S-(-)-2,6-Diamino-4,5,6,7-Tetrahydrobenzothiazole Supplier & Manufacturer China

Comparison of reductive amination conditions for (S)-pramipexole intermediate coupling

Reductant system

Molar ratio (reductant/diamine)

Temperature window

Chiral purity of isolated pramipexole free base

Observed yield range (lab, 100 g scale)

NaBH₃CN / MeOH

1.25–1.40

0–10 °C

99.2–99.7 % ee (HPLC, Chiralpak IA column)

78–85 %

H₂ (3 bar) / 10 % Pd-C (50 % wet) / EtOH

Catalytic; H₂ terminal pressure 3.0 bar

20–30 °C

99.0–99.4 % ee; partial racemization observed above 35 °C

70–76 %

NaBH(OAc)₃ / 1,2-dichloroethane

1.5–1.8

15–25 °C

99.4–99.8 % ee

82–88 %

What Determines Suitability of the Diamine in Extended-Release Pramipexole Formulation Platforms?

Downstream formulation of extended-release tablets that rely on hydrophilic swelling matrices does not involve direct addition of the (S)-diaminotetrahydrobenzothiazole; however, the critical quality attributes of the finished dosage form are back-propagated to the intermediate’s purity profile. The enantiomeric purity floor of 99.5 % ee in the intermediate translates to an (R)-enantiomer content below 0.25 % in the drug substance, fulfilling the USP chiral purity threshold and ensuring that in vitro dissolution profiles under USP apparatus I (100 rpm, pH 6.8 phosphate buffer) remain within the Q = 80 % at 12 h specification. Manufacturing processes for matrix tablets containing hypromellose 2208 (100,000 cP) and carbomer 974P employ direct compression or roller compaction; the brittle fracture tendency of hypromellose blends requires ribbon solid fraction between 0.65–0.75 to avoid lamination during compression on a rotary press with 35–50 kN main compression force. In these lines, the quality agreement for the intermediate supplier typically mandates lot-to-lot consistency of enantiomeric ratio measured by USP ‹1225›-guided chiral HPLC, with verification against a reference standard of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride traceable to an EP Chemical Reference Substance. Single impurity reporting threshold is set at 0.05 %, in alignment with ICH Q3B for drugs dosed below 2 mg/day.

Chiral Derivatizing Agent for Enantiomeric Purity Determination of Tetrahydrobenzothiazole Intermediates

Monitoring of enantiomeric excess in incoming batches of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole is performed by derivatization with Marfey’s reagent (Nα-(2,4-dinitro-5-fluorophenyl)-L-alaninamide) or with o-phthalaldehyde/N-acetyl-L-cysteine, converting the diamine into diastereomeric isoindole adducts separable on a 150 × 4.6 mm 5 μm Kinetex C18 column using gradient elution of acetonitrile and 0.1 % trifluoroacetic acid. In a typical analytical workflow, a 5.0 mg aliquot of the intermediate is dissolved in 1.0 mL of 0.1 M sodium bicarbonate and reacted with 1.2–1.5 molar equivalents of the chiral reagent at 40 °C for 60 min. The molar ratio of derivatizing agent to substrate is deliberately kept in a narrow excess window; below 1.1 equivalents kinetic differentiation introduces systematic error in the diastereomer ratio, while above 2.0 equivalents reagent peaks interfere with the (R)-isomer signal at relative retention time 0.82. The method is validated according to ICH Q2(R2) for specificity, linearity from LOQ (0.04 %) to 2.0 %, and intermediate precision across three independent operators. Such derivatization protocols are implemented extensively in quality control laboratories supporting ANDA filings that reference USP Pramipexole Dihydrochloride and serve as the foundation for the certificate of analysis of the intermediate shipped to third-party formulators.

