Name:4,6-Dichloro-N-(methyl-d3)-3-pyridazinecarboxamide/4,6-Dichloro-N-methylpyridazine-3-carboxamide-d3
CAS No. 1609393-89-6
Chemical Formula C₆H₂D₃Cl₂N₃O
Molecular Weight 209.05 g/mol
InChI InChI=1S/C₆H₅Cl₂N₃O/c1-9-6(12)5-3(7)2-4(8)10-11-5/h2H,1H3,(H,9,12)/i1D3
InChIKey KVLSUFLTCCJFAG-FIBGUPNXSA-N
Water Solubility Slightly soluble in water; soluble in DMSO (100 mg/mL, 478.35 (mM, requires ultrasonic dissolution); soluble in polar organic solvents such as methanol and ethanol.
Storage conditions: -20°C to 2-8°C, sealed, away from moisture; protected by an inert atmosphere (nitrogen or argon).
Sensitivity: Hygroscopic; hygroscopic DMSO significantly affects its solubility.
Appearance: Solid powder.
Specific gravity: Undetermined / No data available.
Color: Yellow to brown / Gray to brown.
MDL number: MFCD32263322
Hazard symbols: GHS07 (exclamation mark, irritant) / GHS06 (skull, acute toxicity)
Hazard phrases (H phrases): H302 (harmful if swallowed); H315 (causes skin irritation); H319 (causes serious eye irritation); H335 (may cause respiratory irritation)
Safety phrases (P phrases) P261 (Avoid inhalation of dust/fume/gas/smoke/vapor/spray); P280 (Wear protective gloves/eye protection/face protection); P302+P352 (If skin contact: rinse thoroughly with water); P305+P351+P338 (If in eyes: rinse carefully with water for several minutes); P304+P340 (If inhaled: move patient to fresh air)
HS Code: 2933990090 (Other nitrogen-containing heterocyclic compounds) / 29252900 (Other amides)
I. Properties
4,6-Dichloro-N-(methyl-d3)-3-pyridazine carboxamide is a deuterated labeled pyridazine heterocyclic compound. Its unlabeled parent compound is 4,6-dichloro-N-methylpyridazine-3-carboxamide (CAS: 1609394-78-6). This compound has a formamide group attached to the 3-position of the pyridazine ring, with a chlorine atom substituting at both the 4- and 6-positions. The methyl group on the amide nitrogen is fully deuterated (CD₃). It is a solid powder, ranging in color from yellow to brown or gray to brown. Due to the introduction of the deuterated methyl group, this compound exhibits unique isotopic labeling characteristics in nuclear magnetic resonance (NMR) and mass spectrometry (MS) analyses, with deuteration purity typically exceeding 98% atom % D.
This compound is stable at room temperature, but contact with strong oxidants, strong bases, and strong acids should be avoided to prevent decomposition or reaction. It is sensitive to humidity; hygroscopic DMSO significantly affects its solubility. It is recommended to use freshly opened DMSO to prepare solutions. This compound has extremely high solubility in DMSO (100 mg/mL), is soluble in polar organic solvents such as methanol and ethanol, but has low solubility in water. Its chemical properties are highly reactive; the chlorine atoms on the pyridazine ring (especially at positions 4 and 6) readily undergo nucleophilic substitution reactions, making them important active sites in drug synthesis.
II. Uses
4,6-Dichloro-N-(methyl-d3)-3-pyridazine carboxamide is an important pharmaceutical research intermediate and isotope labeling reagent. Its main uses include:
Deuterated drug synthesis: It serves as a key intermediate in the synthesis of deuterated drug molecules, particularly deuterated clindamycinib (BMS-986165) and its derivatives. Deuterated clindamycinib is an orally administered selective tyrosine kinase 2 (TYK2) allosteric inhibitor used to treat autoimmune diseases such as psoriasis and psoriatic arthritis. Introducing a deuterium atom can improve the drug’s metabolic stability, pharmacokinetic properties, and safety.
