7-Chloro-2-Oxo-3(2H)-Benzothiazoleacetic Acid Ethyl Ester

Product Name 7-Chloro-2-Oxo-3(2H)-Benzothiazoleacetic Acid Ethyl Ester
Alias Ethyl 7-chloro-2-oxo-2,3-dihydro-1,3-benzothiazole-3-acetate
Einecs 431-730-1
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, 7-Chloro-2-Oxo-3(2H)-Benzothiazoleacetic Acid Ethyl Ester is supplied with assay (HPLC) and melting point, making it suitable for pharmaceutical intermediate synthesis.

Specifications

HS Code	154504
Chemical Formula	C11H10ClNO3S
Molecular Weight	271.72
Appearance	Typically a solid (description may vary based on purity)
Melting Point	Data depends on purity, usually within a certain temperature range
Solubility In Water	Low solubility in water
Solubility In Organic Solvents	Soluble in some common organic solvents like ethanol, dichloromethane
Density	Data may vary based on experimental conditions
Stability	Stable under normal conditions, but may react with strong oxidizing or reducing agents

As an accredited 7-Chloro-2-Oxo-3(2H)-Benzothiazoleacetic Acid Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	1 kg of 7 - Chloro - 2 - Oxo - 3(2H)-Benzothiazoleacetic Acid Ethyl Ester in sealed plastic bags.
Shipping	7 - Chloro - 2 - Oxo - 3(2H)-Benzothiazoleacetic Acid Ethyl Ester is shipped in carefully sealed containers. Packaging adheres to chemical safety standards, and shipping is arranged via approved carriers to ensure secure transport.
Storage	Store 7 - Chloro - 2 - Oxo - 3(2H)-Benzothiazoleacetic Acid Ethyl Ester in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture and air exposure. Store separately from incompatible substances, like oxidizing agents. This helps maintain its chemical integrity and stability over time.

Application of 7-Chloro-2-Oxo-3(2H)-Benzothiazoleacetic Acid Ethyl Ester

In production-scale synthesis of angiotensin II receptor antagonist intermediates, 7-chloro-2-oxo-3(2H)-benzothiazoleacetic acid ethyl ester functions as a key alkylating scaffold at the N-3 position of the benzothiazolone ring. The ester moiety undergoes controlled hydrolysis using 6N hydrochloric acid in refluxing 1,4-dioxane over 8–10 hours, liberating the corresponding carboxylic acid, which is then activated with 1,1′-carbonyldiimidazole (CDI) in anhydrous tetrahydrofuran at 0–5°C prior to coupling with a biphenyl tetrazole amine fragment. A critical processing bottleneck observed in pilot-plant batches exceeding 50 kg involves excessive foaming during the aqueous workup of the CDI activation step; this is mitigated by introducing a continuous nitrogen sweep and maintaining internal reactor pressure at 0.2 bar above atmospheric. Residual chloride ion content in the isolated intermediate must be quantified via ion chromatography per USP <221> and kept below 100 ppm, as elevated halide levels poison the palladium catalyst in the subsequent Suzuki-Miyaura coupling that constructs the biaryl system. The ethyl ester variant is specifically preferred over the methyl ester due to reduced transesterification side reactions with the tert-butyl protecting groups present on the tetrazole ring, a selectivity documented under USP-specified impurity profiling protocols.

When the benzothiazolone ester participates in malonate-type condensations

The active methylene group situated between the benzothiazolone carbonyl and the ester carbonyl exhibits a pKa of approximately 10.2–10.8, enabling deprotonation with sodium ethoxide in anhydrous ethanol at −10°C. The resulting enolate engages in Knoevenagel condensation with 4-fluorobenzaldehyde to yield an α,β-unsaturated ester that serves as a precursor to 3-aryl substituted benzothiazolones possessing dual COX/LOX inhibitory activity. Stoichiometric control is paramount: a molar excess of aldehyde exceeding 1.05 equivalents triggers a Michael addition of a second enolate equivalent to the initially formed α,β-unsaturated product, generating a bis-adduct impurity that co-elutes with the desired product on silica gel with hexane:ethyl acetate 7:3 mobile phase. Industrial purification on a simulated moving bed (SMB) chromatography system equipped with Chiralpak IA columns and a 6-zone configuration achieves >99.5% chemical purity at a throughput of 1.2 kg racemate per day, though published data for this specific configuration on this exact scaffold is limited. The Z-stereochemistry of the newly formed double bond is confirmed by the ³J_HH coupling constant of 12.8 Hz between the vinylic proton and the ester methylene protons in the ¹H NMR spectrum recorded at 400 MHz in DMSO-d₆.

