| HS Code | 211843 |
| Product Name | Trimethyl Orthoformate |
| Iupac Name | Trimethoxymethane |
| Cas Number | 149-73-5 |
| Ec Number | 205-745-7 |
| Molecular Formula | C4H10O3 |
| Molar Mass | 106.12 g/mol |
| Appearance | Colorless liquid |
| Odor | Pungent, ether-like |
| Boiling Point | 101-102 °C |
| Melting Point | -53 °C |
| Density | 0.9676 g/cm3 at 25 °C |
| Refractive Index | n20/D 1.379 |
| Flash Point | 13 °C closed cup |
| Solubility | Miscible with ethanol, diethyl ether, and benzene; decomposes in water |
| Vapor Pressure | 20 mmHg at 20 °C |
| Vapor Density | 3.7 (air = 1) |
As an accredited Trimethyl Orthoformate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Trimethyl orthoformate packaged in 500 mL amber glass bottles with PTFE-lined caps, sealed and labeled moisture-sensitive, flammable. |
| Container Loading (20′ FCL) | Trimethyl Orthoformate loaded into a 20-foot FCL container, securely palletized or drummed, labeled, and compliant with hazmat transport regulations. |
| Shipping | Trimethyl orthoformate is shipped as a flammable liquid, UN 3272, Esters, n.o.s. (Trimethyl orthoformate), Class 3, Packing Group II. It requires approved, tightly closed containers and labeling. Keep away from heat, sparks, flames, and moisture. Follow IATA, IMDG, or ADR regulations, with proper shipping papers and emergency information. |
| Storage | Store trimethyl orthoformate in a cool, dry, well-ventilated flammable-liquid cabinet, away from heat, sparks, open flames, oxidizers, acids, and moisture. Keep containers tightly closed, preferably under nitrogen, and ground/bond during transfer. Protect from water because it hydrolyzes. Use approved safety containers, secondary containment, and adequate ventilation. Follow local regulations, avoid direct sunlight, and inspect containers regularly for leaks or damage. |
| Shelf Life | Trimethyl orthoformate: when properly stored dry, cool, and sealed, shelf life is typically about two years; moisture shortens it. |
In sulfonamide antibiotic intermediate manufacturing, trimethyl orthoformate is metered into a glass-lined batch reactor at 20–35°C to avoid rapid exotherm during preparation of N-formyl aniline derivatives. A typical charge ratio of 1.05–1.25 mol trimethyl orthoformate per mole of primary aromatic amine is used; the reaction mass is heated to 80–110°C over 45–90 min and held for 6–10 h with continuous methanol removal through a reflux splitter. Endpoint is defined by residual free amine below 0.5 area% by GC-FID using an internal standard calibrated under ISO 17025 laboratory procedures. The resulting N-formyl intermediates are isolated by vacuum distillation or crystallization; residual trimethyl orthoformate in the isolated intermediate is controlled below 0.1 wt% because downstream sulfonylation is sensitive to ortho ester carryover. In final active pharmaceutical ingredients, residual methanol is assessed under ICH Q3C(R8), where methanol is Class 2 with a permitted daily exposure of 30 mg/day and a concentration limit of 3000 ppm. Trimethyl orthoformate itself is not assigned an ICH class; therefore site-specific toxicological justification and cleaning validation data are required in the drug master file. The main operating boundary is the water concentration in the amine feed: water above 0.2 wt% increases trimethyl orthoformate demand through competing hydrolysis and generates methyl formate, which must be condensed at −10°C to −15°C before the vacuum pump discharge. Production-scale batches of 5000–8000 kg show jacket temperature offsets of 8–15 K during endothermic methanol distillation; a charge ratio below 1.03 mol eq leaves residual amine above 0.5% and requires rework, adding 3–5 h to the cycle.
Water generated during polyester polycondensation must be reduced below 0.05 wt% before melamine or isocyanate crosslinker addition to avoid premature viscosity rise and curing defects. Trimethyl orthoformate reacts with dissolved water at a stoichiometric ratio of 1 mol water per 1 mol orthoformate, producing 2 mol methanol and 1 mol methyl formate. In a 10 m³ stainless steel polycondensation reactor operated at 120–140°C, trimethyl orthoformate is added at 1.5–3.0 wt% of resin solids after the acid value reaches 8–15 mg KOH/g and before the final dehydration ramp. The addition is made below 60°C to prevent instantaneous hydrolysis at the hot reactor wall; the batch is then heated to 120°C under 40–80 mbar vacuum to strip methanol and methyl formate. The main process constraint is the vacuum pump train: methyl formate has a boiling point of 31.5°C, and failure to condense it at −10°C to −15°C vent condensers leads to VOC excursions above the 150 g/L limit measured by ASTM D2369. A water reduction from 0.25 wt% to 0.04 wt% requires approximately 2.3 wt% trimethyl orthoformate on resin solids; levels above 3.0 wt% do not improve drying efficiency and instead leave residual methyl formate in the final resin. The method is limited to acid-stable polyester formulations because the orthoformate is incompatible with strong sulfuric or p-toluenesulfonic acid catalyst residues at temperatures above 90°C, where exothermic hydrolysis generates methanol vapor at rates that can exceed condenser capacity.
