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(1-Hydroxyethylidene)bisphosphonic acid is a non-nitrogenous, first-generation bisphosphonate with strong metal-chelating properties due to its two phosphonate groups and central hydroxyl structure.
(1-Hydroxyethylidene)bisphosphonic acid is widely used in industrial water treatment systems such as boilers and cooling towers as a scale inhibitor, corrosion inhibitor, and sequestrant.
Clinically, (1-Hydroxyethylidene)bisphosphonic acid was used to treat bone resorption disorders including osteoporosis, Paget’s disease, and hypercalcemia before being largely replaced by more potent nitrogen-containing bisphosphonates.
CAS Number: 2809-21-4
EC Number: 220-552-8
Molecular Formula: C2H8O7P2
Molecular Weight: 206.03 g/mol
Synonyms: Etidronic acid, 2809-21-4, 1-Hydroxyethylidene-1,1-diphosphonic acid, HEDP, EHDP, Etidronsaeure, Acetodiphosphonic acid, Hydroxyethanediphosphonic acid, Turpinal SL, Acido etidronico, Oxyethylidenediphosphonic acid, Acide etidronique, Dequest 2015, Dequest Z 010, Phosphonic acid, (1-hydroxyethylidene)bis-, Ferrofos 510, 1-Hydroxyethane-1,1-diphosphonic acid, Diphosphonate (base), Dequest 2010, 1-Hydroxyethanediphosphonic acid, (1-Hydroxyethylidene)diphosphonic acid, 1-Hydroxyethane-1,1-bisphosphonic acid, (Hydroxyethylidene)diphosphonic acid, Ethane-1-hydroxy-1,1-diphosphonic acid, (1-Hydroxyethylene)diphosphonic acid, Acidum etidronicum, 1-HYDROXY-1,1-DIPHOSPHONOETHANE, (1-Hydroxyethylidene)bis(phosphonic acid), (1-Hydroxyethylidene)bisphosphonic acid, Hydroxyethane-1,1-diphosphonic acid, 1000SL, RP 61, (1-hydroxy-1-phosphonoethyl)phosphonic acid, Phosphonic acid, (1-hydroxyethylidene)di-, M2F465ROXU, NSC-227995, CHEBI:4907, ethane-1-hydroxy-1,1-bisphosphonic acid, DTXSID6023028, M05BA01, Phosphonic acid, P,P'-(1-hydroxyethylidene)bis-, 1-hydroxyethane 1,1-diphosphonic acid, (1-hydroxy-ethylidene)diphosphonic acid, DTXCID103028, NSC227995, Xidiphon, Xydiphone, Dicalcium EHDP, EHDP, Dicalcium, Etidronate, Sodium, Etidronate, Disodium, HEDSPA, Etidronate, Dicalcium, Hydroxyethylidene Diphosphonic Acid, Etidron, Salt Etidronate, Tetrapotassium, Diphosphonic Acid, Hydroxyethylidene, 1-Hydroxyethylene Diphosphonate, Disodium, Diphosphonate, Disodium 1-Hydroxyethylene, (1-hydroxyethylene)diphosphonic acid, Tetrapotassium Salt, V10BX03, (1-Hydroxyethylidene)-1,1-diphosphonic acid, 220-552-8, RefChem:5819, etidronate, 1-Hydroxyethane-1,1-diphosphonate, (1-Hydroxyethane-1,1-diyl)diphosphonic acid, Ethane-1-hydroxy-1,1-diphosphonate, Acide etidronique [INN-French], Acido etidronico [INN-Spanish], Acidum etidronicum [INN-Latin], 1,1,1-Ethanetriol diphosphonate, 1-Hydroxyethylidene-1,1-bisphosphonate, (1-hydroxyethane-1,1-diyl)bis(phosphonic acid), MFCD00070585, (1-Hydroxyethylidene)diphoshonic acid, C2H8O7P2, (1-hydroxy-1-phosphono-ethyl)phosphonic acid, Etidronic acid-d3, CHEMBL871, 2809-21-4 (freeacid), Etidronic acid-d3 Sodium Salt, (1-hydroxyethan-1,1-diyl)bis(phosphonic acid), Etidronic acid [USAN:INN:BAN], SMR000038750, 1-Hydroxyethylidene-1,1-biphosphonate, 358730-93-5, HSDB 5898, 1-Hydroxyethylidenediphosphonic acid, NCGC00159352-02, EINECS 220-552-8, Phosphonic acid, 1-hydroxy-1,1-ethanediyl ester, UNII-M2F465ROXU, NSC 227995, BRN 1789291, Etidronicacid, Etidronic acid (USAN/INN), etidronic-acid, Ethane-1-hydroxy-1,1-bisphosphonate, Etidronic acid;HEDP, HDEPA, OEDFK, OEDP, Etidronate (Didronel), 1-HydroxyEthylidene-1,1-DiphosphonicAcid, Prestwick0_000863, Prestwick1_000863, Prestwick2_000863, Prestwick3_000863, ETIDRONATE [VANDF], EC 