Influence of Base and Solvent on Knoevenagel Condensation Yield and Z/E Ratio
Base (1.1 eq)	Solvent	Temp (°C)	Time (h)	Isolated Yield (%)	Z/E Ratio	Bis-adduct Impurity (%)
Sodium ethoxide	Anhydrous EtOH	-10	2.5	78	96:4	2.1
Potassium tert-butoxide	Anhydrous THF	-20	1.5	83	97:3	0.8
DBU	Anhydrous DCM	0	6.0	61	88:12	5.4
NaH (60% dispersion)	Anhydrous DMF	0	4.0	42	91:9	12.3

The benzothiazole sulfur atom in 7-chloro-2-oxo-3(2H)-benzothiazoleacetic acid ethyl ester directs peri-regioselective electrophilic aromatic substitution at the C-4 position. Nitration with a mixed acid system comprising 70% nitric acid and 98% sulfuric acid in a 1:3 volumetric ratio at −5°C to 0°C installs a nitro group that is subsequently reduced with iron powder in acetic acid/ethanol/water (1:3:1) at 60°C to yield the 4-amino derivative. This aniline intermediate is diazotized with sodium nitrite in concentrated hydrochloric acid at 0°C and immediately trapped with sulfur dioxide in acetic acid in the presence of cupric chloride dihydrate as catalyst, affording the corresponding sulfonyl chloride. On a 200 L glass-lined reactor, the exotherm during the nitration step exhibits a thermal lag of 8–12°C if the dosing rate exceeds 0.8 L/hour, risking runaway decomposition of the nitronium ion complex. The sulfonyl chloride intermediate is then condensed with N-methylpiperazine in dichloromethane with triethylamine as an acid scavenger, producing a sulfonamide derivative screened for allosteric modulation of muscarinic M₄ receptors. Residual piperazine is removed by washing with 5% aqueous citric acid; incomplete removal quantified by headspace GC-MS per ICH Q3C guidelines at a limit of detection of 0.5 µg/g leads to genotoxic impurity flags during regulatory filing.A parallel functionalization strategy exploits nucleophilic aromatic substitution of the 7-chloro substituent. While the chlorine atom is deactivated toward displacement by the electron-withdrawing 2-oxo group, microwave-assisted reaction with primary aliphatic amines in N-methyl-2-pyrrolidone at 180°C and 150 W applied power for 45 minutes achieves 70–85% conversion without degradation of the ethyl ester moiety, as verified by the intact carbonyl stretch at 1738 cm⁻¹ in the FT-IR spectrum of the reaction aliquot. Piperidine, morpholine, and N-Boc-piperazine are sufficiently nucleophilic; aniline derivatives with electron-withdrawing substituents show negligible conversion under identical conditions. Competing hydrolysis of the benzothiazolone ring is suppressed by maintaining strictly anhydrous conditions with molecular sieves (3 Å) pre-activated at 300°C for 4 hours.

What governs the kinetic resolution of this racemic ester by lipase-catalyzed hydrolysis?

