| HS Code | 525307 |
| Product Name | 4,6-Dihydroxypyrimidine |
| Cas Number | 1193-24-4 |
| Iupac Name | pyrimidine-4,6-diol |
| Common Synonyms | 4,6-Pyrimidinediol; Pyrimidine-4,6-diol; 4,6-Dihydroxypyrimidine |
| Molecular Formula | C4H4N2O2 |
| Molecular Weight | 112.09 g/mol |
| Exact Mass | 112.027277 Da |
| Appearance | White to off-white crystalline powder |
| Melting Point | >300 °C (decomposes) |
| Boiling Point | 339.2 ± 22.0 °C at 760 mmHg (predicted) |
| Flash Point | 159.0 ± 22.3 °C (predicted) |
| Density | 1.5 ± 0.1 g/cm³ (predicted) |
| Refractive Index | 1.640 (predicted) |
| Xlogp3 | -0.7 |
| Topological Polar Surface Area | 66.2 Ų |
| Water Solubility | Slightly soluble in water |
| Storage Conditions | Store at room temperature, protected from light and moisture |
| Stability | Stable under normal temperatures and pressures |
As an accredited 4,6-Dihydroxypyrimidine factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 4,6-Dihydroxypyrimidine is supplied in a securely sealed, moisture-protective amber glass bottle containing 25 g, with clear hazard and storage labeling. |
| Container Loading (20′ FCL) | 4,6-Dihydroxypyrimidine loaded into a 20′ FCL container, palletized in sealed drums, securely stowed with proper chemical labeling and shipping documents. |
| Shipping | 4,6-Dihydroxypyrimidine is typically shipped as a non-DG solid, not regulated under DOT/IATA/IMDG, in sealed moisture-resistant containers at ambient temperature. Protect from moisture, light, and oxidizers. Proper shipping name: 4,6-Dihydroxypyrimidine. Verify classification if impurities or mixtures alter hazardous properties. Use UN-approved packaging and local labels. |
| Storage | Store 4,6-Dihydroxypyrimidine in a cool, dry, well-ventilated area in a tightly closed container. Keep away from strong oxidizers, acids, bases, heat, sparks, and direct sunlight. Protect from moisture and contamination. Segregate from food, feed, and drinking water. Follow manufacturer instructions, safety data sheet, and local regulations. Use suitable personal protective equipment when handling. |
| Shelf Life | Shelf life: approximately two years when stored dry, tightly sealed, cool, and protected from light; avoid moisture, heat, and oxidizers. |
4,6-Dihydroxypyrimidine (CAS 1193-24-4, molecular formula C4H4N2O2, molecular weight 112.09 g/mol) is supplied as a white to off-white crystalline powder for heterocyclic intermediate synthesis. Commercial lots are normally controlled to HPLC purity ≥98.0%, loss on drying ≤0.5%, and water content ≤0.3% by Karl Fischer titration. The compound exists in keto-enol tautomeric equilibrium; this property affects reaction kinetics in O-alkylation and chlorination because the enol form provides the reactive oxygen centers. Downstream industrial consumption is not concentrated in direct formulation but in four distinct intermediate manufacturing routes: chlorination to 4,6-dichloropyrimidine, O-methylation to 4,6-dimethoxypyrimidine, mixed-acid nitration to 5-nitro-4,6-dihydroxypyrimidine, and iron-mediated reduction of the nitro intermediate to 5-amino-4,6-dihydroxypyrimidine. Each route imposes specific stoichiometric, thermal, and equipment constraints that separate commercial use from laboratory feasibility.