Reaction of malononitrile with trimethyl orthoformate in a stirred glass-lined vessel yields 2-methoxymethylene malononitrile, a pyrimidine precursor used across sulfonylurea, triazolopyrimidine, and pyrimidinyl carbinol agrochemical actives. A typical charge ratio is 1.0 mol malononitrile to 1.1–1.4 mol trimethyl orthoformate with 0.5–1.0 mol% acetic anhydride or acetyl chloride as catalyst; the mixture is heated at 65–85°C for 3–6 h while methanol is distilled at atmospheric pressure. Conversion is monitored by HPLC area normalization; the specification for crude 2-methoxymethylene malononitrile is typically ≥97.0 area% with dimeric impurities below 1.0%. Batch cooling to 5–10°C precipitates the product; the mother liquor is recycled to the next batch after fractional distillation to recover unreacted trimethyl orthoformate. The downstream heterocyclization with substituted guanidines or amidines requires the methoxymethylene intermediate to contain less than 0.3 wt% water because water opens the methoxymethylene double bond and reduces ring-closure selectivity. The process operates under ISO 9001:2015 quality management and requires REACH Annex II safety data sheet documentation for the recovered methanol/methyl formate stream. Production-scale experience shows that a 2–3 K deviation above the setpoint during methanol distillation increases impurity formation by a factor of 1.5–2.0, so jacket control on the glass-lined vessel uses cascade logic with an internal coil to maintain ±1 K. Published data for specific agrochemical manufacturing configurations using this intermediate are limited; the methoxymethylene malononitrile route is documented in heterocyclic process literature but exact commercial ratios may vary by active ingredient.
In the pyrimidine moiety of thiamine, trimethyl orthoformate participates in a condensation sequence with malononitrile and an amidine source to construct the pyrimidine ring; the resulting cyano intermediate is reduced to the aminomethyl intermediate in a subsequent step. The condensation is run in a glass-lined reactor at 70–90°C with a malononitrile-to-trimethyl orthoformate molar ratio of 1:1.2 to 1:1.5 and an amidine source charged as the hydrochloride salt to buffer the reaction mass at pH 4.5–6.0. Methanol byproduct is removed continuously; the overhead distillate typically contains 80–90 wt% methanol and 10–15 wt% methyl formate, which is recovered in a downstream distillation column with a reflux ratio of 1.5–2.0. The resulting pyrimidine carbonitrile is isolated by crystallization from toluene or methanol at 0–5°C, washed, and dried at 40–50°C under vacuum. Residual methanol in the final vitamin B1 intermediate is controlled to ≤500 ppm because methanol inhibits the subsequent catalytic hydrogenation step over Raney nickel; the limit is verified by headspace GC using a method aligned with USP 467. A recurring production failure mode is the carryover of trimethyl orthoformate into the hydrogenation feed at levels above 0.05 wt%, which causes catalyst fouling and a pressure drop increase of 0.5–1.0 bar across the hydrogenation reactor within 2–3 batches. Process control therefore includes in-process GC sampling after crystallization and before hydrogenation, with release limits of ≤0.03 wt% trimethyl orthoformate. Batch size is typically 2000–4000 L; the main scale-up limitation is the methanol recovery column turndown at low boil-up rates, which requires a minimum reflux ratio of 1.2 to maintain separation.