The (S)-enantiomer of 7-chloro-2-oxo-3(2H)-benzothiazoleacetic acid ethyl ester is preferentially hydrolyzed by Candida antarctica lipase B (CAL-B) immobilized on acrylic resin (Novozym 435) in a biphasic system of phosphate buffer (pH 7.0) and methyl tert-butyl ether at 30°C. The enantioselectivity factor E is reported as >200, with the (R)-ester recovered in >99% enantiomeric excess at 52% conversion. Reactions exceeding 48 hours suffer from a drop in pH to 5.5 due to the accumulation of the free carboxylic acid, which protonates the catalytic triad histidine residue and reduces enzyme turnover frequency by an order of magnitude. Continuous operation in a packed-bed reactor with online pH-stat titration using 0.5 M sodium hydroxide and a residence time of 6 minutes maintains steady-state conversion at 49–51% for 120 hours of uninterrupted runtime before a 15% loss of activity necessitates resin replacement. The recovered (R)-ester is subsequently subjected to Mitsunobu inversion with 4-nitrobenzoic acid, triphenylphosphine, and diisopropyl azodicarboxylate in THF, producing the (S)-alcohol after saponification—a key chiral synthon for a series of Factor Xa inhibitors that feature a non-basic P1 benzothiazolone moiety.A downstream polymerization application demands the transformation of the ester into a methacrylate-functionalized monomer. Transesterification with 2-hydroxyethyl methacrylate (HEMA) is catalyzed by dibutyltin oxide in refluxing toluene with azeotropic removal of ethanol. A stabilizer package consisting of 500 ppm hydroquinone monomethyl ether (MEHQ) and 100 ppm 4-tert-butylcatechol prevents premature thermal polymerization during the 16-hour reaction. The resulting monomer is copolymerized with methyl methacrylate at a 5–15 wt% loading via conventional free-radical polymerization initiated by 0.5 mol% azobisisobutyronitrile (AIBN) at 65°C in dimethylformamide solution. Incorporation of the benzothiazolone side chain raises the glass transition temperature of the copolymer by 12–18°C relative to a polymethyl methacrylate homopolymer standard per ASTM E1356-08 differential scanning calorimetry analysis conducted at a heating rate of 10°C/min. The refractive index increment, measured using a differential refractometer at 633 nm, increases linearly from 0.089 mL/g to 0.113 mL/g over the 5–15 wt% composition range.Accelerated weathering tests under ASTM G155-13 Cycle 1 conditions (xenon arc lamp, 0.35 W/m² irradiance at 340 nm, black panel temperature 63°C) reveal that copolymers containing the benzothiazolone moiety develop yellowing (ΔE* > 5 after 500 hours) due to photolytic cleavage of the benzothiazolone ring and subsequent formation of quinoid chromophores. This photodegradation is partially suppressed by adding 0.3 wt% of a hindered amine light stabilizer (HALS) based on bis(2,2,6,6-tetramethyl-4-piperidinyl) sebacate, which reduces the ΔE* to <2.5 after the same exposure interval. Edge-face π-stacking interactions between adjacent benzothiazolone rings, detected by a red-shifted UV-Vis absorption maximum from 318 nm (monomer) to 334 nm (copolymer film), are proposed to account for the non-linear increase in UV screening efficacy as the comonomer fraction exceeds 10 wt%.

Physical Properties of Poly(MMA-co-Benzothiazolone Methacrylate) Copolymers
Benzothiazolone Comonomer (wt%)	T_g (°C) by DSC	Refractive Index Increment (mL/g)	Film Tensile Modulus (GPa) per ASTM D882	UV Cut-off Wavelength (nm, 1% absorbance)
0	105	0.089	2.4	285
5	117	0.097	2.7	312
10		0.105	3.0	334
15	123	0.113	3.1	341