220-552-8, (1-Hydroxy-1,1-ethanediyl)bis(phosphonic acid), Etidronic acid [MI], SCHEMBL18607, BSPBio_000905, Etidronic acid [INN], 0-02-00-00171 (Beilstein Handbook Reference), MLS002207267, MLS002695948, Etidronic acid [HSDB], Etidronic acid [USAN], SPBio_002826, BPBio1_000997, GTPL7184, orb1310737, Etidronic acid [MART.], Etidronic acid [WHO-DD], Etidronic acid monohydrate (HEDP), HMS3604E03, HY-B0302, Tox21_200417, BBL028139, BDBM50115102, DL-390, s1857, STK721995, AKOS005524039, CCG-266618, DB01077, FH15419, hydroxyethylidene-1,1-diphosphonic acid, s12329, NCGC00159352-04, NCGC00159352-05, NCGC00159352-06, NCGC00159352-14, NCGC00257971-01, CAS-2809-21-4, 1,1-Ethylidenediphosphonic acid, 1-hydroxy-, H0587, NS00006820, (1-Hydroxy-1-phosphono-ethyl)-phosphonic acid, A23202, C07736, D02373, Q2758338, BRD-K37949327-001-06-3, BRD-K37949327-001-07-1, BRD-K37949327-304-06-1, (1-Hydroxyethane-1,1-diyl)diphosphonic acid monohydrate, Z1269201561, (1-Hydroxyethylidene)bisphosphonic acid 60% aqueous solution, 1-Hydroxyethane-1,1-diphosphonic acid (ca. 60% in Water, ca. 4.2mol/L), 1-Hydroxyethylidene-1,1-diphosphonic acid - 60% aqueous solution,~4.2mol/L
(1-Hydroxyethylidene)bisphosphonic acid is a synthetic organophosphorus compound belonging to the bisphosphonate family.
(1-Hydroxyethylidene)bisphosphonic acid appears as a colorless to pale yellow crystalline solid, highly soluble in water, and is valued for its strong chelating and scale-inhibiting properties.
The molecule contains two phosphonate groups linked to a central carbon with a hydroxyl substituent, which provides exceptional affinity for multivalent metal ions such as calcium, iron, and magnesium.
Because of this, (1-Hydroxyethylidene)bisphosphonic acid is widely used in industrial water treatment to prevent scale formation and corrosion in cooling systems, boilers, and pipelines.
In household and personal care products, (1-Hydroxyethylidene)bisphosphonic acid is employed as a stabilizer for peroxides and as a sequestrant in detergents and cosmetics.
Medically, (1-Hydroxyethylidene)bisphosphonic acid is among the earliest bisphosphonates used in the treatment of bone resorption disorders such as osteoporosis, Paget’s disease, and hypercalcemia, where it functions by inhibiting osteoclast-mediated bone degradation.
(1-Hydroxyethylidene)bisphosphonic acid's versatility across industrial, pharmaceutical, and cosmetic fields makes it an important multifunctional compound, though handling requires caution due to its potential irritant effects and the need for controlled dosing in therapeutic applications.
(1-Hydroxyethylidene)bisphosphonic acid is a bisphosphonate drug.
(1-Hydroxyethylidene)bisphosphonic acid is non-nitrogenous bisphosphonate.
(1-Hydroxyethylidene)bisphosphonic acid was patented in 1966 and approved for medical use in 1977.
For medicinal purposes, (1-Hydroxyethylidene)bisphosphonic acid has been obsolete since the early 2010's.
(1-Hydroxyethylidene)bisphosphonic acid is a new type of chlorine-free electroplating complexing agent.
(1-Hydroxyethylidene)bisphosphonic acid is used as the main agent for stable water quality in the circulating cooling water system, and plays the role of corrosion and scale inhibition.
(1-Hydroxyethylidene)bisphosphonic acid is one of the organic polyphosphonic acid-free water tablet conditioners.
There are also some other varieties of such products produced in China, such as aminotrimethylenephosphonic acid (ATMP): [CH2PO(OH)2]3N and ethyl acetate Diaminetetramethylenephosphoric acid (EDTMP) and so on.