Trimethyl orthoformate is metered into the pre-dispersed filler paste of a silane-terminated polyurethane sealant base after the base polymer has been dehydrated to a Karl Fischer water content of ≤0.02 wt%. The dosage ranges from 0.5–1.5 phr relative to polymer; each 1 g of water requires 5.89 g of trimethyl orthoformate on a stoichiometric basis. Mixing is performed in a planetary mixer at 20–40 rpm under −0.09 MPa vacuum for 15–30 min to disperse the low-viscosity scavenger without aerating the sealant. The hydrolysis reaction generates methanol and methyl formate, which are removed in an additional devolatilization step at 40–50°C and 50–80 mbar. Residual methanol above 0.1 wt% in the final sealant is undesirable because methanol can react with silane adhesion promoters and reduce peel adhesion after ASTM C794 testing; production batches are therefore sampled after vacuum mixing and analyzed by headspace GC. Trimethyl orthoformate is selected over triethyl orthoformate in this segment because its molecular weight of 106.12 g/mol gives higher stoichiometric water uptake per unit mass than triethyl orthoformate at 148.20 g/mol. The scavenger must not be added before the filler is fully wetted because free water in filler agglomerates can cause localized hydrolysis pockets and produce methanol vapor that destabilizes the vacuum pump seal. The process is incompatible with aminopropyltriethoxysilane adhesion promoters if the filler paste has not been dehydrated, because the silane can react with water faster than the orthoformate and form silanol oligomers that increase sealant viscosity beyond 1500 Pa·s at 25°C.
Citronellal, phenylacetaldehyde, and other fragrance aldehydes are converted to their dimethyl acetals to stabilize odor profiles and reduce Schiff base formation in consumer products. Trimethyl orthoformate is charged as the methoxy donor at 1.05–1.20 mol per mole of aldehyde in the presence of p-toluenesulfonic acid at 0.05–0.2 wt%. The reaction is maintained at 25–40°C in a jacketed glass-lined reactor because the exotherm from methanol release can raise the batch temperature by 10–15 K if the orthoformate is added faster than 2 kg/min per 1000 kg batch. Methanol and methyl formate are distilled under 200–350 mbar; endpoint is reached when free aldehyde by GC is below 1.0 area%. The acetal product is neutralized with sodium carbonate, washed with water at 20–25°C, and dried under vacuum at 35–40°C. Final fragrance-grade acetals must meet IFRA certificate parameters for acid value below 0.5 mg KOH/g and peroxide value below 5 meq O2/kg; residual methanol is reduced to ≤100 ppm because it contributes to headspace volatility and regulatory VOC limits under California CARB 2020. A process limitation in this sector is the sensitivity of certain aldehydes to acid-catalyzed aldol condensation; for these substrates, the acid catalyst is replaced with pyridinium p-toluenesulfonate at 0.5–1.0 mol% and the temperature is kept below 30°C. Published data for specific aldehyde scope is limited; production campaigns therefore require laboratory glass reactor trials to establish the maximum allowable orthoformate feed rate before scaling to 1000–3000 L vessels.
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Trimethyl orthoformate is handled in bulk chemical commerce as a low-boiling orthoester with CAS registry 149-73-5, molecular formula C4H10O3, and molar mass 106.12 g·mol⁻¹. The substance is a clear, colorless to pale-yellow liquid with a characteristic ethereal odor; flash point measured by ASTM D56-22 is typically 15 °C closed cup. Industrial production proceeds through the reaction of sodium methoxide with chloroform in methanolic solution, followed by distillation in continuous columns under nitrogen. The main commercial specifications include assay ≥ 99.0 area percent by calibrated GC-FID, moisture ≤ 500 mg/kg by ASTM E203, acidity ≤ 0.01 meq/g as formic acid by ASTM D1613-06, color ≤ 15 Pt-Co by ASTM D1209-05, density 0.965–0.970 g/mL at 20 °C by ASTM D4052-22, and distillation range 100.0–104.0 °C at 101.3 kPa by ASTM D1078-11. Low-moisture grades intended for moisture-sensitive synthesis are supplied with moisture ≤ 200 mg/kg and are packaged in smaller nitrogen-pressurized stainless steel containers. The product is hygroscopic and hydrolyzes to methyl formate and methanol; therefore bulk storage requires dry nitrogen blanketing, closed sampling, and exclusion of atmospheric moisture. Repeated partial-container sampling without dry nitrogen purge has been observed to increase moisture from below 100 mg/kg to above 300 mg/kg after fewer than 15 sampling cycles, measured by volumetric Karl Fischer titration. This moisture drift is accompanied by a shift in distillation initial boiling point and an increase in acidity, which can be detected by routine certificate-of-analysis testing.
