4-Thiazoleacetic Acid, 2,3-Dihydro-2-Imino-, Methyl Ester

Product Name 4-Thiazoleacetic Acid, 2,3-Dihydro-2-Imino-, Methyl Ester
Alias Methyl 2-imino-2,3-dihydro-4-thiazoleacetate
Einecs EINECS 256-418-7
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-Thiazoleacetic Acid, 2,3-Dihydro-2-Imino-, Methyl Ester is supplied with purity ≥98% (HPLC) and full characterization by NMR, making it suitable for pharmaceutical intermediate research and synthesis.

Specifications

HS Code	722563
Chemical Formula	C6H8N2O2S

As an accredited 4-Thiazoleacetic Acid, 2,3-Dihydro-2-Imino-, Methyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of 4 - Thiazoleacetic Acid, 2,3 - Dihydro - 2 - Imino - in methyl ester packaging.
Shipping	4 - Thiazoleacetic Acid, 2,3 - Dihydro - 2 - Imino -, Methyl Ester is shipped in accordance with strict chemical transportation regulations. Packaging ensures stability. Shipment may be via specialized carriers to safeguard its integrity during transit.
Storage	4 - Thiazoleacetic Acid, 2,3 - Dihydro - 2 - Imino -, Methyl Ester should be stored in a cool, dry place, away from heat sources and direct sunlight. Keep it in a well - ventilated area to prevent the build - up of vapors. Store in a tightly - sealed container to avoid contact with moisture and air, which could potentially lead to chemical degradation.

Application of 4-Thiazoleacetic Acid, 2,3-Dihydro-2-Imino-, Methyl Ester

What Role Does 2-Imino-4-Thiazolineacetate Play in Cefetamet Pivoxil Side Chain Assembly?

The methyl ester of 4‑thiazoleacetic acid, 2,3‑dihydro‑2‑imino‑, is transformed under aqueous acidic conditions at 85–95 °C to yield 2‑aminothiazole‑4‑acetic acid (ATA), which after protection and activation serves as the 7‑position side chain precursor for cefetamet. In a representative kilo‑lab batch operating under ICH Q7 Chapter 12.7 validated cleaning limits, ATA is generated by charging the ester into 6 N hydrochloric acid, held for 4–6 h until ring aromatization and ester hydrolysis are complete, then isolated via isoelectric precipitation at pH 2.8–3.2. The dried ATA is subsequently converted to its mixed carbonic‑anhydride or thioester active form; typical activation employs 2,2′‑dithiobis(benzothiazole) (MBT‑S) in dimethylacetamide with 1.05–1.15 eq of ATA relative to the 7‑amino‑3‑desacetoxycephalosporanic acid (7‑ADCA) nucleus, affording an acylation yield in excess of 92 % when dosed over 90 min at −5 to 0 °C. Reaction off‑gas monitoring ensures dimethyl sulfide emission remains below the site permit threshold of 5 ppmV. The resulting wet cefetamet acid is converted to the pivoxil prodrug via esterification with chloromethyl pivalate using 1.3 eq of potassium carbonate in N‑methylpyrrolidone. Finished dosage forms include film‑coated tablets containing 250 mg or 500 mg cefetamet pivoxil hydrochloride, which must comply with Ph. Eur. monograph 04/2024:2124 for related substances and residual solvents meeting ICH Q3C options 2A/2B. Solvent residue limits for the ATA precursor stage are typically set at ≤290 ppm for toluene, ≤60 ppm for tetrahydrofuran, and ≤5 ppm for palladium when a catalytic hydrogenation route is employed to reduce any over‑oxidized nitro intermediates.Manufacturing cefpodoxime proxetil demands a methoxyiminoacetyl side chain where the (Z)‑isomer ratio determines final API potency; the 2‑imino‑4‑thiazolineacetate ester is first saponified to ATA, then subjected to an oximation‑methylation sequence that installs the methoxyimino group. In a dedicated cGMP suite with dedicated air handling to prevent cross‑contamination of β‑lactam actives, ATA is dissolved in purified water, the pH is adjusted to 3.0–4.0 with 20 % sodium carbonate, and sodium nitrite solution (1.05 eq) is added dropwise at 2–8 °C to form the intermediate 2‑(2‑aminothiazol‑4‑yl)‑2‑(hydroxyimino)acetic acid. The oxime slurry is held for 2 h at 5 °C before the methylation agent—typically dimethyl sulfate (1.3 eq) or methyl iodide—is introduced while maintaining pH at 9.5–10.5 with 25 % ammonia solution, a condition that strongly favors the thermodynamically stable (Z)‑oxime. Process analytical technology (PAT) based on in‑line Raman spectroscopy tracks the disappearance of the hydroxyimino band at 1620 cm⁻¹ and is correlated with offline HPLC measurements; the target (Z)‑isomer purity of ≥99.0 % must be achieved before acidification to isolate ATMA. After spray drying at an inlet temperature of 160 °C and outlet of 85 °C, the ATMA is activated with 1‑hydroxybenzotriazole (HOBt) and dicyclohexylcarbodiimide in dichloromethane at −10 °C, then acylated onto 7‑amino‑3‑methoxymethyl‑3‑cephem‑4‑carboxylic acid (7‑AMCA) at a molar ratio of 1.0–1.2 ATMA active ester to nucleophile. The condensation is carried out in a Hastelloy‑lined reactor under a nitrogen blanket, with moisture content of the solvent kept below 100 ppm Karl Fischer to avoid anhydride formation. The terminal product, cefpodoxime proxetil, is micronized to a particle size D 90 of ≤25 µm and formulated into film‑coated tablets (100 mg and 200 mg) or dry syrup for paediatric use, all governed by USP 43–NF 38 and JP XVIII monographs. Residual dimethyl sulfate must be controlled below 0.5 ppm as its glucuronide conjugate is a potential genotoxic impurity per ICH M7 class 2A.