Organic polyphosphonic acid is a type of water treatment agent developed in the late 1960s and confirmed around the 1970s.
(1-Hydroxyethylidene)bisphosphonic acid is a 1,1-bis(phosphonic acid) that is (ethane-1,1-diyl)bis(phosphonic acid) having a hydroxy substituent at the 1-position.
(1-Hydroxyethylidene)bisphosphonic acid inhibits the formation, growth, and dissolution of hydroxyapatite crystals by chemisorption to calcium phosphate surfaces.
(1-Hydroxyethylidene)bisphosphonic acid has a role as a bone density conservation agent, a chelator and an antineoplastic agent.
(1-Hydroxyethylidene)bisphosphonic acid is a conjugate acid of an (1-Hydroxyethylidene)bisphosphonic acid(2-).
(1-Hydroxyethylidene)bisphosphonic acid is a first generation bisphosphonate similar to [clodronic acid] and [tiludronic acid].
These drugs were developed to mimic the action of pyrophosphate, a regulator of calcification and decalcification.
(1-Hydroxyethylidene)bisphosphonic acid’s use has decreased over the years in favor of the third generation, nitrogen containing bisphosphonate [zoledronic acid], [ibandronic acid], [minodronic acid], and [risedronic acid].
(1-Hydroxyethylidene)bisphosphonic acid was granted FDA approval on 1 September 1977.
(1-Hydroxyethylidene)bisphosphonic acid acts as a chelating- and sequestering agent for cosmetics.
(1-Hydroxyethylidene)bisphosphonic acid is easy to handle and exhibits good stability.
(1-Hydroxyethylidene)bisphosphonic acid builds complexes with particular transition metals (Fe, Cu, Mn, Zn) and water hardness ions (Ca, Mg) in order to neutralize them.
(1-Hydroxyethylidene)bisphosphonic acid allows the management of slightly hard water, which could interfere with the surfactants of the product.
(1-Hydroxyethylidene)bisphosphonic acid is recommended for formulating toiletries (soaps), makeup, skin-, hair-, sun and baby care products.
(1-Hydroxyethylidene)bisphosphonic acid has a shelf life of 12 months.
(1-Hydroxyethylidene)bisphosphonic acid is a synthetic organophosphorus compound belonging to the class of bisphosphonates, compounds structurally characterized by two phosphonate groups attached to the same carbon atom.
(1-Hydroxyethylidene)bisphosphonic acid appears as a colorless to pale yellow crystalline solid or a viscous liquid in concentrated solutions, with excellent solubility in water and a high affinity for divalent and trivalent metal ions.
The presence of both phosphonate moieties and a hydroxyl group linked to the central carbon gives (1-Hydroxyethylidene)bisphosphonic acid remarkable chelating ability, allowing it to form stable complexes with metals such as calcium, iron, magnesium, and copper.
Because of this property, (1-Hydroxyethylidene)bisphosphonic acid is widely employed in industrial water treatment systems—such as boilers, cooling towers, and desalination plants—where it functions as a scale inhibitor, corrosion inhibitor, and stabilizer of oxidizing agents like chlorine or peroxides.
In the field of detergents, cleaning agents, and cosmetics, (1-Hydroxyethylidene)bisphosphonic acid is incorporated as a sequestrant to reduce water hardness, improve cleaning efficiency, and stabilize formulations against metal-catalyzed decomposition.
Beyond industrial uses, (1-Hydroxyethylidene)bisphosphonic acid holds a significant place in medicine as one of the earliest bisphosphonates developed for clinical applications.
(1-Hydroxyethylidene)bisphosphonic acid acts primarily by binding to hydroxyapatite in bone and inhibiting osteoclast-mediated bone resorption, thereby slowing down bone degradation.
For this reason, (1-Hydroxyethylidene)bisphosphonic acid has been used in the treatment of metabolic bone disorders such as osteoporosis, Paget’s disease of bone, hypercalcemia of malignancy, and conditions associated with abnormal calcification.
Compared to newer bisphosphonates, (1-Hydroxyethylidene)bisphosphonic acid is less potent, but it played an important pioneering role in the development of therapies for bone resorption diseases.
(1-Hydroxyethylidene)bisphosphonic acid's pharmacological effects are dose-dependent, and while therapeutic doses help maintain bone mineral density, excessive or uncontrolled use may lead to defective mineralization and osteomalacia.