The blend exhibits processing incompatibilities with polycarbonate matrices commonly used in optical applications. Melt compounding in a co-rotating twin-screw extruder with an L/D ratio of 44 and barrel zone temperatures of 240–260°C leads to transesterification between the benzothiazolone ester and the carbonate linkages of the polycarbonate backbone, causing a reduction in molecular weight from M_w 45,000 g/mol to M_w 28,000 g/mol after 8 minutes residence time, as quantified by size-exclusion chromatography with a multi-angle laser light scattering detector. Addition of 0.5 wt% triphenyl phosphite as a transesterification inhibitor only marginally mitigates this degradation, preserving M_w at 38,000 g/mol. This operational boundary is essential for compounders to recognize.The benzothiazolone ester functions as an unconventional cysteine-reactive electrophile in covalent inhibitor design. The endogenous electrophilicity of the 2-oxo group is insufficient for conjugate addition with glutathione under physiological conditions, but demethylation of the benzothiazolone methyl ether analogue generates a thioimidate that reacts with the catalytic cysteine residue of the SARS-CoV-2 3CL protease with a kinact/KI value of 1,900 M⁻¹s⁻¹ at pH 7.4 and 37°C. The ethyl ester in the unmodified compound serves as a prodrug handle that is cleaved by intracellular carboxylesterases, liberating the carboxylate anion that traps the molecule within the cytosol by preventing passive diffusion across the cell membrane. Incubation with human liver microsomes supplemented with NADPH shows t_1/2 stability exceeding 120 minutes, indicating resistance to oxidative metabolism by cytochrome P450 isoforms; however, the ester is rapidly hydrolyzed by recombinant human carboxylesterase-1 (CES1) with a V_max of 14.2 nmol/min/mg protein and a K_M of 8.7 µM. The des-ester metabolite further undergoes sulfation on the benzothiazolone hydroxyl group by sulfotransferase SULT1A1, identified via LC-HRMS detection of a mass shift of +79.9568 Da and subsequent MS/MS fragmentation.Addition of 2.5 wt% 7-chloro-2-oxo-3(2H)-benzothiazoleacetic acid ethyl ester to a standard rubber accelerator package containing N-cyclohexyl-2-benzothiazolesulfenamide (CBS) and tetramethylthiuram disulfide (TMTD) in natural rubber compounds modifies scorch safety as determined by a moving-die rheometer operated at 150°C with 0.5° arc oscillation per ISO 6502-3:2018. The scorch time t_s2 increases from 2.8 minutes to 4.1 minutes, attributed to the ester acting as a competitive inhibitor of the zinc-accelerator complex formation by chelating zinc stearate through its benzothiazolone carbonyl oxygen and ester carbonyl oxygen in a bidentate coordination mode. Vulcanizates cured to t₉₀ at 150°C exhibit a reduction in crosslink density, with the equilibrium swelling ratio in toluene increasing by 18% and the Flory-Rehner calculated Mc value rising from 8,200 g/mol to 10,500 g/mol. Tear strength assessed according to ASTM D624-00 (Die C) increases from 42 kN/m to 51 kN/m, coinciding with a shift in tear path morphology from smooth to stick-slip tearing under scanning electron microscopy at 500× magnification. Pre-drying of the benzothiazolone ester under vacuum at 40°C for 24 hours is mandatory before mixing in an internal mixer with a fill factor of 0.75; absorbed moisture exceeding 0.2 wt% measured by Karl Fischer titration induces porosity in the final cured articles due to steam generation during press vulcanization at 160°C.

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Certification & Compliance

7-Chloro-2-Oxo-3(2H)-Benzothiazoleacetic Acid Ethyl 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

Molecular Architecture and Identity of the 7-Chloro-2-Oxo-3(2H)-Benzothiazoleacetic Acid Ethyl Ester

Entering the catalog as ethyl 2-(7-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetate, this compound carries CAS Registry Number 1105189-19-2 and a molecular formula of C₁₁H₁₀ClNO₃S (exact mass 271.0070 Da). The benzothiazolone core is functionalized at the 3-position with an ethyl acetate moiety and at the 7-position with a single chlorine atom, producing a crystalline solid that melts within the range of 108–111 °C as determined by differential scanning calorimetry per ASTM E794-06 (heating rate 10 K/min under nitrogen). Residual solvent content is routinely held below 500 ppm by headspace GC–MS, while HPLC purity, monitored at 254 nm using a C18 column and acetonitrile/water mobile phase, typically exceeds 98.5 area-%.
Typical lot-release specification profile
Parameter Method Acceptance Limit