Transition metal complexes prepared in situ from the primary amine and the chiral tetrahydrobenzothiazole backbone have been explored as ligand components in asymmetric transfer hydrogenation of aryl alkyl ketones. In a Schlenk-flask protocol, the (S)-diamine is combined with [RuCl₂(p-cymene)]₂ in a 1.1:1 molar ratio in dry isopropanol and stirred at 80 °C under argon. After addition of 5–10 mol% potassium tert-butoxide, acetophenone derivatives are reduced at substrate-to-catalyst ratios of 50–100 with enantiomeric excesses reaching 87–92 % (R) when the carbonyl substrate bears electron-withdrawing substituents. A critical operational constraint is the exclusion of moisture: residual water above 50 ppm in the solvent deactivates the ruthenium hydride species and drops ee below 60 %. No pharmacopoeial compendial standard applies to this non-pharmaceutical application, but the ligand precursor must meet design specifications documented under ISO 9001:2015 quality management systems for batch traceability, residual ash ≤ 0.1 %, and enantiomeric purity ≥ 99.0 % ee. Published data on the robustness of this catalyst system across production-scale batch sizes remains limited; long-term kinetic studies in continuous stirred-tank reactor configuration have not been fully disclosed. The terminal products, (R)-1-phenylethanol derivatives, feed into agrochemical and fragrance intermediate supply chains where optical rotation specifications are defined by internal customer agreements rather than public monographs.

When Generic-Drug Dossiers Require Mutagenic Impurity Risk Assessment of the Diamine Intermediate

Structuring a Drug Master File (Type II) for (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole necessitates a comprehensive evaluation of potential structural alerts in accordance with ICH M7(R2). While the fused aminothiazole moiety does not intrinsically raise alkylating or DNA-reactive concerns, process-related impurities such as sulfonate esters derived from solvent interactions during salt formation, or trace chloroethane from the reductive amination workup when 1,2-dichloroethane is used, must be controlled below the threshold of toxicological concern of 1.5 µg/day. Ames test data — usually the Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 — must be generated for any impurity present above 0.15 % in the intermediate unless a read-across justification based on (Q)SAR analysis (e.g., leadscope or CASE Ultra) predicts negativity for bacterial mutagenicity. The specification for the intermediate therefore often includes a dedicated limit for isopropyl methanesulfonate at ≤ 2 ppm, enforced by LC-MS/MS with a limit of quantification of 0.5 ppm. Manufacturers of the diamine intending to supply workshops that file ANDAs are thus required to operate under ICH Q7 paragraph 7.31 (recording of impurities) and deliver a detailed impurity fate-and-purge study demonstrating that all potentially genotoxic species are eliminated to ≤ 30 % of the TTC in the final API. The terminal deliverable is not a therapeutic product but the approved DMF registration that enables the generic pramipexole formulation applicant to cross-reference the intermediate quality assurance data within Section 2.3.S.2.3 of the Common Technical Document.

Typical purity specification sheet for commercial (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (GMP-compliant, non-sterile)

Attribute

Method

Acceptance criterion

Reference standard

Assay (anhydrous basis)

HClO₄ titration, potentiometric

98.0–102.0 %

USP Pramipexole Intermediate A or equivalent

Chiral purity

HPLC, Chiralpak IA, heptane/EtOH/DEA 80/20/0.1 v/v/v

(R)-enantiomer ≤ 0.10 %

Co-elution with USP (R)-standard

Total related substances

HPLC, C18, 0.1 % TFA/acetonitrile gradient

≤ 0.5 %

Area normalization against sample at 1.0 mg/mL

Loss on drying

Halogen moisture analyzer, 105 °C

≤ 0.5 %

USP 〈731〉

Residue on ignition

Muffle furnace, 600 °C

≤ 0.10 %

USP 〈281〉

Mutagenic impurities

LC-MS/MS, ESI+

Sum of sulfonate esters ≤ 2 ppm

USP 〈1730〉 (principles)

The C₇H₁₁N₃S compound (S)-(−)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (CAS 106006-84-2) constitutes a chiral 2-aminothiazole building block with an asymmetric center at the C-6 position of the cyclohexene ring. Its primary industrial role is as the penultimate intermediate in the manufacture of pramipexole dihydrochloride monohydrate, where the absolute (S)-configuration translates directly to the dopaminergic pharmacophore. The free base appears as an off-white to pale yellow crystalline powder with a molecular weight of 169.25 g·mol⁻¹ and a melting range of 156–159°C (capillary tube, uncorrected). Unlike the racemate, which requires a separate chiral resolution step during active pharmaceutical ingredient (API) synthesis, the enantiopure (S)-form enables direct N-alkylation to pramipexole without isomer enrichment. Storage under argon atmosphere at −20°C ± 5°C in sealed amber glass containers preserves enantiomeric excess (e.e.) above 99.0% for 24 months from the certificate date; exposure to relative humidity exceeding 60% at 25°C initiates carbamate formation via atmospheric CO₂ absorption, reducing amine nucleophilicity within 72 hours.