In pharmaceutical and agrochemical intermediate plants, the dominant consumption route is conversion to 4,6-dichloropyrimidine via phosphorus oxychloride chlorination. A typical charge ratio is 3.0–4.5 mol POCl3 per mole of 4,6-DHP, with dimethylformamide added as a nucleophilic catalyst at 0.05–0.10 mol per mole of substrate. The glass-lined reactor is heated to 75–110°C over 60–90 min; the exotherm is controlled by jacket temperature ≤120°C and the off-gas is routed through a caustic scrubber designed for hydrogen chloride partial pressures up to 0.2 MPa. The process is operated under nitrogen to exclude moisture. Residual water in the substrate must be ≤0.2% by Karl Fischer before charging, because hydrolysis of POCl3 reduces effective stoichiometry and generates hydrochloric acid that accelerates glass lining corrosion. After 3–8 h at 75–110°C, the reaction mass is quenched into ice-water at 0–10°C, neutralized to pH 7.0–8.0 with 20% w/w sodium hydroxide, and extracted with dichloromethane or toluene. Distillation at 50–70°C under 100–150 mbar yields 4,6-dichloropyrimidine with GC-FID purity ≥99.0% and residual monochloro impurity ≤0.5%. Published data for this specific configuration is limited to supplier technical bulletins, but batch-to-batch failure in commercial runs is most frequently traced to incomplete water removal before chlorination or to local overheating during the initial exotherm.
Compliance for this stream is governed by ISO 9001:2015 for quality management, with downstream API intermediates subject to ICH Q7. Residual solvent control follows USP <467>; elemental impurities are assessed against ICH Q3D. The terminal product type is not a finished drug but a halogenated pyrimidine building block that enters substitution reactions with amines, thiols, and phenoxides to form pyrimidine-containing active pharmaceutical ingredients and agrochemical actives in antiviral, antineoplastic, and fungicidal programs. Operational boundaries include incompatibility with water before quench and with primary amines at elevated temperatures; accidental contact with amines leads to premature substitution and lowers chlorinated yield by consuming the desired 4,6-dichloropyrimidine before isolation.
Conversion to 4,6-dimethoxypyrimidine is carried out by adding dimethyl sulfate to an aqueous alkaline slurry of 4,6-dihydroxypyrimidine. The charge ratio is 2.2–2.5 mol dimethyl sulfate per mole of substrate, and sodium hydroxide is maintained at 2.1–2.3 mol per mole to keep pH 9.0–11.0. The reactor temperature is held at 40–60°C for 4–8 h; the methylation is fed under closed-loop control because dimethyl sulfate is volatile and genotoxic. A caustic scrubber and activated carbon filter are placed on the vent line. The crude product is isolated by cooling to 5–10°C, filtered, and washed with chilled water at ≤5°C. Vacuum drying at 50–60°C under −0.08 MPa for 4–6 h yields 4,6-dimethoxypyrimidine with GC purity ≥99.0% and water content ≤0.2%. Batch-to-batch residual O-monomethyl impurity is typically controlled to ≤0.4% by extending the second methylation period; failure to maintain pH below 11.0 hydrolyzes dimethyl sulfate to monomethyl sulfate and reduces O-methylation selectivity.
Compliance for the methylated stream is anchored to REACH (EC) No 1907/2006 registration for the raw material, while downstream agrochemical actives are regulated under regional pesticide registration frameworks. Terminal products are sulfonylurea herbicides that contain the 4,6-dimethoxypyrimidin-2-yl carbamoyl side chain, including bensulfuron-methyl, pyrazosulfuron-ethyl, and chlorimuron-ethyl. In the sulfonylurea route, 4,6-dimethoxypyrimidine is further functionalized at the 2-position before coupling with a sulfonyl isocyanate or sulfonyl carbamate; the raw material itself is not directly coupled into the final herbicide. The process limitation is the sensitivity of dimethyl sulfate to hydrolysis above pH 11.0 and temperature above 60°C; excess alkalinity converts DMS to monomethyl sulfate and lowers O-methylation selectivity below the threshold required for pesticide intermediate-grade material.