From a chemical standpoint, (1-Hydroxyethylidene)bisphosphonic acid is highly stable under neutral and alkaline conditions but can decompose slowly in strongly acidic environments.
(1-Hydroxyethylidene)bisphosphonic acid's ability to resist hydrolysis makes it suitable for long-term use in harsh industrial conditions.
Environmentally, (1-Hydroxyethylidene)bisphosphonic acid is regarded as relatively persistent because of its strong binding to metals and mineral surfaces, which can limit biodegradation, though its toxicity is generally considered low compared to other organophosphorus compounds.
Nevertheless, safety precautions are essential in handling concentrated solutions, as the substance can cause irritation to the skin, eyes, and mucous membranes.
Overall, (1-Hydroxyethylidene)bisphosphonic acid is a versatile compound bridging industrial chemistry, household and cosmetic product formulation, and medical therapeutics.
(1-Hydroxyethylidene)bisphosphonic acid's dual role as both a functional additive in material systems and a pharmacological agent for human health underscores its importance across multiple fields of modern science and technology.
Market Overview of (1-Hydroxyethylidene)bisphosphonic Acid:
The global market for (1-Hydroxyethylidene)bisphosphonic acid is experiencing steady growth, driven by its widespread applications across industrial, pharmaceutical, and personal care sectors.
Valued at approximately USD 350–450 million in 2023–2024, the market is projected to reach USD 500–650 million by 2032–2033, with a compound annual growth rate (CAGR) of 4–5%.
The primary growth drivers include rising demand for water treatment chemicals to prevent scale and corrosion, increasing use of (1-Hydroxyethylidene)bisphosphonic acid in detergents, cleaning products, and cosmetics as a sequestrant and stabilizer, and its role in the pharmaceutical industry as one of the earliest bisphosphonates used in the treatment of bone disorders.
Regionally, Asia-Pacific is expected to dominate due to rapid industrialization and infrastructure development, while North America and Europe maintain strong positions supported by stringent environmental regulations and advanced pharmaceutical industries.
However, challenges such as high production costs, availability of alternative chemicals, and environmental concerns may restrict market expansion.
Overall, the versatility of (1-Hydroxyethylidene)bisphosphonic acid across multiple industries ensures its continued relevance, with the most dynamic growth anticipated in the pharmaceutical and cosmetics segments.
Uses of (1-Hydroxyethylidene)bisphosphonic Acid:
(1-Hydroxyethylidene)bisphosphonic acid is a versatile compound with broad applications across industrial, medical, and consumer sectors.
In industrial water treatment, (1-Hydroxyethylidene)bisphosphonic acid is widely employed as a scale and corrosion inhibitor in boilers, cooling towers, pipelines, and desalination systems, where its strong chelating ability prevents the deposition of calcium, magnesium, and other mineral salts.
In the detergent and cleaning industry, (1-Hydroxyethylidene)bisphosphonic acid functions as a sequestrant and stabilizer, improving washing efficiency in hard water conditions and protecting formulations against metal-catalyzed degradation.
In cosmetics and personal care products, (1-Hydroxyethylidene)bisphosphonic acid is added to shampoos, soaps, and skincare formulations to stabilize active ingredients and extend shelf life.
Medically, (1-Hydroxyethylidene)bisphosphonic acid is one of the earliest bisphosphonates used in the treatment of bone-related disorders such as osteoporosis, Paget’s disease, and hypercalcemia, where it slows osteoclast-mediated bone resorption.
Additionally, (1-Hydroxyethylidene)bisphosphonic acid is used in the textile, dyeing, and paper industries as a chelating and stabilizing agent, as well as in construction materials like concrete admixtures to improve durability and reduce scaling.
This wide range of uses highlights the compound’s dual role as both a functional industrial chemical and a therapeutic agent in human health.
(1-Hydroxyethylidene)bisphosphonic acid is used as scale and corrosion inhibition in circulating cool water system, oil field and low-pressure boilers in fields such as electric power, chemical industry, metallurgy, fertilizer, etc.
In light woven industry, (1-Hydroxyethylidene)bisphosphonic acid is used as detergent for metal and nonmetal.
In dyeing industry, (1-Hydroxyethylidene)bisphosphonic acid is used as peroxide stabilizer and dye-fixing agent.
In non-cyanide electroplating, (1-Hydroxyethylidene)bisphosphonic acid is used as chelating agent.
The dosage of 1-10mg/L is preferred as scale inhibitor, 10-50mg/L as corrosion inhibitor, and 1000-2000mg/L as detergent.
Usually, (1-Hydroxyethylidene)bisphosphonic acid is used together with polycarboxylic acid.