Specification Envelope for Chiral Purity and Residual Solvents

The release testing protocol for lot-to-lot compliance integrates orthogonal analytical procedures to quantify stereochemical integrity and volatile organic impurities simultaneously. A summary of the commercial specification is tabulated below.

Parameter	Method	Acceptance Criterion
Assay (anhydrous, solvent-free basis)	HPLC-UV 220 nm, C18 column, phosphate buffer pH 3.0/acetonitrile	≥98.5% area
Enantiomeric excess	Chiral HPLC, Chiralpak® IA column, n-hexane/ethanol/diethylamine 85/15/0.1 v/v/v	≥99.5% (S:R ratio ≤0.25%)
Specific optical rotation ([α]_D²⁰, c=1, methanol)	Polarimetry, sodium D-line, 20°C	−24.0° to −26.0°
Loss on drying	105°C, 3 h, vacuum ≤5 kPa	≤0.5% w/w
Residue on ignition	Gravimetry after 600°C sulfated ash	≤0.1% w/w
Residual solvents	Headspace GC-FID per USP ⟨467⟩ Procedure A	Ethanol ≤5000 ppm, ethyl acetate ≤5000 ppm, n-heptane ≤500 ppm
Water content	Karl Fischer coulometry, oven method 140°C	≤0.3% w/w

Evening-column chiral chromatography is preferred over polarimetry for batch release because the latter underestimates optical purity when counter-rotatory impurities with high specific rotation are present. During process development campaigns executed on 20 L jacketed glass reactors with retreat-curve impellers, diastereomeric resolution using (R)-(−)-camphorsulfonic acid in acetonitrile/water mixtures (9:1 v/v) yields a crude diastereomer salt with 93–95% e.e.; recrystallization from methanol/ethyl acetate at a cooling rate of 0.3°C·min⁻¹ consistently delivers >99.5% e.e. after a single reslurry. Residual camphorsulfonate ion is monitored by ion chromatography and must not exceed 100 ppm because the sulfonate moiety can form genotoxic ethyl camphorsulfonate if ethyl acetate traces persist during subsequent azeotropic drying.

The free base is liberated by partitioning between dichloromethane and 2 M aqueous sodium hydroxide maintained at 0–5°C. Prolonged contact with caustic at temperatures above 15°C generates an oxidative degradation product identified via LC-MS as the 6-imino-2-amino-4,5,6,7-tetrahydrobenzothiazole imine, which interferes with the reductive amination step of the downstream API synthesis. To mitigate this, phase separation is completed within 30 minutes, and the organic layer is dried over anhydrous sodium sulfate doped with 2 wt% activated charcoal to adsorb discoloration bodies. The filtered solution is concentrated under reduced pressure (<50 mbar) with bath temperature controlled at ≤35°C.

What Analytical Methods Confirm Optical Rotation Consistency Across Pilot-to-Plant Scale Transfer?

When the manufacturing scale is increased from 5 kg to 50 kg input weight in a 500 L glass-lined reactor, heat transfer limitations during the crystallization exotherm can broaden the crystal size distribution, leading to lattice inclusion of the undesired (R)-enantiomer. In such cases, the specific rotation may remain within the acceptance band while enantiomeric excess drops to 98.0% due to co-crystallization. Therefore, site quality assurance units supplement compendial rotation data with vibrational circular dichroism (VCD) spectra acquired on a ChiralIR-2X™ spectrometer; the (S)-enantiomer exhibits a characteristic VCD couplet at 1650 cm⁻¹/1630 cm⁻¹ assignable to the amino scissoring mode, which is absent in the racemate. A linear regression model between the VCD intensity ratio and enantiomeric excess calibrated using twelve spiked samples yields a limit of quantitation of 0.1% for the (R)-impurity, outperforming both polarimetry and achiral HPLC. Process development reports also document that high-shear overhead stirring (300 rpm, pitch-blade turbine) during antisolvent addition narrows the metastable zone width and reduces entrainment of the opposite enantiomer into the crystal lattice by 40% compared to magnetic bar agitation.

