Zoledronic acid

Base Information

• Chemical Name: Zoledronic acid
• CAS No.: 118072-93-8
• Molecular Formula: C5H10N2O7P2
• Molecular Weight: 316.055
• Hs Code.: 2933399090
• European Community (EC) Number: 871-741-2
• NSC Number: 721517
• UNII: 70HZ18PH24
• DSSTox Substance ID: DTXSID0042668
• Nikkaji Number: J556.181G
• Wikipedia: Zoledronic_acid
• Wikidata: Q218507
• NCI Thesaurus Code: C80120
• RXCUI: 1546014
• Pharos Ligand ID: M9927MHVJXQR
• Metabolomics Workbench ID: 42761
• ChEMBL ID: CHEMBL924
• Mol file: 118072-93-8.mol

Synonyms:2-(imidazol-1-yl)-1-hydroxyethylidene-1,1-bisphosphonic acid;CGP 42'446;CGP 42446;CGP 42446A;CGP-42'446;CGP-42446;CGP42'446;CGP42446;zoledronate;zoledronic acid;zoledronic acid anhydrous;Zometa

Chemical Property of Zoledronic acid

Chemical Property:

• Appearance/Colour: white crystalline powder
• Vapor Pressure: 1.53E-24mmHg at 25°C
• Melting Point: 193-2040 ºC
• Refractive Index: 1.718
• Boiling Point: 764 ºC at 760 mmHg
• PKA: 1.41±0.10(Predicted)
• Flash Point: 415.8 ºC
• PSA: 172.73000
• Density: 2.13 g/cm³
• LogP: -1.11540
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility.: Soluble in Water (up to 2 mg/ml).
• XLogP3: -4.3
• Hydrogen Bond Donor Count: 5
• Hydrogen Bond Acceptor Count: 8
• Rotatable Bond Count: 4
• Exact Mass: 271.99632466
• Heavy Atom Count: 16
• Complexity: 327

Purity/Quality:

99%MIN ^*data from raw suppliers

Zoledronic Acid ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xi
• Hazard Codes: Xi
• Statements: 21/22-36/37/38
• Safety Statements: 24/25-36/37/39

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: C1=CN(C=N1)CC(O)(P(=O)(O)O)P(=O)(O)O
• Recent ClinicalTrials: HAIC Combined Withzoledronic Acid for the Prevention of Bone Metastases in Advanced HCC
• Recent EU Clinical Trials: Bisphosphonate vs. Placebo Prior to Parathyroidectomy in Primary Hyperparathyroidisme: A Randomized, blinded Placebo-controlled Trial
• Recent NIPH Clinical Trials: Risk-specific multicenter phase II clinical trial for Langerhans cell histiocytosis in children and young adults
• Description: Zoledronic acid is a white, crystalline powder that is available in vials for reconstitution for IV infusion over at least 15 minutes. It does not undergo metabolic transformation and does not inhibit CYP450 enzymes. Clearance of this agent is dependent on the patient's creatinine clearance, not on dose. Serum creatinine levels should be evaluated before every treatment. Zolendronic acid is contraindicated in patients with severe renal impairment.
• Uses: Bisphosphonate antiresorptive agent bone resorption inhibitor Zoledronic acid induces apoptosis in osteoclasts by inhibiting enzymes of the mevalonate pathway and preventing the isoprenylation of small GTP-binding proteins such as Ras and Rho.
• Therapeutic Function: Bone calcium regulator
• Biological Functions: Zoledronic acid, a bisphosphonate, was approved by the U.S. FDA in 2001 for the treatment of hypercalcemia of malignancy, a metabolic complication that can be life-threatening. Hypercalcemia of malignancy can occur in up to 50% of patients diagnosed with advanced breast cancer, multiple myeloma, and nonsmall cell lung cancer. This condition arises when chemical moieties produced by the tumor cause overstimulation of osteoclasts. When there is an increase in bone degradation, there is a concomitant release of calcium into the plasma. When serum concentrations of calcium rapidly elevate, the kidneys are unable to handle the overload, and hypercalcemia results. This can lead to dehydration, nausea, vomiting, fatigue, and confusion. Zoledronic acid effectively decreases plasma calcium concentrations via inhibition of bone resorption (inhibition of osteoclastic activity and induction of osteoclast apoptosis). It also prevents the increase in osteoclastic activity caused by tumor-based stimulatory factors. Additionally zoledronic acid has been approved by the U.S. FDA for the treatment of multiple myeloma and bone metastases associated with solid tumor–based cancers (e.g., prostrate and lung). This agent is currently in late-stage clinical trials for the treatment and prevention of osteoporosis and, if approved, will be formulated as a 5-mg, once-yearly IV infusion.
• Clinical Use: Zoledronic acid is most commonly given to patients whose cancer is no longer responding to hormones, but it also may be given to prevent the bone thinning and weakening that results from hormonal treatments.
• Drug interactions: Potentially hazardous interactions with other drugs Other nephrotoxic drugs: use with caution as can enhance nephrotoxicity

Technology Process of Zoledronic acid

There total 15 articles about Zoledronic acid which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 99.0%

imidazol-1-ylacetic acid (22884-10-2) → 1-hydroxy-2-(imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (118072-93-8)

Guidance literature:

imidazol-1-ylacetic acid; With phosphoric acid; phosphorus trichloride; In 1,2-propylene cyclic carbonate; PEG 600 (polyethylene glycol); at 40 - 60 ℃;

With water; In 1,2-propylene cyclic carbonate; PEG 600 (polyethylene glycol); at 85 ℃; for 18h; Product distribution / selectivity;

Reference yield: 98.7%

→ 1-hydroxy-2-(imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (118072-93-8)

Guidance literature:

With hydrogenchloride; In ethanol; water; at 0 - 85 ℃; pH=1.7 - 3.7; Purification / work up;

Reference yield: 85.27%

C8H8N4O2*ClH → 1-hydroxy-2-(imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (118072-93-8)

Guidance literature:

C₈H₈N₄O₂*ClH; With phosphoric acid; phosphorus trichloride; In toluene; at 90 ℃;

With hydrogenchloride; In water; toluene; at 20 ℃; Reagent/catalyst; Temperature; Solvent; Reflux;

upstream raw materials:

imidazol-1-ylacetic acid

2-(1-imidazolyl)acetic acid hydrochloride

imidazol-1-yl-acetyl chloride

tetrakis(O-trimethylsilyl)hydroxyethylidenediphosphonic acid

Downstream raw materials:

zoledronic acid trihydrate

Carbonic acid isopropyl ester 2-(2,3,4-trihydroxy-3-imidazol-1-ylmethyl-2,4-dioxo-2λ5,4λ5-[1,5,2,4]dioxadiphosphinan-6-yl)-phenyl ester

zoledronic acid monohydrate

Refernces

• 1、 Lebedev, A. V.,Sheludyakov, V. D.,Ustinova, O. L.,Lebedeva, A. B.. "Silylation of hydroxyalkylidenediphosphonic acids as an effective method of their purification". . . Retrieved 2012.
• 2、 Grün, Alajos,Keglevich, Gy?rgy,Szalai, Zsuzsanna. "“Greener” Synthesis of Zoledronic Acid from Imidazol-1-yl-acetic Acid and P-Reagents Using Diethyl Carbonate as the Solvent Component". . p. 8 - 12. Retrieved 2021/03/19.
• 3、 -. "Zoledronic acid intermediate compound". Paragraph 0056; 0059-0060; 0061; 0064-0065; 0066; 0069-0070. . Retrieved 2021/03/31.