| HS Code | 387331 |
| Product Name | 1,1-Cyclohexanediacetic Acid Monoamide |
| Cas Registry Number | 99189-60-3 |
| Molecular Formula | C10H17NO3 |
| Molecular Weight | 199.25 g/mol |
| Iupac Name | 2-[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid |
| Synonyms | 1,1-Cyclohexanediacetic acid monoamide; 2-[1-(carbamoylmethyl)cyclohexyl]acetic acid |
| Chemical Class | Carboxylic acid amide; cyclohexane derivative |
| Appearance | White to off-white crystalline powder |
| Melting Point | 139-143 °C |
| Boiling Point | 476.6 ± 28.0 °C at 760 mmHg (predicted) |
| Density | 1.135 ± 0.06 g/cm³ (predicted) |
| Refractive Index | 1.497 (predicted) |
| Flash Point | 242.1 ± 24.8 °C (predicted) |
| Pka | 4.53 ± 0.10 (predicted) |
| Logp | 0.73 (predicted) |
| Water Solubility | Slightly soluble |
| Smiles | NC(=O)CC1(CC(=O)O)CCCCC1 |
| Storage Conditions | Store in a cool, dry, well-ventilated area in a tightly closed container |
| Hazard Classification | Irritant; may cause eye, skin, and respiratory irritation |
As an accredited 1,1-Cyclohexanediacetic Acid Monoamide factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 1,1-Cyclohexanediacetic Acid Monoamide supplied in 25 kg net polyethylene-lined fiber drums, securely sealed and labeled for shipping. |
| Container Loading (20′ FCL) | Container Loading (20′ FCL): 1,1-Cyclohexanediacetic Acid Monoamide securely loaded in suitable sealed packaging, with compliant shipping documentation for export. |
| Shipping | 1,1-Cyclohexanediacetic Acid Monoamide is normally shipped as a nonhazardous solid in lined fiber drums or polyethylene bags. It requires no UN number or hazard class under standard transport regulations. Keep containers sealed, cool, dry, and protected from moisture, contamination, and incompatible oxidizers. Follow all applicable local shipping rules. |
| Storage | Store 1,1-Cyclohexanediacetic Acid Monoamide in a cool, dry, well-ventilated area away from direct sunlight, heat, moisture, and incompatible substances such as strong oxidizers. Keep containers tightly closed, labeled, and upright. Use secondary containment where appropriate. Avoid dust generation and protect from ignition sources. Maintain normal room temperature unless supplier specifies otherwise, and follow local regulations and SDS guidance. |
| Shelf Life | 1,1-Cyclohexanediacetic Acid Monoamide: typically shelf-stable for about two years when sealed, cool, dry, and protected from light and moisture. |
Fusion-bonded epoxy (FBE) coatings for steel reinforcement and oil-country tubular goods require reactive additives that reduce crosslink density without introducing free plasticizer fugitivity. 1,1-Cyclohexanediacetic acid monoamide carries one free carboxyl group and one primary amide group on a cyclohexane ring; the carboxyl reacts with bisphenol A glycidyl ether at bake temperatures of 120–180°C to form a β-hydroxy ester linkage, while the amide group remains available for hydrogen bonding within the epoxy/hydroxy network. Production-scale extrusion work on similar cycloaliphatic amide-acids has been performed on counter-rotating twin-screw extruders with L/D 40 barrel assemblies and barrel temperatures held between 70°C and 95°C. A screening window of 2–10 wt% on total organic binder is used for initial powder trials, but the final level must be matched to the epoxy equivalent weight and dicyandiamide hardener content; published data for this specific configuration is limited. The monoamide should not be pre-blended with free amine curatives before extrusion, because acid-base salt formation can raise extruder torque and initiate premature reaction at screw temperatures above 95°C. After melt mixing, the chilled extrudate is ground to a median particle size of 35–50 µm with a top cut below 100 µm, then electrostatically sprayed at 30–80 kV onto preheated steel. Panel cures are tested by differential scanning calorimetry per ISO 11357-2; if the glass transition temperature falls below 100°C, the formulation must be adjusted to avoid elevated cathodic disbondment risk under ISO 21809-1 or ASTM A775/A775M. The terminal product is a fusion-bonded epoxy coating for pipeline steel or reinforcing bar.