Medical:
(1-Hydroxyethylidene)bisphosphonic acid is a bisphosphonate once used to strengthen bone, treat osteoporosis, and treat Paget's disease of bone.
Bisphosphonates primarily reduce osteoclastic activity, which prevents bone resorption, and thus moves the bone resorption/formation equilibrium toward the formation side and hence makes bone denser in the long run.
(1-Hydroxyethylidene)bisphosphonic acid, unlike other bisphosphonates, also prevents bone calcification.
For this reason, other bisphosphonates, such as alendronate, are preferred when fighting osteoporosis.
To prevent bone resorption without affecting too much bone calcification, (1-Hydroxyethylidene)bisphosphonic acid is administered only for a short time once in a while, for example for two weeks every 3 months.
When given on a continuous basis, say every day, (1-Hydroxyethylidene)bisphosphonic acid will altogether prevent bone calcification.
This effect may be useful and (1-Hydroxyethylidene)bisphosphonic acid was in fact used this way to fight heterotopic ossification.
But in the long run, if used on a continuous basis, (1-Hydroxyethylidene)bisphosphonic acid will cause osteomalacia.
Chemical:
(1-Hydroxyethylidene)bisphosphonic acid is a versatile phosphonate compound known for its corrosion inhibition, chelating, and stabilizing properties, making it valuable across a range of industrial and consumer applications.
In industrial contexts, (1-Hydroxyethylidene)bisphosphonic acid acts as a retardant of cement hydration in concrete, extending the dormant period before hardening begins.
(1-Hydroxyethylidene)bisphosphonic acid is also used as a scale and corrosion inhibitor in circulating cooling water systems, oil fields, and low-pressure boilers, serving industries such as electric power, chemical manufacturing, metallurgy, and fertilizer production.
Beyond these applications, (1-Hydroxyethylidene)bisphosphonic acid is utilized in the dyeing industry as a peroxide stabilizer and dye-fixing agent, and in non-cyanide electroplating where it functions as a chelating agent.
In the light woven industry, (1-Hydroxyethylidene)bisphosphonic acid serves as a detergent for cleaning metal and non-metal surfaces and is often combined with polycarboxylic acids (superplasticizers) as a reducing agent.
Typical dosages range from 1–10 mg/L for scale inhibition, 10–50 mg/L for corrosion inhibition, and 1000–2000 mg/L for detergent use.
As a chelating agent, (1-Hydroxyethylidene)bisphosphonic acid binds to calcium, iron, and other metal ions, helping to reduce their potential environmental impact, particularly through greywater discharge into groundwater.
(1-Hydroxyethylidene)bisphosphonic acid's phosphonate structure also imparts corrosion resistance to unalloyed steel, and it retards rancidification and oxidation of fatty acids.
In detergents and cleaning agents, (1-Hydroxyethylidene)bisphosphonic acid and its salts help mitigate the adverse effects of hard water and stabilize peroxides during bleaching by inhibiting degradation caused by transition metals.
Within the cosmetics industry, (1-Hydroxyethylidene)bisphosphonic acid is used as a radical formation suppressant, emulsion stabilizer, and viscosity control agent.
Although approved for use in cosmetic products, (1-Hydroxyethylidene)bisphosphonic acid is recommended that products containing (1-Hydroxyethylidene)bisphosphonic acid, particularly soaps, be thoroughly rinsed from the skin after use.
(1-Hydroxyethylidene)bisphosphonic acid also finds application in swimming pool maintenance, where it functions as a stain inhibitor by preventing metal ions from precipitating and staining pool surfaces.
Industry Uses:
Not Known or Reasonably Ascertainable
Corrosion inhibitors and anti-scaling agents
Dispersing agent
Chelating agent
Anti-scaling agent
Intermediates
Dyes
Cleaning agent
Lubricating agent
Paint additives and coating additives not described by other categories
Processing aids not otherwise specified
Corrosion inhibitor
Consumer Uses:
Lubricating agent
Paint additives and coating additives not described by other categories
Not Known or Reasonably Ascertainable
Corrosion inhibitors and anti-scaling agents
Anti-scaling agent
Anti-stain agent
Benefits of (1-Hydroxyethylidene)bisphosphonic Acid:
(1-Hydroxyethylidene)bisphosphonic acid offers a wide range of benefits thanks to its unique chemical structure and strong chelating properties.
In industrial applications, (1-Hydroxyethylidene)bisphosphonic acid provides long-lasting protection against scale formation and corrosion, which not only extends the service life of boilers, cooling towers, pipelines, and desalination equipment but also reduces maintenance costs and improves operational efficiency.