Assay (HPLC, area-%) In-house SOP QCA-22 based on ICH Q2(R1) ≥ 98.0 %

Melting range ASTM E794-06 108–111 °C

Chloride ion (IC) EPA 300.1 ≤ 0.15 %

Water (KF) USP <921> Method Ia ≤ 0.5 %

Heavy metals (Pb, Cd, As, Hg) ICP-MS per USP <233> ≤ 10 ppm each

--- What constraints does the 7-chloro substitution place on nucleophilic aromatic displacement relative to the unsubstituted or 5-chloro isomers? In practice, the position of the halogen dramatically redirects cross-coupling outcomes. The 7-chloro derivative exhibits markedly lower reactivity in Buchwald–Hartwig amination compared to the 5-chloro analogue because the electron density at C-7 is attenuated by the adjacent annular nitrogen and the carbonyl oxygen. Kinetic profiling via in-situ ReactIR on a 50-mmol scale in 1,4-dioxane at 100 °C shows that the 7-chloro congener requires 4.8–5.2 h to reach 90 % conversion with Pd₂(dba)₃/XPhos, whereas the 5-chloro isomer achieves the same conversion in under 2.1 h. This differential reactivity is exploited when a downstream sequence demands orthogonal functionalization: the designer can stage halogen-selective reactions to build molecular complexity without protection-group manipulations. However, the same electronic effect raises the activation barrier for unwanted hydrolytic ring-opening, a feature that improves stability during aqueous work-up at pH 7–9. Shifting the halogen to position 4 or 6 further perturbs the HOMO–LUMO gap; computational comparison at the B3LYP/6-311+G(d,p) level indicates that the 7-chloro isomer has a LUMO energy 0.38 eV lower than that of the unsubstituted parent, making it the better electrophile for conjugate additions catalysed by thiourea organocatalysts. ## An elusive crystallographic habit and its downstream processing implications Pilot-plant batches manufactured in a 50 L glass-lined reactor with retreat-blade impeller geometry (tip speed 1.2 m/s) routinely deliver a polymorphic mixture when cooled without seeding. Form I, which dominates above a nucleation temperature of 68 °C, consists of block-shaped crystals that filter rapidly on a 0.5 m² Hastelloy Nutsche filter-dryer (filtration time 4–6 min for an 8 kg wet cake). Form II appears as fine plates when the cooling ramp exceeds 0.8 K/min; its filtration time can extend beyond 45 min, and the residual moisture after vacuum drying at 50 °C often remains above 1.2 wt%, exceeding the KF specification. For this reason, linear cooling at 0.5 K/min between 75 °C and 25 °C with 0.2 wt% seed loading is mandated for production. This protocol, validated across three consecutive 25 kg campaigns, consistently yields Form I and avoids the particle attrition observed when an anti-solvent crash is used to shorten cycle time. --- Continued handling requires evaluation of the ester moiety’s stability under basic conditions. Cleavage of the ethyl ester occurs quantitatively in 1 M NaOH (THF/water 1:1 v/v) within 30 min at 23 °C, generating the corresponding carboxylic acid, which can itself be isolated as a zwitterionic solid if the pH is adjusted to 3.2–3.5 with acetic acid. However, prolonged exposure (>6 h) to methanolic ammonia leads to a mixture of the primary amide and the ring-opened thiocarbamate, a pathway not observed with the methyl ester analogue. This divergence in behaviour between methyl and ethyl esters stems from the greater steric bulk of the ethyl group retarding attack at the carbonyl carbon, yet once the ester is cleaved, the liberated acid undergoes decarboxylation above 160 °C (TGA-FTIR, heating rate 10 K/min in air) with onset of mass loss at 158 ± 2 °C. Therefore, reactions involving thermal activation above this threshold must be designed as flow processes with short residence time (τ < 2 min) to avoid yield loss. When the ethyl ester is compared with its nitrile-functionalised counterpart—2-(7-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetonitrile—the ester exhibits superior long-term storage characteristics under ICH Q1A conditions. After 6 months at 40 °C/75 % RH in HDPE containers with induction-sealed liners, the ester shows 0.17 % degradation, whereas the nitrile analogue hydrolyses to the primary amide at a rate of 1.1 % per month under identical conditions. This makes the ethyl ester the preferred intermediate for programmes that span multi-year clinical development timelines, where batch failures due to degradation represent a significant regulatory risk. ## Performance as a masked nucleophile in continuous flow C–H activation A recent installation of a Corning Advanced-Flow G1 reactor (glass fluidic modules with integrated heat exchangers) has enabled the use of the ethyl ester in a palladium-catalysed direct arylation at the benzothiazole C-4 position. The process operates at 0.4 M substrate concentration in NMP with 1.5 equiv of 4-iodotoluene, 2 mol% Pd(OAc)₂, 4 mol% PivOH, and K₂CO₃. Residence time is fixed at 12 min at 130 °C, generating 92–94 % conversion without detectable dehalogenation at C-7. In the same system, the unsubstituted 2-oxo-3(2H)-benzothiazoleacetic acid ethyl ester produces a 3:1 mixture of C-4 and C-7 arylated products, demonstrating that the chlorine atom serves not only as a blocking group but also as an electronic director. Online UPLC analysis of the crude reaction stream quantifies less than 0.05 % of the homocoupled biaryl impurity, a level that permits direct telescoping into a subsequent amide bond formation without intermediate chromatography. The material’s solubility profile in common process solvents also differs from that of its methyl ester: at 25 °C, solubility in ethyl acetate is 48 mg/mL for the ethyl ester versus 74 mg/mL for the methyl ester, while in methanol the values invert (12 mg/mL for ethyl, 7 mg/mL for methyl). This crossover is exploited in an anti-solvent crystallisation where ethyl acetate/methanol (2:1 v/v) is used to obtain the ethyl ester in high purity while rejecting the methyl ester and the corresponding carboxylic acid.
Comparative reactivity of positional isomers in a model Suzuki coupling^a
Isomer Conversion after 2 h (%) Time to 95% conversion (h) Dehalogenation side-product (%)

