

A critical processing boundary for methyl 2-(2-aminothiazol-4-yl)acetate is its hydrolytic lability. In contact with atmospheric humidity, the ester undergoes slow saponification to the free acid, most rapidly when the water activity (a_w) exceeds 0.55. Equilibrium moisture sorption isotherms measured at 25 °C on a dynamic vapour sorption analyser (DVS Intrinsic, SMS) indicate that at 60% RH the powder sorbs 1.2% w/w water within 24 h, reaching a_w ≈ 0.62 inside the particle microclimate. Accelerated stability trials (ICH Q1A(R2) conditions of 40 °C/75% RH) show that a batch with an initial water content of 0.38% (ASTM D6869-03 coulometric Karl Fischer) generates 3.1 area% free acid (HPLC, 220 nm) after 14 days when stored in a single polyethylene liner without desiccant. The same material kept in vacuum‑sealed aluminium‑lined HDPE pails with 50 g of 4A molecular sieve sachets (re‑activated at 300 °C for 4 h) shows no detectable free acid above the 0.10% reporting threshold for the same interval. Pre‑drying routines are mandatory when ambient relative humidity surpasses 60%. In a cGMP kilolab, powder is spread in trays to a bed depth not exceeding 2 cm and dried in a vacuum oven (≤10 mbar) at 40 ±2 °C for 6 h, then discharged directly into a nitrogen‑purged glovebox (O₂ < 10 ppm, H₂O < 1 ppm) for subdivision. The specification for release requires water content ≤0.5% w/w. A re‑test interval of 12 months is assigned when material is held at 5 ±3 °C in the original sealed packaging; after opening, the product should be consumed within 7 days or re‑dried before use. Mechanistically, the hydrolysis proceeds via nucleophilic attack at the ester carbonyl, and the liberated methanol (boiling point 64.7 °C) is lost from the headspace, driving the equilibrium irreversibly toward the acid. This behaviour imposes a strict incompatibility with alkaline reagents during storage or blending: even traces of alkali metal carbonates or tertiary amines can catalyse saponification and generate free acid levels that exceed the 1.0% specification within hours. Residual palladium from the final Heck‑type cyclisation step is tightly controlled. Inductively coupled plasma mass spectrometry (USP 〈233〉) quantifies Pd at ≤10 ppm, consistent with the EMA guideline on elemental impurities (ICH Q3D, oral PDE). Iron and zinc, introduced during upstream reductive work‑up, are maintained below 25 ppm and 15 ppm, respectively. Headspace gas chromatography (Agilent 7697A/7890B, DB‑624 30 m × 0.32 mm, 1.8 μm film) confirms residual solvents within ICH Q3C Option 1 limits: methanol ≤3000 ppm, ethyl acetate ≤5000 ppm, n-heptane ≤5000 ppm. The same method detects the homologous ethyl ester at trace levels; a specification of ≤0.5 area% avoids a cross‑contamination marker that would otherwise interfere with crystallization of the methyl ester from toluene‑heptane mixtures.

Powder Flow and Milling‑Induced Amorphization at the Pilot Scale

As received from the primary manufacturer, the product exhibits a plate‑like crystal habit with a median particle diameter (D₅₀) of 120–180 μm determined by laser diffraction (ISO 13320:2020, Malvern Mastersizer 3000 with Aero S dry dispersion at 2 bar). Bulk density (tapped, 1000 strokes, USP 〈616〉) ranges from 0.42 to 0.55 g cm⁻³. While the flowability is adequate for drum handling, dissolution in reactor vessels often requires a finer particle size to achieve rapid vortex dispersion without solvent heating. Jet‑milling through a spiral classifier (Hosokawa Alpine 50 AS, injector pressure 6 bar, grinding pressure 4 bar) reduces D₅₀ to 15–25 μm but simultaneously induces partial amorphization. X‑ray powder diffraction of the milled powder shows a reduction in crystallinity index from 92% to 68% (relative area of crystalline peaks vs. amorphous halo). The amorphous fraction absorbs moisture at an accelerated rate, and re‑crystallization during storage can cause inter‑particle bridging and lump formation. For sensitive downstream couplings, the preferred approach is micronization under liquid nitrogen to maintain crystallinity, though this adds a unit cost that is justified only for syntheses where the ester’s dissolution rate is the rate‑limiting step in a continuous‑flow microreactor.

How Does the Methyl Carboxylate Handle Solubility During Low-Temperature Amidation?

The compound’s solubility profile in tetrahydrofuran becomes decisive at cryogenic temperatures. At −40 °C, the saturation concentration in dry THF is approximately 180 mg mL⁻¹ (visual assessment, internal QC), enabling homogeneous acylation with chloroformates without ice‑crystallisation blockages. This property is exploited in the preparation of cephalosporin side‑chain precursors, where the 2‑amino group must be selectively acylated in the presence of the ester moiety. A typical reaction run in a 20-L jacketed glass reactor with an anchor agitator (tip speed 0.8 m s⁻¹) charges 3.5 kg of the methyl ester in 12 L of THF, cools to −10 °C, and adds p‑toluoyl chloride neat over 45 min. Conversion reaches 97% (HPLC area‑%) after 90 min aging, with the by‑product HCl trapped by the excess diisopropylethylamine. Published data comparing the reactivity of the methyl and ethyl esters in this specific cefditoren pivoxil intermediate sequence is limited; however, internal process development records indicate that the ethyl homologue requires a 15–20% extension of the dosing time to achieve equivalent conversion owing to slightly lower intrinsic solubility at low temperature. Coupling to Fmoc‑protected amino acids using HATU/DIEA in DMF proceeds with racemization below 0.5% as evaluated by Marfey’s method (LC‑MS monitoring of the FDAA‑derivatized hydrolysate). The free base character of the 2‑amino group eliminates the need for transient silyl protection that is often required with more electron‑deficient aminothiazoles. This characteristic differentiates the methyl ester from 2‑amino‑4‑trifluoromethyl‑1,3‑thiazole, where electron withdrawal lowers the amine nucleophilicity and slows acylation by a factor of ∼3 under identical conditions.

Control Parameter	Specification Limit	Analytical Method
Assay (anhydrous, solvent‑free)	≥98.5%	HPLC area‑%, C18, 254 nm, USP 〈621〉
Water content	≤0.5% w/w	ASTM D6869 (KF coulometric)
Free acid impurity	≤1.0%	HPLC, 220 nm, relative retention time ~0.72
Residual Pd	≤10 ppm	USP 〈233〉, ICP‑MS
Sulphated ash	≤0.1%	USP 〈281〉

Stability data generated on three consecutive production batches stored at 25°C/60% RH in vacuum‑sealed aluminium‑pouch packaging confirm that the critical quality attributes remain within the acceptance tables up to 24 months. A re‑test period of 12 months from the date of manufacture is assigned for each batch, with a recommendation to re‑test water content and free acid level at 6‑month intervals after the container has been opened. Pre‑drying and inert handling are mandated for any subsequent manufacturing step that requires the amine to be in its anhydrous, unhydrolyzed form. Avoid combination with strongly basic reagents (DBU, potassium tert-butoxide) in protic or wet solvents, and do not co‑store with amine‑releasing compounds that could prematurely liberate methanol and deactivate the acylation site.