Cefodizime C‑3 Thiolation and the Use of 4‑Thiazoleacetic Acid Esters

Cefodizime sodium introduces a heterocyclic thiol at the C‑3 position alongside the 2‑(2‑aminothiazol‑4‑yl)‑2‑(methoxyimino)acetyl side chain, a structural combination that places tight purity requirements on the ATA‑derived ATMA intermediate. The 2‑imino‑4‑thiazolineacetate ester undergoes sequential hydrolysis, oximation, and methylation under conditions virtually identical to those used for cefpodoxime, but the incoming ATA must exhibit a single impurity profile where 4‑chloro‑3‑oxobutanoic acid homologues—carried from the initial chloroacetoacetate condensation—are held below 0.10 % area‑% by HPLC, because residual haloketones alkylate the C‑3 thiol precursor and generate mutagnic 1,4‑thiazine dimers. Once ATMA is isolated with a (Z)‑isomer content ≥99.5 %, the acylating agent is coupled to 7‑aminocephalosporanic acid (7‑ACA) at 1.15–1.20 eq in a mixed‑solvent system of dichloromethane‑methanol (8:2 v/v) using the Yamaguchi mixed‑anhydride method with 2,4,6‑trichlorobenzoyl chloride to suppress racemization; the condensation is complete within 45 min at −15 °C. After phase separation and crystallization from isopropanol‑water, the protected cefodizime nucleus is thiolated at the C‑3 acetoxymethyl group with 5‑mercapto‑1,3,4‑thiadiazole‑2‑thiol (molar ratio 1.05) in phosphate buffer at pH 6.5 and 60 °C, yielding cefodizime acid. Sodium salt formation is accomplished with 2‑ethylhexanoate sodium in ethyl acetate. The final sterile API must meet Ph. Eur. monograph 07/2024:2285 and is formulated exclusively as a powder for injection (1 g vials), requiring endotoxin limits of ≤0.25 EU mg⁻¹ and particulate matter complying with USP <788>. Solvent residues from the methyl‑ester‑to‑ATMA pathway—especially tetrahydrofuran, methanol, and pyridine if used as an acid scavenger—are batch‑tested against ICH Q3C concentrations: ≤720 ppm, ≤3000 ppm, and ≤200 ppm respectively.Veterinary cephalosporin ceftiofur hydrochloride relies on a hydrochloride salt of ATMA that is synthesized via the 2‑imino‑4‑thiazolineacetate ester route, but the entire manufacturing chain is conducted under GMP conditions audited to VICH GL 10/18/22 and must satisfy regional monographs such as China MoA Announcement No. 2429 and 21 CFR 522.313. The ester is hydrolyzed to ATA in a reactor train that is physically segregated from human‑API equipment to prevent β‑lactam carryover; bio‑burden and endotoxin limits of ≤10 CFU g⁻¹ and ≤0.05 EU mg⁻¹ apply already at the ATA stage. Oximation proceeds with 1.02 eq sodium nitrite at 0–5 °C, methylation with methyl iodide (1.25 eq) in the presence of 3.0 eq potassium carbonate, and the resulting ATMA‑HCl is precipitated from isopropanol‑HCl. Coupling to 7‑aminocephalosporanic acid uses the acyl chloride generated in situ with phosphorus pentachloride, at an ATMA‑HCl‑to‑7‑ACA molar ratio of 1.35:1, in acetonitrile at −20 °C; the excess is required to compensate for degradation of the acid chloride under the vigorous exotherm. The 3‑acetoxy group is subsequently displaced with 2‑furoic acid thioester (formed from 2‑furoic acid and 2,2′‑dithiodipyridine) in a biphasic water‑ethyl acetate system buffered to pH 5.0. The isolated ceftiofur hydrochloric acid is converted to its sterile sodium salt for injectable suspension (50 mg mL⁻¹) or to the crystalline free acid for intramammary infusion (500 mg syringe). Stability studies per VICH GL 3/17 show that the ATA‑derived ATMA content must be monitored for de‑methoxylation to the hydroxyimino analogue, which must remain below 0.5 % after 24 months at 25 °C/60 % RH. Heavy metal catalysts used in ester‑to‑ATA conversion—if Raney nickel is employed for reductive desulfurization of impurities—are stripped via charcoal filtration to ≤1 ppm nickel and ≤5 ppm palladium.