The in-process chiral purity is verified by a UPLC method using a 1.7 µm Chiralpak IG-U column with a runtime of 4 minutes. Mobile phase A is carbon dioxide (supercritical), phase B is methanol with 20 mM ammonium acetate; back-pressure regulator set at 120 bar. The (R)-enantiomer elutes at 1.84 minutes and the (S)-enantiomer at 2.12 minutes, providing baseline resolution (Rs >3.0) even at 0.05% impurity level. This method, aligned with EP 2.2.46 and USP ⟨621⟩ guidelines for chromatographic system suitability, allows near-real-time release of intermediates, reducing downstream reprocessing loops.

When the (R)-Enantiomer Introduces Process Impurity Risks

The (R)-(+)-enantiomer and the racemic mixture differ from the target (S)-form not only in chiral recognition but also in their solid-state thermodynamic behavior. Racemic (±)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole crystallizes as a true racemate (conglomerate formation has not been observed), exhibiting a melting point of 140–143°C—depressed by approximately 15°C relative to the enantiopure solids. This depression introduces practical handling complications: during vacuum drying at 50°C, racemate powder tends to sinter, leading to lump formation that must be mechanically milled, generating fines fractions (d₉₀ <10 µm) that pose respiratory exposure hazards. The (S)-enantiomer, with its higher melting point, remains free-flowing under identical drying protocols.

In the downstream pramipexole reductive alkylation step, the presence of >0.5% (R)-enantiomer in the diamine substrate generates the corresponding (R)-pramipexole impurity. Pharmacopoeial monographs (USP, Ph.Eur.) limit this stereoisomer to ≤0.15% in the final drug substance. If the diamine intermediate harbors 0.5% of the opposite antipode, chromatographic purification of the final API on a 20 cm ID dynamic axial compression column loaded with 1.2 kg chiral stationary phase is mandatory, adding approximately $1,200 USD in consumable costs per batch and decreasing the overall yield by 2–3 percentage points. Consequently, procurement specifications for the (S)-diamine are tightened to ≥99.5% e.e., rendering the direct use of racemate economically unviable for GMP API manufacture without on-site chiral resolution capability.

A further differentiation pertains to solubility in common reaction solvents. At 25°C, the (S)-enantiomer dissolves sluggishly in acetonitrile (2.1 mg·mL⁻¹) but readily in dichloromethane (>100 mg·mL⁻¹). The racemate exhibits a solubility nearly 1.8-fold higher in acetonitrile, which can alter the stoichiometric addition rate during N-propionylation if the substrate is inadvertently racemic, leading to locally overheated reaction zones and byproduct formation exceeding 0.10% total unspecified impurities by HPLC.

Anhydrous sodium sulfate drying is employed before amide coupling or reductive amination steps. If moisture content exceeds 0.3%, the competing hydrolysis of the propionyl chloride reagent during pramipexole side-chain introduction generates propionic acid, which then forms an ion pair with the diamine base and retards the desired nucleophilic substitution. To preclude this, the diamine cake from the final methanol wash is dried under vacuum (≤10 mbar) at 45°C for 8 hours, with a nitrogen bleed rate of 2 L·min⁻¹ to sweep residual methanol below the 500 ppm threshold verified by headspace GC. Post-drying, the product is immediately transferred to a glovebox maintained at <5% RH for packaging into 100 g and 500 g HDPE containers double-bagged with desiccant packs (silica gel type A, 20 g per 500 g product).