High-solids coil primer resins for galvanized steel are typically condensation polymers; replacement of part of the aromatic diacid with a cycloaliphatic amide-acid is evaluated to modify adhesion and reduce aromatic monomer residues. The monoamide cannot act as a dibasic acid because it contains only one carboxyl; it is therefore introduced as a chain-end regulator at 0.5–3.0 mol% of total acid charge during a two-stage polyesterification at 210–240°C. At this addition level, it caps growing polyester chains and leaves terminal amide groups that interact with hexamethoxymethyl melamine crosslinkers during coil primer stoving. The assembled primer is applied by reverse roll coating at 5–8 µm dry film thickness on hot-dip galvanized coil and baked to a peak metal temperature of 130–150°C. Accelerated weathering is evaluated under EN ISO 9227 neutral salt spray and EN ISO 6270-1 condensation. Incidental food-contact suitability is not automatic; migration testing under FDA 21 CFR 175.300 is required, and EU monomer residue and reaction by-product status must be verified under REACH before commercial use. The terminal product is a pre-primed architectural coil stock for roof and wall cladding.
| Performance attribute | Test method | Acceptance basis |
|---|---|---|
| Crosshatch adhesion after neutral salt spray | EN ISO 2409 | ≤1 rating after 500 h |
| T-bend crack resistance | EN 13523-7 | ≤1T after condensation exposure |
| Condensation resistance | EN ISO 6270-1 | No blisters after 500 h |
| Neutral salt spray scribe creep | EN ISO 9227 | Creep ≤2 mm after 500 h |
On mixed-metal pretreatment lines running galvanized and electrogalvanized steel, a zirconium/vanadium conversion bath can be stabilized by carboxylic-amide ligands that coordinate metal ions and delay precipitation. The monoamide is screened at 0.5–5.0 g/L in a bath containing 50–200 ppm Zr and 10–50 ppm Cu as an accelerant, with pH adjusted to 3.2–4.5 using dilute ammonia or acetic acid. Bath temperature is held at 25–40°C, and contact time is 20–120 s in spray or immersion equipment. The free carboxyl forms a coordination bond with zirconium oxide/hydroxide, while the amide group adsorbs on oxide surfaces through hydrogen bonding; this dual interaction increases the density of the conversion layer without introducing hexavalent chromium. Panels are rinsed with deionized water and dried at 60–90°C before powder coating. Neutral salt spray exposures are run under ASTM B117, and filiform corrosion is evaluated under ISO 4623. If bath pH drops below 2.8, the ligand becomes protonated and zirconium precipitation accelerates, causing sludge and uncontrolled coating mass; automatic pH dosing with ICP-OES bath analysis is therefore required at least once per shift. Published data for this specific configuration is limited, so bath performance must be re-established against substrate-specific oil and mill scale conditions. The terminal product is a chrome-free treated steel or aluminum sheet for architectural and appliance powder finishing.
In dimer acid–based polyamide hot-melt adhesives, melt viscosity and open time are governed by molecular weight distribution and terminal group balance. The monoamide is introduced late in the polycondensation reactor, typically after the reactor mass reaches 235–250°C, at 0.2–2.0 wt% of total initial reactants. Its single free carboxyl reacts with terminal amine groups, reducing amine number to below 2 mg KOH/g; the amide terminus remains in the polymer chain and modifies cold crystallization during film formation. The reaction continues under vacuum below 20 mbar until acid number stabilizes at 5–10 mg KOH/g, with process samples analyzed by attenuated total reflectance infrared spectroscopy. The molten product is cast as film or extruded through a slot die and laminated at 120–150°C between textile substrates or automotive interior panels. Melt flow rate is determined at 160°C/2.16 kg per ISO 1133-1:2022, and block resistance is evaluated by oven aging tests based on ASTM D2565 or customer-specific laminate shear methods. Loadings above 2.0 wt% risk excessive chain termination and softening of the adhesive; this particular monoamide has not been widely reported in published hot-melt literature, so pilot-reactor validation is required before production use. The terminal product is a low-melt polyamide film adhesive for automotive interior lamination and textile bonding.