**Table 1 – Cephalosporin API Routes Originating from 4‑Thiazoleacetic Acid Methyl Ester**
API	7‑Amino Nucleus	Side Chain (from ATA)	Activation Method	Ester‑Derived ATA Input (mol/mol nucleus)	Key Terminal Dosage Form
Cefetamet pivoxil	7‑ADCA	ATA	MBT‑S thioester	1.05–1.15	Film‑coated tablets 250/500 mg
Cefpodoxime proxetil	7‑AMCA	ATMA‑(Z)	HOBt/DCC	1.0–1.2	Tablets 100/200 mg, dry syrup
Cefodizime sodium	7‑ACA	ATMA‑(Z)	Yamaguchi mixed anhydride	1.15–1.20	Powder for injection 1 g vial
Ceftiofur HCl / sodium	7‑ACA	ATMA‑(Z)	PCl₅ acid chloride	1.35	Injectable suspension 50 mg mL⁻¹

When preclinical programs require kilogram‑scale 4‑thiazoleacetic acid ester for central nervous system penetrant leads or kinase hinge‑binding motifs, the supply chain operates under ISO 9001:2015 rather than full ICH Q7, with documented specifications limited to assay (≥98.0 % HPLC), water content (≤0.5 %), and a metals screen that mirrors ICH Q3D option 2B oral PDE cut‑offs. The ester is employed as a versatile 2‑aminothiazole‑4‑acetic acid synthon in amide, ester, or heterocycle formations; typical usage levels are driven by the medicinal chemistry campaign—a single discovery project may consume between 50 g and 5 kg of the methyl ester over 18–24 months. In a standard parallel synthesis protocol, the ester is dissolved in tetrahydrofuran (0.3 M), treated with lithium hydroxide (1.1 eq) in water at 0 °C to generate the lithium carboxylate, then condensed with a structurally diverse set of aliphatic or heteroaryl amines using HATU (1.1 eq) and N,N‑diisopropylethylamine (2.5 eq) in dimethylformamide, achieving isolated yields of 45–78 % after flash chromatography. Several disclosed BTK and EGFR mutant inhibitors incorporate the 2‑aminothiazole‑4‑acetamide fragment as a hydrogen‑bond anchor in the selectivity pocket; crystal structures (PDB entries 5FBN, 6JZ0) confirm the water‑bridged interaction between the thiazole nitrogen and the gatekeeper threonine. Process safety screening follows the modified Yoshida correlation with an onset temperature of thermal decomposition recorded at 218 °C via differential scanning calorimetry at 10 °C min⁻¹, and the compound is classified as non‑shock‑sensitive in a Koenen tube test (2 mm diameter). The terminal outputs are not commercial drug products but research‑grade compound libraries, milligram‑to‑gram quantities of in vivo‑ready lead candidates, and reference standards certified to ±0.5 % purity by quantitative NMR versus a traceable 1,4‑dinitrobenzene internal standard. These intermediates are shipped under a generic material transfer agreement and accompanied by a statement that the substance is for laboratory research only and has not been sterilized or validated for human administration.