Drug Impurities and Reference Standards: Serves as Deucravacitinib Impurity 10 and BMS-986165 Related Compound 5 for drug quality control, impurity profiling, and stability studies.
Isotope Labeling Studies: Used as a tracer in drug metabolism kinetics (DMPK), drug metabolism studies, hydrogen-deuterium exchange experiments, and reaction mechanism studies to help track the metabolic pathways and distribution of drugs in vivo.
Analytical Chemistry Standards: Used as internal standards or reference standards in liquid chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR) analyses to improve the accuracy and sensitivity of quantitative analysis.
Building Blocks for New Drug Development: Serves as a building block for the synthesis of pyridazine heterocyclic compounds to construct novel bioactive drug molecules, particularly in the fields of antitumor, anti-inflammatory, and immunomodulatory applications.
III. Preparation Methods
The preparation methods for 4,6-dichloro-N-(methyl-d3)-3-pyridazine carboxamide mainly include the following, which summarize common synthetic routes from patent literature and chemical databases:
Method 1: Deuterated Methylamine Condensation Method (Common Method)
Raw Material Preparation: Using 4,6-dichloropyridazine-3-carboxylic acid or its derivatives (such as acyl chlorides or esters) as raw materials, a condensation reaction is carried out with deuterated methylamine (CD₃NH₂, usually used in its hydrochloride form, i.e., deuterated methylamine hydrochloride, CAS: 7436-22-8).
Condensation Reaction: In an organic solvent (such as THF, DMF, or dichloromethane) and in the presence of a base (such as triethylamine, DIPEA, LiHMDS, or KHMDS), 4,6-dichloropyridazine-3-carboxyl chloride or its active ester is reacted with deuterated methylamine hydrochloride to generate 4,6-dichloro-N-(methyl-d3)-3-pyridazine carboxamide.
Post-treatment and Purification: After the reaction, the reaction solution is treated by extraction, washing, drying, and concentration. The product is then purified using column chromatography (e.g., silica gel column, eluent: methanol/dichloromethane), recrystallization, or preparative HPLC to obtain the target compound in high purity.
Method Two: Deuterated Methylation Method
Amideation: First, 4,6-dichloropyridazine-3-carboxamide (non-deuterated) is synthesized.
Deuteration methylation: Under alkaline conditions, the amide nitrogen is methylated using a deuteration methylating agent (such as dimethyl deuterium sulfate (CD₃)₂SO₄) to introduce a deuterated methyl group.
Purification: The target product is obtained by column chromatography or recrystallization. This method may produce multi-substituted byproducts, and the reaction conditions need to be optimized to improve selectivity.
Method 3: Patented Synthetic Route (Refer to WO2020/086616, WO2023/165574, etc.)
According to patent literature, this compound can be prepared through the following steps:
Starting with methyl 4,6-dichloropyridazine-3-carboxylate or 4,6-dichloropyridazine-3-carboxyl chloride;
Reacting with deuterated methylamine hydrochloride in an inert solvent (e.g., THF) in the presence of a strong base (e.g., LiHMDS, 1M in THF) at room temperature or low temperature;
Quenching the reaction solution with saturated ammonium chloride solution, extracting with ethyl acetate, drying and concentrating the organic phase, and then purifying by rapid column chromatography or Flash chromatography to obtain the target product, with a yield typically between 70% and 90%.
IV. Safety Information
Hazard Overview
GHS Hazard Categories: Acute toxicity (oral, Category 4); Skin corrosion/irritation (Category 2); Serious eye damage/eye irritation (Category 2A); Specific target organ toxicity (single exposure, respiratory irritation, Category 3).
Warning Words: WARNING
Hazard Statement: H302 (Harmful if swallowed); H315 (Causes skin irritation); H319 (Causes serious eye irritation); H335 (May cause respiratory irritation).