(1-Hydroxyethylidene)bisphosphonic acid's stability in high-temperature and alkaline environments makes it highly effective where other inhibitors may degrade.
In the detergent and cleaning industry, (1-Hydroxyethylidene)bisphosphonic acid enhances product performance by preventing mineral buildup, stabilizing peroxide-based formulations, and ensuring consistent cleaning results even in hard water conditions.
In cosmetics and personal care products, (1-Hydroxyethylidene)bisphosphonic acid protects formulations from metal-catalyzed oxidation, helping to preserve color, texture, and shelf life.
From a medical perspective, (1-Hydroxyethylidene)bisphosphonic acid was the first bisphosphonate introduced for clinical use, offering significant benefits in managing osteoporosis, Paget’s disease, and hypercalcemia by slowing bone resorption and maintaining bone density.
Environmentally, while (1-Hydroxyethylidene)bisphosphonic acid is persistent, its relatively low toxicity compared to many other organophosphorus compounds makes it safer for controlled applications.
Overall, the benefits of (1-Hydroxyethylidene)bisphosphonic acid lie in its ability to combine efficacy, stability, and multifunctionality, making it a valuable compound across industries ranging from heavy engineering to healthcare.
Properties of (1-Hydroxyethylidene)bisphosphonic Acid:
(1-Hydroxyethylidene)bisphosphonic acid is an organophosphoric acid corrosion inhibitor.
(1-Hydroxyethylidene)bisphosphonic acid can chelate with Fe, Cu, and Zn ions to form stable chelating compounds.
(1-Hydroxyethylidene)bisphosphonic acid can dissolve the oxidized materials on these metals’ surfaces.
(1-Hydroxyethylidene)bisphosphonic acid shows excellent scale and corrosion inhibition effects under temperature 250℃.
(1-Hydroxyethylidene)bisphosphonic acid has good chemical stability under high pH value, hard to be hydrolyzed, and hard to be decomposed under ordinary light and heat conditions.
(1-Hydroxyethylidene)bisphosphonic acid's acid/alkali and chlorine oxidation tolerance are better than that of other organophosphoric acids (salt).
(1-Hydroxyethylidene)bisphosphonic acid can react with metal ions in water system to form hexa-element chelating complex, with calcium ion in particular.
Therefore, (1-Hydroxyethylidene)bisphosphonic acid has good antiscale and visible threshold effects.
When built together with other water treatment chemicals, (1-Hydroxyethylidene)bisphosphonic acid shows good synergistic effects.
The solid state of (1-Hydroxyethylidene)bisphosphonic acid is crystal powder, suitable for usage in winter and freezing districts.
Because of its high purity, (1-Hydroxyethylidene)bisphosphonic acid can be used as cleaning agent in electronic fields and as additives in daily chemicals.
Production of (1-Hydroxyethylidene)bisphosphonic Acid:
(1-Hydroxyethylidene)bisphosphonic acid is produced industrially through a phosphonation reaction involving phosphorus trichloride (PCl₃), acetic acid (CH₃COOH), and phosphorous acid (H₃PO₃) under controlled conditions.
In the most common process, acetic acid serves as the precursor for the hydroxyethylidene group, while PCl₃ and H₃PO₃ provide the phosphonate functionalities.
The reaction is typically carried out in a solvent-free or aqueous medium at elevated temperatures (around 90–120 °C), with careful control of stoichiometry and reaction time to maximize yield and minimize by-products such as phosphoric acid.
After the reaction, the crude mixture undergoes neutralization, hydrolysis, and purification steps, often resulting in either a concentrated aqueous solution or crystalline solid, depending on the end-use requirements.
Industrial-scale production focuses on ensuring high purity because impurities such as excess phosphoric acid or unreacted phosphorus compounds can reduce its effectiveness in water treatment and other applications.
Safety precautions are critical during production due to the reactivity and corrosive nature of PCl₃, which can release toxic hydrogen chloride gas upon contact with moisture.
The overall process is well-established, cost-intensive due to raw material pricing, and highly regulated to ensure both worker safety and environmental protection during manufacturing.
Synthesis of (1-Hydroxyethylidene)bisphosphonic Acid:
(1-Hydroxyethylidene)bisphosphonic acid can be prepared by reactions of dialkylphosphites and carboxylic acid anhydrides.
Other precursors include phosphorus trichloride and phosphorous acid.
In industry, glacial acetic acid and phosphoryl trichloride are usually used, and then the acylation product and phosphorous trichloride hydrolyzate are condensed.