Polyester diol syntheses for reactive moisture-cure polyurethane hot-melt adhesives require precise control of terminal hydroxyl functionality. In a two-stage polyesterification, the monoamide is introduced at 1–5 mol% of the total acid charge together with adipic acid, isophthalic acid, and neopentyl glycol. The reactor is heated to 180–220°C under a nitrogen sweep, then vacuum is applied to 10–30 mbar until acid number falls below 0.5 mg KOH/g. Because the monoamide has only one carboxyl, it terminates growing polyester chains with a cyclohexyl amide group; this increases steric hindrance and reduces crystallinity of the resulting polyol. The polyol is then reacted with 4,4'-diphenylmethane diisocyanate to an isocyanate content of 2–4% and applied at 110–130°C as a reactive hot-melt adhesive. Cure tensile properties are measured under DIN 53504, and viscosity stability is checked with a rotational viscometer at 120°C. The solvent-free process must remain below 240°C; amide-containing systems can undergo imidization or discoloration above that threshold. If raw material water content exceeds 500 ppm or storage relative humidity exceeds 60%, pre-drying is required to prevent premature hydrolysis of the amide group and unstable acid number. The terminal product includes edge-banding adhesives and wood-flooring bondlines.
In semisynthetic metalworking fluid concentrates, a water-soluble corrosion inhibitor must protect both ferrous and aluminum surfaces without excessive ash or foam. The monoamide is neutralized with triethanolamine to a pH of 8.8–9.3 and incorporated at 0.3–1.5 wt% of the concentrate. The resulting concentrate is diluted to 3–7 vol% in water for central machine sumps. The carboxylate forms a weak coordination film on cast iron, while the amide group adsorbs on aluminum oxide; this dual mechanism reduces galvanic attack in mixed-metal machining. Concentrate stability is evaluated after 7-day storage at 50°C and -5°C, and demulsibility is checked per ISO 6614. Steel corrosion protection is tested by ASTM D665A/B, and aluminum staining by DIN 51360-2. In high-chloride water above 150 ppm Cl⁻, the dosage must be increased or a phosphate ester added to avoid pitting. Published data for this specific configuration is limited; therefore laboratory corrosion panel data must be generated for each water quality and alloy combination. The terminal product is a hard-water-tolerant semisynthetic machining fluid for automotive and aerospace mixed-metal operations.
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1,1-Cyclohexanediacetic acid monoamide, IUPAC 2-[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid and CAS 99189-60-3, is a low-volatility crystalline solid with molecular formula C10H17NO3 and relative molecular mass 199.25 g/mol. The compound is a pharmaceutical intermediate rather than a finished formulation and is commonly listed in vendor documentation as CDMA, CDA monoamide, or cyclohexanediacetic acid monoamide. It comprises a cyclohexane ring carrying two acetic acid-derived substituents on the same carbon, one terminating as a primary amide and the other as a free carboxylic acid. This mixed functionality is the basis of its use in gabapentin synthesis: the primary amide is available for Hofmann rearrangement to an aminomethyl group, while the free carboxyl remains in place as the gabapentin acid function. The compound contains one less free carboxyl than 1,1-cyclohexanediacetic acid and one more acidic hydrogen than 1,1-cyclohexanediacetic acid diamide. No public pharmacopoeial monograph exists for the intermediate; specifications are established by quality agreement and supplier certificate of analysis.