Nitration is performed with 98% nitric acid in 96–98% sulfuric acid at 0–5°C. The nitric acid charge is 1.05–1.25 mol per mole of 4,6-DHP, and the sulfuric acid mass charge is 4.0–6.0 kg per kg of substrate. The substrate is dissolved in sulfuric acid first, then nitric acid is dosed over 2–4 h while the jacket is supplied with brine at −10°C to −5°C. The exothermic enthalpy is managed by limiting nitric acid addition rate to ≤0.5 kg/min per 1000 L reactor volume. After addition, the batch is held at 0–5°C for 1–2 h, warmed to 15–20°C, and drowned into ice-water. The precipitated 5-nitro-4,6-dihydroxypyrimidine is filtered, washed with cold water, and dried at 50°C under vacuum. HPLC at 254 nm shows residual 4,6-DHP ≤0.5%; dinitration byproduct is controlled by keeping HNO3 stoichiometry below 1.3 mol/mol and temperature below 10°C. Local hot spots above 15°C increase dinitration and ring degradation, a critical processing boundary that requires continuous-temperature monitoring and slow acid dosing.
Compliance for the nitration stream is governed by ISO 9001:2015 quality systems for fine chemical nitration; where the nitro intermediate is subsequently reduced and cyclized into 2,4,5,6-tetraaminopyrimidine sulfate used as an oxidative hair dye base, final cosmetic regulation falls under EC No 1223/2009. Terminal product types include 5-amino-4,6-dihydroxypyrimidine and 2,4,5,6-tetraaminopyrimidine sulfate; the latter is consumed in permanent oxidative hair color formulations where it functions as an oxidation base. Operational boundary: mixed-acid nitration must not be mixed with oxidizable solvents or residual organic matter; spent acid containing nitroaromatics is separated and treated according to site-specific effluent limits before discharge.
After the mixed-acid nitration stream is isolated and dried, the 5-nitro compound is reduced to 5-amino-4,6-dihydroxypyrimidine by iron-mediated reduction in dilute hydrochloric acid. The charge ratio is 3.0–5.0 mol iron powder per mole of nitro substrate, with 1.0–2.0 mol hydrogen chloride per mole of substrate; water volume is 8–12 L per kg of nitro compound. The mixture is heated to 70–90°C for 2–4 h, then neutralized with sodium carbonate to pH 6.5–7.5. The iron sludge is removed by filtration at 60–70°C through a plate filter press. The filtrate is cooled to 5–10°C, and 5-amino-4,6-dihydroxypyrimidine is isolated as the hydrochloride or free base. HPLC purity after recrystallization is ≥98.0%; residual iron is controlled to ≤20 ppm by ICP-OES. Published reactor-scale data for iron-mediated reduction of this exact nitro compound is limited to supplier process reports; the charge window provided is a conservative range derived from analogous 5-nitropyrimidine reductions and must be verified against the specific crystallinity of the nitro substrate.
Compliance for the reduction stream is anchored to ISO 9001:2015 for production consistency and to REACH (EC) No 1907/2006 for substance registration; local effluent limits apply to iron and nitroaromatic discharge. The terminal product type is a diazo component for azo dyes and a building block for fused pyrimidine active ingredients. Operational limitation: the iron sludge contains adsorbed nitroaromatic; it is filter-pressed and disposed as hazardous solid. Alternative catalytic hydrogenation with Raney nickel at 0.5–1.0 MPa and 50–70°C is used when iron sludge disposal is restricted or when residual iron limits below 20 ppm cannot be consistently achieved in the Bechamp process.
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4,6-Dihydroxypyrimidine is a nitrogen-containing heterocycle with hydroxyl groups at the 4- and 6-positions of the pyrimidine ring. The CAS registry number is 1193-24-4, the molecular formula is C4H4N2O2, and the molecular weight is 112.09 g mol⁻¹. It is supplied as a white to off-white crystalline powder, typically in packaging sizes of 25 g, 100 g, 500 g, 1 kg, and 25 kg. Because this material is a chemical intermediate rather than a finished instrument, there is no equipment-style model number; the product identifier is the CAS number together with the supplier’s lot number. The industrial significance of 4,6-dihydroxypyrimidine derives from its use as a symmetrical pyrimidine core in the synthesis of agrochemical and pharmaceutical intermediates. Both hydroxyl groups are equivalent with respect to chlorination, so downstream conversion to 4,6-dichloropyrimidine can proceed with fewer regioisomeric side products than an unsymmetrical dihydroxypyrimidine. The compound tautomerizes between diol and lactam forms, and this equilibrium is responsible for its acidic character and its solubility in dilute aqueous alkali. A representative high-purity release specification includes an HPLC assay of ≥98.0% area at 254 nm, moisture by Karl Fischer of ≤0.5% w/w, and residue on ignition of ≤0.1% w/w. The following technical sections address the structural comparison, analytical release matrix, chlorination process boundaries, and handling limitations relevant to this product.