Add the metered amount of water and glacial acetic acid into the reaction kettle and stir evenly.
Phosphorus trichloride was added dropwise under cooling, and the reaction temperature was controlled at 40-80°C.
The reaction by-product hydrogen chloride gas is condensed and sent to the absorption tower to recover hydrochloric acid.
The overflowed acetyl chloride and acetic acid were condensed and returned to the reactor.
After dropping phosphorus trichloride, the temperature was raised to 100-130°C, and refluxed for 4-5h.
After the reaction, hydrolyzed with steam to evaporate the residual acetic acid and low boilers to obtain 1-Hydroxyethylidene-1,1-diphosphonic acid.
History of (1-Hydroxyethylidene)bisphosphonic Acid:
(1-Hydroxyethylidene)bisphosphonic acid, holds a special place in the history of bisphosphonates as it was the first compound of this class to be synthesized and introduced into medicine.
Bisphosphonates were first developed in the late 19th and early 20th century as industrial chemicals due to their ability to inhibit scale formation and bind strongly to metal ions.
However, their medical significance was not recognized until the 1960s, when researchers discovered that these compounds could interact with hydroxyapatite in bone and inhibit bone resorption.
(1-Hydroxyethylidene)bisphosphonic acid was the earliest bisphosphonate used clinically, entering therapeutic practice in the 1970s, primarily for the treatment of Paget’s disease of bone, osteoporosis, and hypercalcemia associated with malignancy.
(1-Hydroxyethylidene)bisphosphonic acid's approval marked the beginning of a new era in the management of metabolic bone disorders, paving the way for the development of newer, more potent bisphosphonates such as alendronate, risedronate, and zoledronic acid.
Despite being gradually replaced in clinical practice by these second- and third-generation drugs due to higher efficacy and fewer side effects, (1-Hydroxyethylidene)bisphosphonic acid remains historically significant as the pioneer bisphosphonate that demonstrated the therapeutic potential of this entire drug class, while continuing to be valued in industrial and cosmetic applications.
Handling and Storage of (1-Hydroxyethylidene)bisphosphonic Acid:
Handle in well-ventilated areas, avoiding inhalation of vapors, mists, or dust.
Use appropriate personal protective equipment (PPE), including gloves, goggles, and protective clothing.
Do not eat, drink, or smoke when using (1-Hydroxyethylidene)bisphosphonic acid.
Store in tightly closed containers, preferably in plastic or lined steel, in a cool, dry, and well-ventilated place.
Protect from moisture, extreme heat, and direct sunlight.
Keep away from incompatible substances such as strong oxidizing agents, strong bases, and reducing agents.
Stability and Reactivity of (1-Hydroxyethylidene)bisphosphonic Acid:
Chemical stability:
Stable under recommended storage conditions.
Reactivity:
Strong chelating agent; can form complexes with metals.
Conditions to avoid:
Excessive heat, strong acids or alkalis, and prolonged exposure to sunlight.
Hazardous decomposition products:
Phosphorus oxides (POₓ), carbon oxides (CO/CO₂) may be released on thermal decomposition.
Incompatibility:
Avoid contact with alkaline materials, oxidizing agents, and reactive metals.
First Aid Measures of (1-Hydroxyethylidene)bisphosphonic Acid:
Inhalation:
Move victim to fresh air.
If breathing is difficult, provide oxygen and seek medical attention.
Skin contact:
Wash thoroughly with soap and water.
Remove contaminated clothing.
Seek medical advice if irritation persists.
Eye contact:
Rinse immediately with plenty of water for at least 15 minutes while holding eyelids open.
Seek medical attention.
Ingestion:
Rinse mouth with water (do not induce vomiting).
Give water to drink if conscious.
Seek immediate medical attention.
Firefighting Measures of (1-Hydroxyethylidene)bisphosphonic Acid:
Suitable extinguishing media:
Use water spray, foam, dry chemical, or carbon dioxide (CO₂).
Unsuitable media:
High-pressure water jets may spread the material.
Hazards from combustion:
Thermal decomposition may release irritating and toxic fumes (phosphorus oxides, carbon oxides).
Protective equipment for firefighters:
Wear self-contained breathing apparatus (SCBA) and full protective gear.
Accidental Release Measures of (1-Hydroxyethylidene)bisphosphonic Acid:
Personal precautions:
Use PPE (gloves, goggles, protective clothing).
Avoid inhalation and contact with skin or eyes.