Safe Handling and Protection
Personal Protective Equipment: Wear appropriate protective gloves (e.g., nitrile gloves), safety glasses or face shield, respirator (half-face or full-face), and protective clothing. Avoid direct contact with skin and eyes.
Ventilation Requirements: Operate in a well-ventilated environment. Avoid inhaling dust or vapors. Use local exhaust ventilation or fume hoods.
Avoid Contact: Avoid direct contact with skin and eyes; avoid inhaling dust; avoid contact with strong oxidizers, strong alkalis, and strong acids.
Storage Conditions: Store in a tightly closed container in a cool (-20°C to 2-8°C), dry, well-ventilated place; it is recommended to use an inert gas (e.g., nitrogen or argon) for protection; keep away from sources of ignition and heat; store separately from oxidizers and alkalis.
Emergency Measures:
* Skin Contact: Immediately wash with plenty of soap and water for at least 15 minutes. Remove contaminated clothing and seek medical attention.
* Eye Contact: Immediately flush with plenty of water for at least 15 minutes, turning eyelids inside out to ensure thorough rinsing. Seek medical attention.
* Inhalation: Quickly move to fresh air, keep the airway open, and provide artificial respiration or oxygen if necessary. Seek medical attention.
* Ingestion: Rinse mouth, drink plenty of warm water, induce vomiting (only for conscious individuals), and seek immediate medical attention.
* Disposal: Dispose of in accordance with local regulations. Avoid discharge into sewers or the environment. Waste should be collected separately and disposed of by a qualified disposal agency.
* Transport Information:
* UN Number: No specific UN number (usually transported as general chemicals or irritants).
* Packaging Category: Packed according to regulations for irritants or hazardous chemicals.
* Customs Supervision: Import and export must comply with relevant regulations for hazardous chemicals. An MSDS and compliant declaration must be provided. Customs codes are typically 2933990090 (other nitrogen-containing heterocyclic compounds) or 29252900 (other amides), subject to local customs classification.
V. Our Production Advantages and Capacity
5.1 Core Technology and Process Advantages
Mature Deuteration Synthesis Platform
Our company possesses independently developed technology for the directed synthesis and purification of deuterated methylamine (CD₃NH₂). The purity of deuterated methylamine hydrochloride raw materials is ≥99.5%, and the deuteration abundance (Atom % D) consistently reaches 98%–99.5% or higher, fundamentally guaranteeing the isotope labeling quality of the final product.
Highly Selective Amideation Process
Utilizing a low-temperature directed condensation and active ester/acyl chloride dual-system process, side reactions (such as hydrolysis and nucleophilic substitution) at the chlorine atoms at positions 4 and 6 of the pyridazine ring are effectively suppressed. The selectivity of the target product is ≥95%, significantly reducing the formation of isomer impurities and disubstituted byproducts.
Advanced Separation and Purification Technology
Equipped with a multi-stage purification platform including preparative HPLC, Flash rapid column chromatography, and low-temperature recrystallization, it can stably control single impurities ≤ 0.1% and total impurities ≤ 0.5%, meeting the quality requirements for innovative drug applications (IND/NDA) and reference standards.
5.2 Production Capacity and Supply Capacity
Regular production capacity: From kilograms (kg) to tens of kilograms, flexibly adjustable according to orders.
Single batch output: Multiple specifications available, including 0.5 kg / 1 kg / 5 kg.
Customization Capacity: Supports gradient scale-up from milligram (mg) samples to kilogram (kg) commercial batches.
Delivery Time: Samples: 1–2 weeks; Regular batches: 3–4 weeks; Bulk orders: Negotiable.
Packaging Specifications: 1 g / 5 g / 10 g / 100 g / 1 kg / 5 kg, custom packaging supported.
Storage and Transportation: Inert atmosphere (nitrogen/argon) sealed packaging, cold chain or ambient temperature transportation, worldwide delivery.
Post time: May-15-2026