In one-component moisture-cured urethane systems, trimethyl orthoformate is added at 0.5–2.0 parts per hundred resin to scavenge dissolved water before packaging. The hydrolysis stoichiometry consumes 1 mol water per 1 mol orthoester and releases 1 mol methyl formate and 2 mol methanol. This reaction is acid-catalyzed; in neutral media the orthoester can remain largely intact for hours at 25 °C, while in the presence of strong acid the reaction becomes nearly instantaneous. In formulated urethane systems, the limiting factor is often mass transfer at the liquid-vapor interface rather than intrinsic hydrolysis rate. Open-top addition tests at 80% relative humidity have shown moisture ingress in partially filled vessels exceeding 100 mg/kg·h in the headspace region, which makes closed-loop transfer and nitrogen blanketing more important than elevated shear. Mixing in 5,000 L vertical high-shear dispersers with jacket temperature held at 25–35 °C is adequate; the orthoester is charged after resin and solvent drying to a moisture endpoint below 500 mg/kg. Methanol and methyl formate reduce the flash point of the mixed formulation, so vapor-phase oxygen monitoring and explosion-relief sizing according to ASME BPVC Section VIII are required when vessels are not continuously inerted. Compared with p-toluenesulfonyl isocyanate as a moisture scavenger, trimethyl orthoformate introduces methanol and methyl formate rather than carbon dioxide; the choice is governed by volatile organic compound limits and by the permissible methanol residual in the cured film. Published kinetic data for specific urethane resin matrices is limited, and plant trials are required to establish the minimum hold time at the target moisture endpoint.
Pharmaceutical intermediate synthesis uses trimethyl orthoformate as an acid-catalyzed methyl esterification and water-removal reagent. A charge of 1.2–1.5 molar equivalents relative to total water and reactive carboxylic acid is typical for conversion of carboxylic acids to methyl esters in methanol. The reaction is carried out in glass-lined reactors of 2,000–6,000 L with PTFE-lined agitators, under nitrogen, at 60–65 °C for 4–8 h. Endpoint control relies on Karl Fischer moisture below 1,000 mg/kg and GC area percent of the free acid below 0.5 area percent. Methyl formate byproduct boils at 31.5 °C and is removed by fractional distillation or by venting through a chilled condenser; condenser coolant load, not agitator tip speed, is the main cycle-time constraint. Because methanol is a Class 2 residual solvent under ICH Q3C with a permitted daily exposure of 30 mg/day, downstream crystallization or distillation must demonstrate methanol below the applicable drug-substance limit. Batch-to-batch variability in starting-material water content is a larger source of yield drift than orthoformate assay variation, so incoming solvents are tested by ASTM E203 before charging. The orthoester should not be combined with anhydrous perchloric acid or concentrated aqueous acids in closed equipment because the hydrolysis exotherm and vapor evolution can exceed relief capacity. Published data for specific API configurations is limited; process development at pilot scale is required to define the exact excess and hold time for each substrate.
Release testing for trimethyl orthoformate is organized around distillation behavior, moisture, acidity, and organic impurities. Table 1 summarizes typical certificate-of-analysis parameters and methods. Because the liquid is hygroscopic, samples are collected in sealed vials under nitrogen and tested immediately; moisture and acidity are regarded as the most storage-sensitive properties. Distillation range measured by ASTM D1078-11 at 101.3 kPa is a rapid indicator of hydrolytic decomposition: a broadened interval greater than 4 °C or an initial boiling point below 99 °C typically indicates methanol and methyl formate accumulation. GC-FID assay on a 30 m polar capillary column with 0.25 mm inner diameter and 0.25 µm film resolves methanol, methyl formate, and trimethyl orthoformate; the reporting limit is 0.05 area percent. For high-purity material produced via the sodium methoxide–chloroform route, residual chloroform is monitored by purge-and-trap GC-MS and chloride by ion chromatography; typical release limits in pharmaceutical grade material are 50 mg/kg for chloroform and 10 mg/kg for chloride.
| Parameter | Method | Typical limit |
|---|---|---|
| Assay | Calibrated GC-FID | ≥ 99.0 area% |
| Moisture | ASTM E203 | ≤ 500 mg/kg |
| Color | ASTM D1209-05 | ≤ 15 Pt-Co |
| Distillation range | ASTM D1078-11 | 100.0–103.0 °C at 101.3 kPa |
| Density at 20 °C | ASTM D4052-22 | 0.965–0.970 g/mL |
| Nonvolatile residue | ASTM D1353-13 | ≤ 0.005 wt% |
In addition to release testing, user sites commonly repeat moisture and acidity testing after receipt because transport and sampling can introduce water. A qualified supplier change-control procedure compares lot-to-lot distillation range, moisture, acidity, and color against the release limits; if any parameter drifts beyond the limit, the material is re-dried with molecular sieve 3A or returned to distillation. Molecular sieve drying can reduce moisture below 100 mg/kg without affecting assay, but it must be performed in a closed column with nitrogen blanketing to prevent atmospheric moisture ingress. The need for such drying is highest when drums have been opened repeatedly or stored in non-climate-controlled warehouses in humid climates.