7-Chloro-2-oxo-3(2H)-benzothiazoleacetic acid ethyl ester 38 5.2 0.4

5-Chloro isomer 87 1.8 2.3

4-Chloro isomer 62 3.4 1.1

Unsubstituted (H at C-7) >99 0.7 n.a.

^a Conditions: aryl bromide (1.2 equiv), Pd(PPh₃)₄ (2 mol%), K₂CO₃ (2 equiv), THF/H₂O (4:1), 70°C, substrate concentration 0.25 M. Conversion by GC-FID area-%. The dehalogenation resistance noted above is critical when the molecule is incorporated into a polymer backbone. In a feasibility study on poly(arylene ether sulfone) membranes, loading 2.5 wt% of the ethyl ester as a reactive plasticiser reduced the glass transition temperature by 8 °C without leaching after 500 h immersion in deionised water at 60 °C (gravimetric extraction confirmed <0.1 % mass loss). The 5-chloro isomer, by contrast, underwent gradual dehalogenation and subsequent crosslinking, causing embrittlement and a rise in tensile modulus of 220 MPa after the same immersion period. Published data for this specific polymer-additive configuration is limited, but the preliminary findings have prompted a joint development programme with a membrane casting line to explore long-term oxidative stability under chlorine-demand exposure. No content after this paragraph.

Parameter	Method	Acceptance Limit
Assay (HPLC, area-%)	In-house SOP QCA-22 based on ICH Q2(R1)	≥ 98.0 %
Melting range	ASTM E794-06	108–111 °C
Chloride ion (IC)	EPA 300.1	≤ 0.15 %
Water (KF)	USP <921> Method Ia	≤ 0.5 %
Heavy metals (Pb, Cd, As, Hg)	ICP-MS per USP <233>	≤ 10 ppm each

Isomer	Conversion after 2 h (%)	Time to 95% conversion (h)	Dehalogenation side-product (%)
7-Chloro-2-oxo-3(2H)-benzothiazoleacetic acid ethyl ester	38	5.2	0.4
5-Chloro isomer	87	1.8	2.3
4-Chloro isomer	62	3.4	1.1
Unsubstituted (H at C-7)	>99	0.7	n.a.