Cinacalcet hydrochloride

Base Information

• Chemical Name: Cinacalcet hydrochloride
• CAS No.: 364782-34-3
• Molecular Formula: C22H22F3N.HCl
• Molecular Weight: 393.88
• Hs Code.: 29214990
• European Community (EC) Number: 620-490-5
• UNII: 1K860WSG25
• DSSTox Substance ID: DTXSID3046792
• Wikidata: Q27121179
• NCI Thesaurus Code: C47450
• RXCUI: 384379
• Pharos Ligand ID: QVAZDS6A5DRX
• ChEMBL ID: CHEMBL1200776
• Mol file: 364782-34-3.mol

Synonyms:Mimpara;Regpara;Sensipar;1-Naphthalenemethanamine,a-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-,hydrochloride, (aR)-(9CI);

Chemical Property of Cinacalcet hydrochloride

Chemical Property:

• Appearance/Colour: Off-white to tan solid
• Melting Point: 175-177 °C
• Boiling Point: 440.9 °C at 760 mmHg
• Flash Point: 220.5 °C
• PSA: 12.03000
• LogP: 7.33490
• Storage Temp.: -20°C Freezer
• Solubility.: insoluble in H2O; ≥17.85 mg/mL in DMSO; ≥56 mg/mL in EtOH
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 4
• Rotatable Bond Count: 6
• Exact Mass: 393.1471119
• Heavy Atom Count: 27
• Complexity: 422

Purity/Quality:

98%min ^*data from raw suppliers

CinacalcetHydrochloride ^*data from reagent suppliers

Safty Information:

• Safety Statements: 24/25

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CC(C1=CC=CC2=CC=CC=C21)NCCCC3=CC(=CC=C3)C(F)(F)F.Cl
• Isomeric SMILES: C[C@H](C1=CC=CC2=CC=CC=C21)NCCCC3=CC(=CC=C3)C(F)(F)F.Cl
• Recent ClinicalTrials: Study of KHK7580 in Subjects With Secondary Hyperparathyroidism in Asia
• Recent EU Clinical Trials: Treatment of Primary Hyperparathyroidism with Denosumab and Cinacalcet
• Recent NIPH Clinical Trials: Prescription change from cinacalcet hydrochloride to evocalcet in hemodialysis patients
• Description: Cinacalcet is the first entry in a new class of therapeutic agents called the calcimimetics. It was launched as an oral treatment for secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease on dialysis and for hypercalcemia in patients with parathyroid carcinoma. SHPT is associated with increased parathyroid hormone (PTH) secretion, which is triggered by low serum levels of calcium resulting from the failure of the kidney to clear phosphorous from the body and its inability to produce sufficient quantities of vitamin D. The consequences of increased PTH include stimulation of osteoclastic activity, cortical bone resorption and marrow fibrosis. PTH secretion is primarily regulated by the calcium-sensing receptor (CaR), which is located on the surface of the chief cell of the parathyroid gland. Calcimimetics bind to CaR and increase the sensitivity of CaR to extracellular calcium, thereby enabling its activation at subnormal levels of serum calcium. As a result, in the presence of these agents, the low levels of endogenous calcium in patients with renal failure are able to exert a suppressive effect on PTH secretion. Parathyroid carcinoma is also associated with elevated PTH levels, which are driven by autonomous parathyroid gland activity and subsequently lead to hypercalcemia. Although surgical resection is the primary therapy for treating hypercalcemia in parathyroid carcinoma patients, calcimimetics offer a nonsurgical alternative for patients with failed parathyroidectomy, metastatic parathyroid carcinoma, or high surgical risk. The recommended dosage of cinacalcet for the treatment of SHPT in chronic kidney disease is 30mg once daily at start and subsequent titration to 60, 90, 120 or 180 mg once daily. The dosage for the treatment of hypercalcemia in patients with parathyroid carcinoma is 30 mg twice daily at start and subsequent titration to 60 or 90 mg twice daily, or 90mg three or four times daily as necessary to normalize serum calcium level. After oral administration of cinacalcet, maximum plasma concentration is achieved in approximately 2 to 6 hours. It has a terminal half-life of 30 to 40 hours and steady-state drug levels are reached within 7 days. Cinacalcet has a high volume of distribution (1000 L) and high protein binding (93%–97%). It is extensively metabolized in the liver, mainly by CYP3A4, CYP2D6 and CYP1A2. The primary routes of elimination are in the urine (80%) and in the feces (15%). In Phase III clinical trials involving 1136 patients with SHPT, administration of cinacalcet at 30–180 mg/day doses for 6 months produced 38–48% decrease in intact PTH. Overall, 64% of patients given cinacalcet achieved at least a 30% reduction in PTH, versus 11% of placebo patients. Calcium-phosphorous product was reduced 14% by the active treatment and did not change in the placebo group. In a much smaller clinical study involving 21 hypercalcemic patients with parathyroid carcinoma, administration of 60–360 mg/day doses of cinacalcet resulted in 71% of patients achieving a target reduction of ≥1 mg/dL in serum calcium. The most common adverse events in these trials were nausea and vomiting. In vitro, cinacalcet is a strong inhibitor of CYP2D6; therefore, dose adjustments may be required when coadministered with medications that are predominantly metabolized by CYP2D6 and have a narrow therapeutic index (e.g. flecainide, vinblastine, thioridazine and most tricyclic antidepressants). Cinacalcet is prepared in a two-step synthesis starting from 3-[3-(trifluoromethyl)phenyl]propionaldehyde, by first condensing with (R)-(1-naphthyl)ethylamine to form the corresponding imine and subsequent reduction of the imine with sodium cyanoborohydride.
• Uses: Cinacalcet hydrochloride can be used in clinical trial in secondary hyperparathyroidism.