In agrochemical intermediate synthesis, trimethyl orthoformate is used as an electrophilic one-carbon synthon for the formylation of aryl Grignard reagents. The orthoester is added to the organomagnesium mixture at −20 °C to 0 °C under dry nitrogen, producing an aryl dimethyl acetal intermediate that is subsequently hydrolyzed to the corresponding benzaldehyde derivative at pH 6–8. This route avoids dimethylamine emissions associated with dimethylformamide formylation and can be operated in ether or mixed ether–toluene solvents. The production-scale constraint is moisture exclusion: reactor pre-drying is continued until the vent gas dew point is below −40 °C, and the solvent Karl Fischer reading is held below 100 mg/kg before the Grignard reaction. In pyrazole and triazole fungicide intermediate sequences, the dimethyl acetal can be carried through subsequent halogenation or alkylation before acid deprotection. The methoxy acetal is generally less sterically hindered than the ethoxy acetal from triethyl orthoformate, which can reduce deprotection time in acid hydrolysis. Methanol and methyl formate recovery from the quench stream requires fractional distillation; methyl formate is the lowest-boiling component and may carry methanol overhead. Published comparative data for specific agrochemical intermediates is limited, but development reports consistently identify byproduct recovery as the main difference in production economics.
Selection of trimethyl orthoformate instead of triethyl orthoformate changes the byproduct alcohol, boiling point, and solvent-recovery loop. Trimethyl orthoformate boils at 101 °C and can be removed from high-boiling reaction mixtures by atmospheric distillation, whereas triethyl orthoformate boils at 146 °C and often requires vacuum distillation or aqueous extraction. The methanol byproduct from trimethyl orthoformate is fully miscible with water and has a threshold limit value–time-weighted average of 200 ppm according to ACGIH documentation; ethanol from triethyl orthoformate has a different occupational exposure profile. Table 2 compares the two orthoformates on properties relevant to equipment design. In ketal and acetal formation, the methyl orthoester is generally more reactive toward acid-catalyzed exchange because the methoxy leaving group is less hindered, but the liberated methanol can transesterify acid-sensitive substrates or esters. The methyl orthoester also has a higher vapor pressure at ambient temperature, which increases evaporative losses from unsealed vessels and requires more aggressive condenser cooling. Production lines that already recover ethanol by azeotropic distillation may favor the ethyl orthoester, while lines designed for methanol–water separation may favor the methyl orthoester. The choice is therefore a process-engineering decision based on distillation capability, solvent-recovery infrastructure, and substrate sensitivity rather than on a single reactivity ranking.
| Property | Trimethyl orthoformate | Triethyl orthoformate |
|---|---|---|
| Normal boiling point | 101 °C | 146 °C |
| Byproduct alcohol | Methanol | Ethanol |
| Density at 20 °C | 0.9676 g/mL | 0.891 g/mL |
| Moisture sensitivity | Hydrolyzes rapidly in acid | Hydrolyzes more slowly |
| Typical assay | ≥ 99.0 area% | ≥ 99.0 area% |
| Byproduct alcohol recovery | Fractional distillation from water | Azeotropic distillation |
Trimethyl orthoformate is stored under dry nitrogen at 20–30 kPa gauge with pressure-vacuum relief set below 35 kPa. Transfer uses 316L stainless steel or PTFE-lined equipment; long-term contact with mild steel is avoided because iron oxides catalyze decomposition and increase color. When ambient relative humidity exceeds 60%, day tanks and sample ports are purged before opening. In formulation or synthesis operations, the material is added after the reactor contents have been dried by vacuum stripping or molecular-sieve treatment to below 500 mg/kg moisture. Contact with strong acids, strong bases, or oxidizing agents is avoided because rapid hydrolysis generates methanol and methyl formate, and the vapor pressure rise in closed equipment must be considered in relief sizing. The methanol released during hydrolysis is classified as acute toxic and organ-damaging under GHS; therefore exposure monitoring in process areas uses fixed infrared analyzers with alarm set points below the applicable occupational exposure limit. Residues in product formulations must be controlled through the appropriate pharmacopoeial or material-safety limits, and closed-loop recovery of methanol–methyl formate mixtures is preferred over atmospheric venting.