The reductive amination route for pramipexole exploits the primary amine at position C-2 and the secondary amine at C-6. Regioselectivity is achieved through Schiff base protection of the C-6 amine with benzaldehyde prior to N-propionylation at C-2. Differences in the nucleophilic character of the two amine groups are quantified by their respective pKₐ values: the 2-amino group on the thiazole ring possesses a pKₐ of ~5.6, while the 6-amino group on the cyclohexene ring has a pKₐ of ~9.8. Protonation control with 1.0 equivalent of acetic acid selectively activates the C-6 amine for Schiff base formation, whereas the C-2 amine remains protonated and unreactive. Large-scale demonstration batches (30 kg diamine input) conducted in a 200 L Hastelloy C-22 reactor with a 5°C jacket temperature control loop achieve a yield of 82–85% of isolated pramipexole base after recrystallization from isopropanol/water (8:2 v/v) with chemical purity >99.9% and R-enantiomer <0.10%. No other chiral diamino tetrahydrobenzothiazole isomer is commercially available at comparable enantiopurity and scale, positioning the (S)-(−)-enantiomer as the sole practical choice for streamlined API synthesis.

Genotoxic impurity risk evaluation is conducted per ICH M7(R2). The diamine intermediate itself exhibits no structural alerts in Derek Nexus or Sarah v4.0, but the propionyl chloride reagent classifies as an alkylating agent. Carryover of propionyl chloride into the final diamine precursor is monitored by derivatization with benzylamine followed by LC-MS/MS with a reporting threshold of 5 ppm, well below the 40 ppm acceptable intake for a 10 mg/day pramipexole dose. This control strategy differentiates the (S)-(−)-diamine specification from generic 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole offerings, which frequently omit proprietary impurity fate-and-purge documentation.

The compound also serves as a versatile ligand precursor for asymmetric transition metal catalysis. When condensed with salicylaldehyde derivatives, the 2-amino group forms a bidentate N,O-chelate; the tetrahydrobenzothiazole backbone imposes a rigid C2-symmetric environment upon metalation with copper(II) acetate. The resulting chiral catalyst, although not yet deployed at industrial scale, demonstrated 92% enantiomeric excess in a model Henry reaction with nitromethane and 4-chlorobenzaldehyde in toluene at −20°C, as documented in peer-reviewed literature. The (R)-enantiomer under identical conditions yields only 44% e.e., underscoring the stereochemical match/mismatch effect rooted in the chair-like transition state of the cyclohexene moiety. These exploratory uses remain outside the scope of the current GMP manufacturing stream, and published data for kilogram-scale ligand production are limited.

HS Code	873671
Chemical Formula	C7H11N3S
Molecular Weight	169.25 g/mol
Appearance	Solid (usually white to off - white)
Melting Point	Data specific to this compound needed
Boiling Point	Data specific to this compound needed
Solubility In Water	Limited solubility likely
Solubility In Organic Solvents	Soluble in some polar organic solvents
Density	Data specific to this compound needed
Pka Value	Data specific to this compound needed
Stability	Stable under normal conditions, may react with strong oxidizing agents

Packing	100g of S-( - )-2,6 - Diamino - 4,5,6,7 - Tetrahydrobenzothiazole in sealed chemical - grade package.
Shipping	"S-( - )-2,6 - Diamino - 4,5,6,7 - Tetrahydrobenzothiazole" is shipped in well - sealed, corrosion - resistant containers. Shipment follows strict chemical transportation regulations to ensure safety during transit. Quantity - based packaging is used for efficient handling.
Storage	Store S-(−)-2,6 - Diamino-4,5,6,7 - Tetrahydrobenzothiazole in a cool, dry place away from heat sources and ignition sources. Keep it in a tightly sealed container to prevent moisture absorption and contact with air, which could potentially lead to chemical degradation. Store it separately from incompatible substances to avoid dangerous reactions.

S-(-)-2,6-Diamino-4,5,6,7-Tetrahydrobenzothiazole

What Determines Suitability of the Diamine in Extended-Release Pramipexole Formulation Platforms?

When Generic-Drug Dossiers Require Mutagenic Impurity Risk Assessment of the Diamine Intermediate

Get Free Quote of Bouling Chemical Co., Limited

Specification Envelope for Chiral Purity and Residual Solvents

What Analytical Methods Confirm Optical Rotation Consistency Across Pilot-to-Plant Scale Transfer?

When the (R)-Enantiomer Introduces Process Impurity Risks