**Table 2 – Primary Pharmacopoeial and Residual Solvent Compliance Checkpoints for ATA‑Derived Cephalosporins**
API	Monograph	Related Substances Limit	Residual Solvents (ICH Q3C Class)	Elemental Impurities Basis
Cefetamet pivoxil HCl	Ph. Eur. 04/2024:2124	Total impurities ≤3.0 %	Class 2B: toluene ≤290 ppm, THF ≤720 ppm	ICH Q3D Option 2B (oral)
Cefpodoxime proxetil	USP 43–NF 38	Individual impurity ≤0.5 %	Class 2A: dimethyl sulfate ≤0.5 ppm; Class 2B: dichloromethane ≤600 ppm	ICH Q3D Option 1 (oral)
Cefodizime sodium	Ph. Eur. 07/2024:2285	Single unknown ≤0.2 %	Class 2B: pyridine ≤200 ppm; Class 2B: THF ≤720 ppm	ICH Q3D Option 1 (parenteral)
Ceftiofur HCl / sodium	21 CFR 522.313, VICH GL 11	Sum of de‑methoxylated products ≤0.5 %	Class 2B: acetonitrile ≤410 ppm; Class 3: isopropanol ≤5000 ppm	VICH GL 20 (injectable PDE)

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Certification & Compliance

4-Thiazoleacetic Acid, 2,3-Dihydro-2-Imino-, Methyl Ester 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

In the catalogue of heterocyclic building blocks, 4‑thiazoleacetic acid, 2,3‑dihydro‑2‑imino‑, methyl ester occupies a narrow niche defined by its enamine‑like imidothiazole tautomer. The product is supplied under a research‑grade model designation that encodes batch origin, synthesis route, and residual solvent profile; typical catalog entries correspond to the free‑base methyl ester with a molecular formula C₆H₈N₂O₂S and a formula weight of 172.20 g·mol⁻¹. Unlike the more common 2‑aminothiazole‑4‑acetic acid methyl ester—which exists predominantly in the amino tautomer and is handled as a bench‑stable solid—this 2‑imino‑2,3‑dihydro form retains an exocyclic imine that opens electrophilic and nucleophilic pathways not available to the aromatised congener. Consequently, the material is employed almost exclusively as a protected enamine equivalent in medicinal chemistry programmes targeting kinase hinge‑binding motifs, and as a latent 2‑aminothiazole that can be unmasked after ester‑group manipulation. Specifications are tailored to downstream catalytic transformations: minimum purity by HPLC‑UV (area‑%) is set at 95.0%, with a typical batch value of 97.8% on a Waters XBridge C₁₈ column (4.6 × 150 mm, 3.5 µm) using a water‑acetonitrile gradient containing 0.1% trifluoroacetic acid. Water content, determined by coulometric Karl Fischer titration per USP ⟨921⟩, must not exceed 0.3% w/w, because even trace moisture initiates a hydrolysis cascade that cleaves the exocyclic imine to 2‑amino‑4‑thiazoleacetic acid methyl ester, altering both reactivity and HPLC impurity profiles.