The substitution pattern controls the final chlorinated pyrimidine. 4,6-Dihydroxypyrimidine yields 4,6-dichloropyrimidine, CAS 1193-21-4, when treated with phosphorus oxychloride; 2,4-dihydroxypyrimidine, commonly named uracil, yields 2,4-dichloropyrimidine under analogous conditions. The two hydroxyls in the 4,6-isomer are equivalent under the molecular symmetry of the ring. As a result, the first chlorination step produces one possible mono-chloro intermediate, and the final product is not contaminated by a regioisomeric dichloropyrimidine. For uracil, the C-2 and C-4 oxygen-bearing positions are not equivalent with respect to the two ring nitrogens; the different electronic distribution changes the reactivity of the ring and the impurities to be expected during chlorination. In a pilot reactor, the 4,6-isomer can be followed by reverse-phase HPLC as a two-component system: one mono-chloro intermediate and the 4,6-dichloro product. This symmetry reduces the number of standards and impurity markers required for in-process control. The 2,4-isomer does not share this symmetry and is selected only when the desired downstream structure corresponds to the uracil substitution pattern. The distinction also appears in purification: 4,6-dihydroxypyrimidine deprotonates under alkaline conditions and can be separated from neutral organic impurities by aqueous extraction. The practice is to keep the aqueous alkaline phase below 10 °C when the pH exceeds 10, because prolonged exposure to strong alkali can degrade the ring. Published stability data for all pH and temperature combinations are limited, so the extraction temperature and residence time must be verified by process-development studies.
A representative industrial release specification for chlorination-grade material is not a universal standard but a supplier-defined control matrix. The table below lists typical parameters and test standards that appear on certificates of analysis. The assay is normally determined by reverse-phase HPLC with UV detection at 254 nm and area normalization; an external standard is used for high-purity material. The moisture limit is operationally important because water consumes the chlorinating agent. The residue on ignition limit detects sodium chloride and inorganic filter aids left from neutralization; values above 0.1% w/w usually indicate insufficient washing. Residual solvents are controlled by headspace gas chromatography according to the methodology of USP <467>; the specific solvent limit depends on the manufacturing route and the user’s regulatory status. Elemental impurities for pharmaceutical intermediates are managed under the risk-based framework of ICH Q3D. The user should request the complete certificate of analysis because the specification alone does not identify all process-specific impurities.
| Parameter | Representative release limit | Test method / standard | Operational note |
|---|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection under standard light source | Discoloration may indicate thermal degradation or iron contamination. |
| HPLC assay | ≥98.0% area at 254 nm | USP <621> | External standard for high-purity grade; area normalization for routine release. |
| Moisture | ≤0.5% w/w | USP <921> Method Ia | Moisture above 0.5% w/w consumes POCl₃ during chlorination. |
| Residue on ignition | ≤0.1% w/w | USP <281> | Furnace at 600 °C. |
| Residual solvents | Total ≤5000 ppm | USP <467> | Validated for the process solvent system. |
| Elemental impurities | Per ICH Q3D option-based control | ICH Q3D | Risk assessment required for pharmaceutical intermediate use. |
Chromatographic method verification for 4,6-dihydroxypyrimidine release includes more than an area-percent HPLC result. A reverse-phase HPLC method with a C18 column of 150 mm × 4.6 mm and 5 µm particles is representative; the mobile phase contains aqueous buffer at pH 3.0 and methanol. If the pH is not controlled, enolate formation shifts retention and distorts peak shape. The symmetrical structure gives a simple but solvent-dependent 1H NMR spectrum; in DMSO-d6, the acidic protons and the heterocyclic methylene protons are typically broadened by tautomeric exchange. LC-MS with electrospray ionization in negative mode detects the deprotonated molecular ion [M−H]− at m/z 111.0. The FTIR spectrum of the solid shows broad hydrogen-bonded O–H and N–H absorption, but the exact band position shifts with particle size and salt form, so infrared analysis is used for identity confirmation rather than quantitative release. For moisture determination, USP <921> Method Ia is used; if the material is suspected to contain bound water, an oven method at 120 °C with coulometric detection can be compared with direct injection. The difference between these two moisture results can indicate water trapped in the crystal lattice. For a lot to be used in chlorination, the direct-injection moisture value is the more relevant control because it measures the water available to react with POCl₃ in the initial reactor charge.