Commercial product designations are typically purity-suffixed. A supplier may offer CDAMA-98 for general intermediate duty and CDAMA-99 for pharmaceutical intermediate duty, where the suffix denotes the minimum HPLC area percent assay. Packaging is commonly 25 kg or 50 kg high-density polyethylene drums with double low-density polyethylene liners. The material is shipped as an off-white crystalline powder. Because the molecule is achiral, enantiomeric purity is not a specification parameter; the critical quality attributes are residual diacid, diamide, lactam, and solvent levels, as well as water content, residue on ignition, and elemental impurities. Published data for this specific configuration is limited outside supplier documentation, and each lot is typically qualified against the application-specific impurity profile before use.
The monoamide's selective activation is governed by the pH-dependent solubility of the carboxyl group and the lower electrophilicity of the primary amide relative to a carboxylic acid or ester. In water, the protonated solid is only sparingly soluble; addition of 1.0 equivalent of aqueous sodium hydroxide or potassium hydroxide converts the free acid to the carboxylate salt and improves dissolution without hydrolyzing the amide under ambient conditions. This solubility switch is used to separate neutral impurities during workup: the alkaline aqueous layer is extracted with a water-immiscible solvent, then re-acidified to crystallize the monoamide. The primary amide does not provide a second acidic proton, so the compound behaves as a monobasic acid in titration. Under strongly acidic or alkaline conditions at elevated temperature, the amide can hydrolyze to the parent 1,1-cyclohexanediacetic acid, which is why the Hofmann rearrangement is run under controlled alkalinity and low temperature rather than indefinite exposure to hot sodium hydroxide.
The Hofmann rearrangement itself consumes the amide and requires an alkaline hypohalite or halogen in sodium hydroxide. The reaction proceeds through an N-haloamide and isocyanate intermediate to the amine. Because the free carboxyl is present on the same molecule, it can transiently stabilize the isocyanate through intramolecular interactions, but the primary side reaction remains cyclization to the five-membered lactam if the pH falls or if the isocyanate is not rapidly hydrolyzed. Production-scale control therefore maintains the reaction mass above pH 10 and below 15°C during the active halogenation phase. The free acid groups also buffer the reaction mixture and can shift local pH if addition of sodium hypochlorite is too rapid; dosing over 30 to 60 minutes is used in pilot-scale equipment to maintain homogeneity.
In full-scale gabapentin production through the monoamide route, 1,1-cyclohexanediacetic acid monoamide is charged into a jacketed reactor with aqueous sodium hydroxide and cooled to a target temperature before controlled addition of sodium hypochlorite solution. The primary amide undergoes Hofmann rearrangement to the isocyanate, which hydrolyzes to 1-(aminomethyl)cyclohexaneacetic acid. The free carboxyl of the intermediate is retained as the gabapentin carboxyl group. This route structurally avoids the symmetrical diamine that would be produced from 1,1-cyclohexanediacetic acid diamide. The reaction is strongly exothermic; the cooling system must be sized for the heat of hypohalite addition and the rearrangement exotherm. In glass-lined reactors, internal coils or jacket cooling with brine are used, and the addition nozzle is positioned below the liquid surface to reduce localized overheating. The reaction mixture is held under alkaline conditions after the addition is complete, then acidified with hydrochloric acid to precipitate the crude gabapentin. The crude solid is washed with purified water and recrystallized from a water-alcohol mixture. In-process high-performance liquid chromatography is sampled at the post-halogenation step and after crystallization. Residual monoamide and the lactam impurity are quantified using a C18 column with ultraviolet detection at 210 nm, typically with a phosphate-buffered mobile phase and acetonitrile gradient. The lactam impurity, 2-azaspiro[4.5]decan-3-one, is monitored because it forms by intramolecular cyclization of gabapentin or the isocyanate intermediate and is difficult to purge once present in the final recrystallization.