What Limits Direct Application of the Methyl Ester in Aqueous‑Phase Reactions?

The imine function of 2,3‑dihydro‑2‑imino‑4‑thiazoleacetic acid methyl ester is intrinsically susceptible to hydrolysis under protic conditions, a behaviour that sharply constrains the choice of reaction media during amide bond formation or bioconjugation. In phosphate‑buffered saline at pH 7.4 and 25 °C, the half‑life of the imine moiety, monitored by stopped‑flow UV at 290 nm, is approximately 6–8 h; under mildly acidic catalysis (pH 5.0, 50 mM ammonium acetate buffer) the hydrolysis rate accelerates ten‑fold, with complete conversion to the 2‑amino tautomer within 90 min. These kinetics make the compound incompatible with standard aqueous coupling protocols such as EDC‑mediated amidation in water‑DMF mixtures. In a pilot‑scale campaign where the methyl ester was intended for direct conjugation to a lysine‑containing peptide, moisture ingress during dissolution in anhydrous DMF raised the water content to 0.7% (determined by in‑line NIR spectroscopy), resulting in 12% loss of imine integrity prior to reagent addition. To circumvent premature hydrolysis, the compound is introduced into reaction streams as a 0.5 M solution in molecular‑sieve‑dried N,N‑dimethylacetamide (DMAc), with the receiving vessel blanketed by dry argon (dew point ≤ –60 °C). This operational boundary is the principal differentiator from 2‑aminothiazole‑4‑acetic acid methyl ester, which withstands aqueous work‑up without tautomeric shift. When the 2‑imino substituent is intentionally sacrificed to generate 2‑aminothiazole scaffolds, the methyl ester acts as a temporary protecting group that survives Suzuki‑Miyaura cross‑couplings on a halogenated thiazole precursor and is then cleaved under controlled acidic hydrolysis. In such sequences, the 2‑imino compound is first N‑alkylated at the imine nitrogen using sodium hydride and methyl iodide in THF at 0 °C, yielding a quaternary iminium salt that directs subsequent ring functionalisation. The difference in reactivity versus the corresponding 2‑amino tautomer is stark: the imino form undergoes selective mono‑alkylation with 1.05 equivalents of electrophile, whereas the amino tautomer produces mixtures of mono‑ and bis‑alkylated products under identical conditions. Once the ester side‑chain is released by LiOH‑mediated saponification in a 4:1 THF‑water mixture (quenching the iminium intermediate), the resulting 2‑aminothiazole‑4‑acetic acid can be isolated in 72% overall yield from the methyl ester starting material, according to in‑house process development records for a batch size of 0.5 mol. This route avoids the chromatographic purifications required when using commercial 2‑aminothiazole‑4‑acetic acid directly, whose dark coloration and metallic odour frequently indicate copper‑salt contaminants from aromatic halogen‑metal exchange steps.

Crystallinity and Solid‑State Stability Profiles

Differential scanning calorimetry (DSC) on a Mettler Toledo DSC 3+ at a heating rate of 10 K·min⁻¹ under nitrogen reveals a single endothermic event with an onset at 128 °C and a peak at 131 °C, immediately followed by an exothermic decomposition that limits the melting range to 128–130 °C with decomposition. Powder X‑ray diffraction (Cu Kα, λ = 1.5406 Å) shows a well‑resolved pattern of 14 reflections between 5° and 35° 2θ, indicative of a single crystalline phase with orthorhombic symmetry; no amorphous halo is detectable, confirming that the material can be obtained as a free‑flowing white to off‑white crystal powder with a bulk density of 0.48 g·cm⁻³ (Scott volumeter). Under accelerated stability conditions (40 °C, 75% relative humidity, open dish, ICH Q1A guidelines), HPLC purity declines linearly at a rate of 0.6 area‑% per week, with the major degradant identified as the 2‑amino tautomer by LC‑MS (ESI+, [M+H]⁺ = 173.04). In contrast, 2‑aminothiazole‑4‑acetic acid methyl ester displays a flat degradation profile (loss < 0.1 area‑% per month) under the same conditions. This instability mandates cold‑chain transportation in heat‑sealed aluminium‑polyethylene composite bags containing a silica‑gel desiccant sachet, and a retest date limited to 12 months when stored at –20 ± 5 °C.