The conversion of 4,6-dihydroxypyrimidine to 4,6-dichloropyrimidine is among the most demanding operations at kilo and pilot scale because the reaction is exothermic, generates hydrogen chloride, and is sensitive to residual moisture. In a 500 L to 2000 L glass-lined reactor, the solid is charged under nitrogen, and phosphorus oxychloride is added in a molar ratio of 3.0 mol to 5.0 mol per mole of substrate. The mixture is heated to 80 °C–110 °C; hydrogen chloride is routed through a reflux condenser to a caustic scrubber. The processing window narrows primarily at two points: the initial moisture control point and the final quench. If the substrate contains more than 0.5% w/w water, the POCl₃ is partially consumed before chlorination begins. The result is an apparent loss of stoichiometry, incomplete conversion, and the formation of viscous partial esters that can foul the reactor lower drain. In batch records from pilot-scale campaigns, a moisture excursion is typically visible as a slow increase in the mono-chloro intermediate with no corresponding increase in the dichloro product, even after extended heating. The corrective action is to pre-dry the material in a vacuum dryer at 60 °C for 2 h and to verify moisture by Karl Fischer before charging. The second narrowing point is the quench of excess POCl₃. The reactor mass is transferred slowly into chilled water or dilute aqueous alkali while the quench temperature is maintained below 40 °C. Above this threshold, localized ring degradation and colored tar formation are observed, although published thermal decomposition data for this specific quench mixture are limited. The use of glass-lined equipment is preferred because hot POCl₃-HCl mixtures can cause chloride stress corrosion cracking of stainless steel internals. If a metallic component is unavoidable, tantalum or PTFE-lined parts are specified. Agitation must suspend the organic solids without drawing a gas vortex; a retreat-blade impeller at 60 rpm to 90 rpm is representative for pilot vessels, but the exact speed is set by vessel geometry and baffle configuration. In-process control typically involves HPLC of a quenched aliquot; conversion above 95% to the mono-chloro and dichloro products is targeted before terminal quench. The quenched slurry is filtered through a Nutsche filter or a centrifuge; the filter cake is washed with water to remove phosphoric acid and chloride, then dried under vacuum at 40 °C–50 °C. The drying temperature is kept below the point at which the product softens or discolors.
5-Substituted pyrimidines prepared from 4,6-dihydroxypyrimidine appear in pharmaceutical and crop protection intermediate libraries. Electrophilic bromination with N-bromosuccinimide in DMF at 0 °C to 25 °C places bromine at the activated 5-position; the resulting bromo derivative is then used in transition-metal-catalyzed coupling or converted to the dichloro intermediate. The scaffold is also used as a bioisosteric replacement for barbituric acid when a less acidic pyrimidine core is needed. In medicinal chemistry, the lower acidity and symmetrical donor set alter solubility and binding compared with 2,4,6-trihydroxypyrimidine. In materials synthesis, the compound functions as a polyfunctional oxygen ligand that can bridge metal centers. The resulting coordination polymers are characterized by single-crystal X-ray diffraction, thermogravimetric analysis under nitrogen at 10 K min⁻¹, and N₂ adsorption at 77 K. Published surface-area data for pyrimidine-bridged frameworks are limited, so BET values must be interpreted only for the specific activation protocol used. The use of this ligand in a material is not defined by a single standard; phase purity is assessed by powder X-ray diffraction, and thermal stability is reported as the onset temperature of mass loss under the stated heating rate.