Compared with the parent 1,1-cyclohexanediacetic acid, the monoamide contains only one free carboxyl, so activation with thionyl chloride or oxalyl chloride is limited to a single acyl chloride site. This avoids the symmetrical bis-acid chloride that complicates selective coupling of the diacid. In comparison with 1,1-cyclohexanediacetic acid diamide, the monoamide retains an acid handle that allows salt formation and pH-dependent workup; the diamide is neutral and cannot be extracted into aqueous base. The monoester derivatives of the diacid are less desirable as Hofmann precursors because they require separate hydrolysis after rearrangement, whereas the monoamide route retains the target gabapentin acid function without an ester hydrolysis step. The dinitrile route to gabapentin passes through 1-(cyanomethyl)cyclohexaneacetic acid or an analogous nitrile acid, which is hydrogenated to the aminomethyl derivative; this route introduces a nitrile-bearing intermediate and requires high-pressure hydrogenation equipment, whereas the monoamide route requires only atmospheric-pressure reactors for the Hofmann step. The trade-off is that the monoamide generates spent hypochlorite or bromide waste and requires strict control of chlorinated by-products, while the nitrile route generates spent hydrogenation catalyst and demands control of residual cyanide. The selection between these routes on production scale depends on the available corrosion-resistant reactor train and the site’s waste treatment permits.
| Cyclohexane diacetic acid derivative | Functional groups | Selectivity consequence | Typical downstream route |
|---|---|---|---|
| 1,1-Cyclohexanediacetic acid | Two carboxylic acids | Symmetrical activation can produce bis-esters or bis-amides | Esterification, anhydride formation, partial ammonolysis |
| Monoamide | One carboxylic acid, one primary amide | Single-site Hofmann rearrangement; carboxyl retained | Hofmann rearrangement to gabapentin |
| Diamide | Two primary amides | Double Hofmann rearrangement yields diamine; no acid handle | Synthesis of symmetrical diamine building blocks |
| 1-(Cyanomethyl)cyclohexaneacetic acid | One carboxylic acid, one nitrile | Nitrile reduction to aminomethyl; requires hydrogenation | Catalytic reduction to gabapentin |
Because no harmonized monograph exists for the intermediate, release specifications are established by the supplier and the user through a quality agreement, with International Council for Harmonisation guidance documents applied to residual solvents and impurities. The analytical profile is dominated by reversed-phase high-performance liquid chromatography. The sample is dissolved in a polar mobile phase at a concentration of approximately 1.0 mg/mL, and injection volumes are commonly 20 µL on a 250 mm × 4.6 mm column packed with 5 µm C18 silica. Ultraviolet detection at 210 nm is used because the chromophore is weak and the analytes must be quantified by end absorption. The mobile phase is typically a mixture of phosphate buffer at pH 2.5 and acetonitrile; an initial condition of 80:20 buffer-acetonitrile with a linear gradient is typical for separating the monoamide from diacid, diamide, and lactam-related substances. The method is validated for specificity, linearity, repeatability, and limit of detection under ICH Q2(R1). Water content is determined by coulometric Karl Fischer titration; the sample is dissolved in a suitable anhydrous solvent because the amide can release water slowly. Residual solvents are analyzed by headspace gas chromatography using a 624 capillary column and flame ionization detection, with calibration against Class 2 solvent standards.
| Parameter | Test method | Typical acceptance criterion |
|---|---|---|
| Appearance | Visual inspection | White to off-white crystalline powder |
| Identification | Infrared spectroscopy | Matches reference spectrum |
| Assay | HPLC/UV 210 nm | ≥98.0% or ≥99.0% by grade |
| Water | Coulometric Karl Fischer | ≤0.50% |
| Residue on ignition | USP 281 | ≤0.10% |
| Elemental impurities | ICH Q3D risk assessment / ICP-MS | As, Cd, Hg, Pb controlled to ICH Q3D PDE |
| Individual related substance | HPLC area % | ≤0.50% |
| Total related substances | HPLC area % | ≤1.0% |
| Residual solvents | Headspace GC, ICH Q3C | Class 2 solvents below Option 1 limits |
Residual solvents are controlled according to ICH Q3C Option 1. Methanol, if used in recrystallization, is typically controlled below 3,000 ppm; dichloromethane, if used, is controlled below 600 ppm. These are Class 2 limits from ICH Q3C and must be converted to actual concentration limits based on the gabapentin maximum daily dose. No product-specific harmonized monograph applies to the monoamide, so each supplier certificate must be compared with the downstream process solvent profile and the finished API monograph.