Environmental precautions:
Prevent leakage into drains, soil, or natural waterways, as the substance can cause long-term aquatic effects.
Methods for cleaning up:
Contain the spill with absorbent materials (sand, earth, vermiculite).
Neutralize carefully with dilute alkali (e.g., sodium carbonate) if appropriate.
Collect in suitable labeled containers for disposal in accordance with local regulations.
Exposure Controls / Personal Protection of (1-Hydroxyethylidene)bisphosphonic Acid:
Engineering controls:
Ensure adequate ventilation, especially in confined areas.
Local exhaust ventilation recommended.
Personal protective equipment (PPE):
Respiratory protection:
Use approved respirators if exposure limits are exceeded or in case of insufficient ventilation.
Hand protection:
Chemical-resistant gloves (e.g., nitrile or neoprene).
Eye protection:
Safety goggles or face shield.
Skin/body protection:
Lab coat, protective apron, long sleeves, and closed footwear.
Hygiene measures:
Wash hands, face, and exposed skin after handling.
Do not eat, drink, or smoke while working with the substance.
Identifiers of (1-Hydroxyethylidene)bisphosphonic Acid:
IUPAC name: (1-Hydroxyethan-1,1-diyl)bis(phosphonic acid)
CAS Number: 2809-21-4
PubChem CID: 3305
IUPHAR/BPS: 7184
DrugBank: DB01077
ChemSpider: 3189
UNII: M2F465ROXU
KEGG: D02373
ChEBI: CHEBI:4907
ChEMBL: ChEMBL871
CompTox Dashboard (EPA): DTXSID6023028
ECHA InfoCard: 100.018.684
Formula: C2H8O7P2
Molar mass: 206.027 g·mol−1
SMILES: O=P(O)(O)C(O)(C)P(=O)(O)O
InChI: InChI=1S/C2H8O7P2/c1-2(3,10(4,5)6)11(7,8)9/h3H,1H3,(H2,4,5,6)(H2,7,8,9)
Key:DBVJJBKOTRCVKF-UHFFFAOYSA-N
Linear Formula: CH3C(OH)[PO(OH)2]2
CAS Number: 2809-21-4
Molecular Weight: 206.03
Beilstein: 1789291
EC Number: 220-552-8
MDL number: MFCD00070585
UNSPSC Code: 12352100
PubChem Substance ID: 57654267
NACRES: NA.22
Quality Level: 200
Assay: 55.0 -65.0%
form: liquid
suitability: suitable for photographic applications
SMILES string: CC(O)(P(O)(O)=O)P(O)(O)=O
InChI: 1S/C2H8O7P2/c1-2(3,10(4,5)6)11(7,8)9/h3H,1H3,(H2,4,5,6)(H2,7,8,9)
InChI key: DBVJJBKOTRCVKF-UHFFFAOYSA-N
Properties of (1-Hydroxyethylidene)bisphosphonic Acid:
Molecular Weight: 206.03 g/mol
XLogP3-AA: -3.7
Hydrogen Bond Donor Count: 5
Hydrogen Bond Acceptor Count: 7
Rotatable Bond Count: 2
Exact Mass: 205.97452659 Da
Monoisotopic Mass: 205.97452659 Da
Topological Polar Surface Area: 135 Ų
Heavy Atom Count: 11
Complexity: 211
Isotope Atom Count: 0
Defined Atom Stereocenter Count: 0
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Covalently-Bonded Unit Count: 1
Compound Is Canonicalized: Yes
Melting point: 198~199℃
Boiling point: 578.8±60.0 °C(Predicted)
Density: 1.45 (60% aq.)
vapor pressure: 0Pa at 25℃
storage temp.: Sealed in dry,Room Temperature
solubility: Methanol (Slightly), Water (Slightly)
pka: 1.35, 2.87, 7.03, 11.3(at 25℃)
form: Powder
color: white
PH: pH (1.7→100, 25℃) : 1.3～1.8
Water Solubility: Soluble in water.
Merck: 14,3863
BRN: 1789291
Stability: Stable. Incompatible with strong oxidizing agents.
InChIKey: DBVJJBKOTRCVKF-UHFFFAOYSA-N
LogP: -3.5
Melting point:198~199℃
Boiling point:578.8±60.0 °C(Predicted)
Density 1.45 (60% aq.)
storage temp. Sealed in dry,Room Temperature
form Powder
pka1.35, 2.87, 7.03, 11.3(at 25℃)
color white
PHpH (1.7→100, 25℃) : 1.3～1.8
Water Solubility Soluble in water.
Merck 14,3863
BRN 1789291