The 5-position of 4,6-dihydroxypyrimidine is electron-rich because the two oxygen-bearing carbons donate electron density into the ring. The equilibrium between the diol and dione forms shifts with solvent, pH, and temperature, and this shift changes the rate of electrophilic substitution. Under nitration conditions, the reactive tautomer is generated in situ; in concentrated sulfuric acid the substrate can remain partly undissolved, which creates a mass-transport-limited reaction. If the temperature is kept below 50 °C, unreacted solid may persist; if the temperature exceeds 70 °C, dinitro and oxidized impurities can increase. Pilot-scale equipment for this transformation usually includes a jacketed vessel with controlled mixed-acid dosing and a recirculation loop to maintain solids suspension. The quench into ice water must be externally cooled to hold the slurry below 25 °C because the heat of dilution is significant. The crude 5-nitro derivative is isolated by vacuum filtration; filtration can be slow when the crystal habit is needle-like. A Nutsche filter with a pore size of 0.5 mm to 1.0 mm is representative, but the exact filtration medium is selected after crystal-size distribution is measured. Drying is conducted at 50 °C under reduced pressure to avoid thermal decomposition. Published kinetic data for this specific nitration are limited; calorimetric screening and reaction calorimetry are required before scale-up. The same tautomeric mobility affects salt formation: the compound forms alkali and amine salts, but the exact stoichiometry depends on the solvent and the pKₐ of the base. This is why a pH-controlled extraction can be used for purification but also why the raw material should not be stored as an alkaline solution for prolonged periods.
Table 2 compares the product with the structural analogs most often encountered in route scouting.
| Compound | CAS / substitution | Key difference from 4,6-dihydroxypyrimidine | Downstream relevance |
|---|---|---|---|
| 2,4-Dihydroxypyrimidine (uracil) |
66-22-8, OH at 2,4 | Unsymmetrical donor set; different tautomer and pH behavior | Leads to 2,4-dichloropyrimidine; used in nucleoside chemistry. |
| 4,6-Dichloropyrimidine | 1193-21-4, Cl at 4,6 | Electrophilic chloride leaving groups; no enolic proton; moisture-sensitive | Direct SNAr substrate for amination, etherification, and thioetherification. |
| Barbituric acid | 67-52-7, OH at 2,4,6 | Additional C-2 hydroxyl increases acidity and shifts ring electronics | Forms more acidic barbiturate structures; different biological profile. |
Storage and charging boundaries are dictated by moisture, metal, and amine contact. The material is stored in tightly closed HDPE or PTFE-lined drums under dry nitrogen at 15 °C to 25 °C. It is not classified as acutely toxic under the EU CLP criteria in typical supplier safety data sheets; however, fine dust should be controlled with local exhaust ventilation to avoid respiratory irritation and combustible dust accumulation. The product is incompatible with strong oxidizing agents, acid chlorides, and acid anhydrides; contact with phosphorus oxychloride or thionyl chloride should occur only in the intended reactor. Combining the dry powder with concentrated alkali or amines outside a controlled process can release heat and degrade the ring; neutralization must be temperature-controlled. If moisture exceeds 0.5% w/w, vacuum drying at 60 °C for 2 h is commonly applied before chlorination; the dryer is nitrogen-purged before discharge to prevent condensation on cool surfaces. Retest dating after 12 months is appropriate for material stored in the original sealed container under dry conditions. Within the European Economic Area, the user should confirm that a REACH registration dossier is available for the specific tonnage band; safety data sheets are prepared under REACH Annex II and should include exposure scenario information for industrial use. No specific harmonized model code applies to this intermediate; procurement is instead controlled by the CAS registry number, the certificate of analysis, and the intended downstream process.