The drying operation for the monoamide must reduce water and residual alcohol without inducing particle fusion or amide hydrolysis. Double-cone vacuum dryers are used below the melting point of the product. A jacket temperature of 45°C to 55°C and vacuum below 20 mmHg are common for wet cake from an aqueous alcohol recrystallization. Agitated dryers with lump breakers are preferred when the wet cake is cohesive. Residual water above 0.50% can cause bridging in feed hoppers and poor flow through rotary valves, especially if the material is subsequently milled. Milling is performed with a fitzmill or jet mill, and the milled material is screened through a 40-mesh sieve. If the powder is dried too aggressively, localized heat can cause partial melting and subsequent formation of hard lumps, which reduce the efficiency of downstream dissolution in the Hofmann reactor. The residual solvent profile is also influenced by the final washing solvent. Alcohol solvents require longer drying than acetone or ethyl acetate; however, alcohol washing often provides better rejection of the polar diacid impurity.
The most critical impurity in the Hofmann conversion of the monoamide is the cyclic lactam formed by intramolecular attack of the carboxylate on the isocyanate or by cyclization of gabapentin under acidic conditions. Lactam formation is suppressed by maintaining pH above 10 and by keeping the reaction mixture at low temperature during the active halogenation phase. In production, the pH is monitored with an inline electrode, and the sodium hypochlorite addition is interrupted automatically if the pH drops below the lower alarm limit. The addition of acid for precipitation is performed slowly because rapid acidification of the alkaline reaction mass can cause local pH excursions and lactam growth. After isolation, the crude gabapentin is washed with water and alcohol to remove residual inorganic salts. The mother liquors contain residual monoamide, diacid, lactam, and chlorinated by-products; these streams are treated by chemical oxidation or sent to licensed incineration because the chlorinated amide by-products are not released to biological effluent treatment without evaluation of persistent organic halogen content.
Handling controls for solid 1,1-cyclohexanediacetic acid monoamide are typical for a low-dusting organic acid amide. Local exhaust ventilation is used at bag charging and milling stations to keep airborne dust below occupational exposure limits. The powder is not highly volatile, but fine dust dispersed in air may form an explosible atmosphere; grounding, bonding, and inerting are applied during transfer and size reduction. The compound should be stored in tightly closed containers at controlled room temperature, protected from moisture and strong oxidizing agents. Contact with nitrite-based reagents under acidic conditions should be avoided because primary amides can form N-nitroso derivatives; this is relevant in cleaning validation when nitrite-bearing cleaning agents are used in shared equipment. The monoamide should not be blended with strong acids or bases without process control because hydrolysis to the diacid can occur at elevated temperature. The material is intended for industrial and pharmaceutical intermediate use only and is not formulated for direct human administration.
Regulatory status varies by jurisdiction. In the European Economic Area, placing the monoamide on the market as an isolated intermediate may require registration under REACH if manufactured or imported at or above 1 tonne per year. Downstream users should confirm that the supplier has registered the substance for the identified use or that an exemption applies. In the United States, the compound may be listed on the TSCA inventory for commercial chemical use, but inventory status must be verified with the supplier for the specific CAS number. Because the material is used as an intermediate in an active pharmaceutical ingredient synthesis, the finished gabapentin manufacturer is responsible for demonstrating that residual solvents and impurities are controlled to the levels accepted by the relevant pharmacopoeial monograph and good manufacturing practice requirements.