Technology Process of Cinacalcet hydrochloride

There total 81 articles about Cinacalcet hydrochloride 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: 98.25%

(R)-1-(1-Naphthyl)ethylamine (3886-70-2) + methylsulfonyl-3-(3-trifluoromethylphenyl)propyl ester (21172-43-0) → cinacalcet hydrochloride (364782-34-3,1217809-88-5)

Guidance literature:

(R)-1-(1-Naphthyl)ethylamine; methylsulfonyl-3-(3-trifluoromethylphenyl)propyl ester; With potassium carbonate; potassium iodide; 1-(n-butyl)-3-methylimidazolium triflate; In acetonitrile; for 6h; Reflux;

With hydrogenchloride; at 50 - 55 ℃; for 1h; Reagent/catalyst;

Reference yield: 98.2%

(R)-tert-butyl (1-(naphthalen-1-yl)ethyl)(3-(3-(trifluoromethyl)phenyl)propyl)carbamate (1204313-91-6) → cinacalcet hydrochloride (364782-34-3,1217809-88-5)

Guidance literature:

With hydrogenchloride; In ethyl acetate; at 25 ℃; for 0.25h;

Reference yield: 96.22%

(R)‐N‐(1‐(naphthalen‐1‐yl)ethyl)‐3‐(3‐trifluoromethylphenyl)propanamide (1005450-55-4,955371-05-8) → cinacalcet hydrochloride (364782-34-3,1217809-88-5)

Guidance literature:

(R)‐N‐(1‐(naphthalen‐1‐yl)ethyl)‐3‐(3‐trifluoromethylphenyl)propanamide; With sodium tetrahydroborate; iodine; In tetrahydrofuran; at 0 - 75 ℃; for 6.5h;

With hydrogenchloride; In hexane; water; for 1h;

upstream raw materials:

cinacalcet

(R)‐N‐(1‐(naphthalen‐1‐yl)ethyl)‐3‐(3‐trifluoromethylphenyl)propanamide

(R)-N-(1-naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-(E)-acrylamide

N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane acetate

Downstream raw materials:

cinacalcet

(R)-(1-naphthalen-1-ylethyl)-N,N-bis[3-(3-trifluoromethylphenyl)propyl]amine

1-chloroethyl carbamate cinacalcet

Refernces

• 1、 -. "Preparation method of cinacalcet hydrochloride and intermediate thereof". Paragraph 0054-0069. . Retrieved 2021/05/05.
• 2、 Jing, Hongyu,Li, Jiong,Li, Wen-Hao,Li, Yadong,Wang, Dingsheng,Wang, Yu,Yang, Jiarui,Zhang, Jian,Zhao, Jie. "Creating High Regioselectivity by Electronic Metal-Support Interaction of a Single-Atomic-Site Catalyst". . p. 15453 - 15461. Retrieved 2021/09/30.