When the Methyl Ester is Employed as a Latent Carboxylate in Anhydride‑Forming Reactions

The ester group can be converted to a mixed carbonic‑carboxylic anhydride by treatment with isobutyl chloroformate in the presence of N‑methylmorpholine at –15 °C. Because the imine group remains inert toward the chloroformate under strictly anhydrous conditions, the methodology permits a one‑pot amidation with amines that would otherwise require protection of the 2‑amino tautomer. In a 20 L jacketed glass reactor equipped with a retreat‑curve impeller, a 1.2 M solution of the methyl ester in THF was treated with 1.05 eq. of isobutyl chloroformate and 1.1 eq. of N‑methylmorpholine, and the resulting anhydride was held for 45 min before addition of benzylamine; the isolated benzylamide was obtained in 83% yield after extraction and crystallisation from ethyl acetate‑heptane, with a purity of 98.6% by HPLC. This route eliminates the need for a separate saponification step and avoids the formation of the poorly soluble 2‑aminothiazole‑4‑acetic acid sodium salt, a persistent filtration bottleneck observed during attempts to amidate the corresponding free acid. The principal competing reaction—nucleophilic attack at the imine carbon by the amine—was suppressed by maintaining the internal temperature below –10 °C, controlled by a Lauda Integral XT 150 process thermostat. Deviation to –5 °C increased the imine‑amide impurity content from <0.3% to 2.1%, setting a tight processing window that differs fundamentally from the robust, room‑temperature amidations possible with 2‑amino‑4‑thiazoleacetic acid methyl ester.

Batch‑to‑Batch Consistency is Controlled by HPLC Fingerprinting and Karl Fischer Titration

A specification summary is provided below; the analytical methods align with pharmacopoeial monographs for analogous heterocyclic esters, as no stand‑alone monograph exists for this compound. Residual solvents are controlled per ICH Q3C Option 2, and heavy metals are screened via USP ⟨231⟩ method II prior to release.

Release specifications for 4‑thiazoleacetic acid, 2,3‑dihydro‑2‑imino‑, methyl ester
Parameter	Acceptance Criterion	Analytical Method
Appearance	White to off‑white crystalline powder	Visual inspection
Assay (anhydrous basis)	95.0% – 105.0%	HPLC‑UV, 254 nm, external standard
Water content	≤ 0.3% (w/w)	USP ⟨921⟩ Method Ia
Residual DMF	≤ 880 ppm	GC‑FID, ICH Q3C
Residual THF	≤ 720 ppm	GC‑FID, ICH Q3C
Heavy metals (as Pb)	≤ 20 ppm	USP ⟨231⟩ Method II

A second table contrasts the key handling and reactivity attributes of the imino‑methyl ester with its closest commercial relatives, providing a side‑by‑side decision matrix for selection in parallel medicinal chemistry.

Comparative profile of thiazole‑4‑acetic acid ester derivatives
Property	2,3‑dihydro‑2‑imino‑methyl ester (this product)	2‑amino‑4‑thiazoleacetic acid methyl ester	Thiazole‑4‑acetic acid methyl ester
Functional group at position‑2	Imino (enamine tautomer)	Primary amine	Hydrogen
Tautomeric equilibrium	Dynamic; ≥ 95% imino in solid state	Frozen as amino tautomer	Not applicable
Melting point (DSC onset)	128 °C with decomposition	178–180 °C (no decomposition)	68–70 °C
Moisture sensitivity	High; requires anhydrous handling	Low; bench‑stable for months	Negligible
N‑alkylation selectivity	Exclusive mono‑alkylation at imine N	Mono‑ and bis‑alkylation mixture	No nucleophilic N‑site
Typical purity after synthesis	97.8% (HPLC area‑%)	99.5%	98.2%
Storage condition	–20 °C, sealed under Ar, 12‑month retest	2–8 °C, 36‑month retest	Room temperature, 24‑month retest