(1R,9S,12S,15R,16E,18R,19R,21R,23R,24Z,26E,28E,30S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone

Base Information

• Chemical Name: (1R,9S,12S,15R,16E,18R,19R,21R,23R,24Z,26E,28E,30S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
• CAS No.: 159351-69-6
• Molecular Formula: C53H83NO14
• Molecular Weight: 958.24
• Hs Code.: 29349990
• European Community (EC) Number: 621-003-9
• Wikipedia: Everolimus
• Mol file: 159351-69-6.mol

Synonyms:159351-69-6;AKOS025402216;AC-6494

Chemical Property of (1R,9S,12S,15R,16E,18R,19R,21R,23R,24Z,26E,28E,30S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone

Chemical Property:

• Appearance/Colour: off white solid
• Vapor Pressure: 0mmHg at 25°C
• Melting Point: NA
• Refractive Index: 1.548
• Boiling Point: 998.7 °C at 760 mmHg
• PKA: 10.40±0.70(Predicted)
• Flash Point: 557.8 °C
• PSA: 204.66000
• Density: 1.18 g/cm³
• LogP: 6.13510
• Storage Temp.: −20°C
• Solubility.: Soluble in DMSO (up to 100 mg/ml) or in Ethanol (up to 100 mg/ml).
• Water Solubility.: Soluble in dimethysulfoxide,ethanol and chloroform. Slightly soluble in water.
• XLogP3: 5.9
• Hydrogen Bond Donor Count: 3
• Hydrogen Bond Acceptor Count: 14
• Rotatable Bond Count: 9
• Exact Mass: 957.58135632
• Heavy Atom Count: 68
• Complexity: 1810

Purity/Quality:

99%, ^*data from raw suppliers

Everolimus ^*data from reagent suppliers

Safty Information:

• Pictogram(s): T
• Hazard Codes: T,Xn,F
• Statements: 48/25-36-20/21/22-11
• Safety Statements: 45-36/37-26-16

MSDS Files:

SDS file from LookChem

Total 1 MSDS from other Authors

Useful:

• Canonical SMILES: CC1CCC2CC(C(=CC=CC=CC(CC(C(=O)C(C(C(=CC(C(=O)CC(OC(=O)C3CCCCN3C(=O)C(=O)C1(O2)O)C(C)CC4CCC(C(C4)OC)OCCO)C)C)O)OC)C)C)C)OC
• Isomeric SMILES: C[C@@H]1CCC2C[C@@H](/C(=C/C=C/C=C\[C@@H](C[C@H](C(=O)[C@@H]([C@@H](/C(=C/[C@H](C(=O)C[C@H](OC(=O)[C@@H]3CCCCN3C(=O)C(=O)[C@@]1(O2)O)[C@H](C)C[C@@H]4CC[C@H]([C@@H](C4)OC)OCCO)C)/C)O)OC)C)C)/C)OC
• Recent EU Clinical Trials: Phase 1b/3 global, randomized, controlled, open-label trial comparing treatment with RYZ101 to standard of care (SoC) therapy in subjects with inoperable, advanced, somatostatin receptor expressing (SSTR+), well-differentiated gastro-enteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following prior treatment with 177Lu-labelled somatostatin analogue (177Lu-SSA) therapy (ACTION-1)
• Indications: Everolimus is indicated for the treatment of numerous diseases and disorders. It indicated for the treatment of the following cases including both tumors and organ transplantation: Patients with advance kidney cancer[7]; Postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer(advanced HR+ BC)?in combination with exemestane, after failure of treatment with letrozole or anastrozole[8-10]; Adult patients with progressive neuroendocrine tumors of pancreatic origin(PNET)?with unresectable, locally advanced or metastatic disease[9, 10]; Adult patients with advanced renal cell carcinoma(RCC)?after failure of treatment with sunitinib or sorafenib; Adult patients with renal angiomyolipoma and tuberous sclerosis complex(TSC), not requiring immediate surgery[11]; Pediatric and adult patients with tuberous sclerosis complex(TSC)?for the treatment of subependymal giant cell astrocytoma(SEGA)?that requires therapeutic intervention but cannot be curatively resected[12]; Adult and pediatric patients aged 2 years and older with Tuberous Sclerosis Complex(TSC)-associated partial-onset seizures[10]; Preventing the organ rejection during/after renal and liver transplantation[14, 15]; Progressive, well-differentiated non-functional, neuroendocrine tumors[NET] of gastrointestinal(GI)?or lung origin with unresectable, locally advanced or metastatic disease[16].
• Description: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that, as part of two distinct complexes (mTORC1 and mTORC2), plays pivotal roles in intracellular signaling. Everolimus is a hydroxyethyl ether rapamycin derivative that inhibits mTOR signaling through both mTORC1 and mTORC2 when added to cells at 20 nM. It is orally available and shows improved pharmacokinetics and pharmacodynamics over rapamycin. Through its inhibition of mTOR, everolimus inhibits cell proliferation, metabolism, and angiogenesis in certain types of cancer. It also acts as an immunosuppressive agent in the context of organ transplantation. Everolimus, an oral immunosuppressant for the treatment of kidney and heart transplant rejection, is the 40-O-(2-hydroxyethyl) derivative of rapamycin. It has immunosuppressive properties similar to those of rapamycin, but with improved pharmacokinetic profile. In addition, the 40-O-(2-hydroxyethyl) group alters the physico-chemical properties of the macrolide to allow galenic formulation. Everolimus is prepared in a two-step semisynthesis starting from rapamycin, by alkylation of the 40-hydroxyl group with t-butyldimethylsilyloxyethyl triflate and subsequent cleavage of the silyl protecting group. Everolimus, like rapamycin, is a proliferation signal inhibitor that exerts its immunosuppressive effect by inhibiting the activation of p70 S6 kinase, thereby blocking growth factor-driven proliferation of T cells, B cells and vascular smooth muscle cells, and arresting cell cycle at the G1 phase. Inhibition of p70 S6 kinase activation by everolimus and rapamycin is mediated by their binding to FKBP12 (FK506 binding-protein 12). Everolimus inhibits FK506 binding to FKBP12 with an IC50 of 1.8–2.6 nM, and it is about 3- to 5-fold less potent than rapamycin (IC50=0.4–0.9 nM). The in vitro immunosuppressive activity of everolimus is also slightly less than that of rapamycin as demonstrated in a mixed lymphocyte reaction (MLR) assay (IC50=0.2–1.6 nM versus 0.07–0.5 nM, respectively) and in antigen-specific human helper T-cell clones (IC50=0.05–0.17nM versus 0.014–0.37nM, respectively). However, the in vivo immunosuppressive activity of oral everolimus 1–5 mg/ kg/day is similar to that of rapamycin at equivalent doses in rat models of renal or cardiac transplantation, localized graft-versus-host disease, and autoimmune glomerulonephritis. The recommended dosage of everolimus is 0.75 mg twice daily, and it is used in combination with cyclosporine microemulsion and corticosteroids. Following oral dosing, the peak concentration (Cmax) of everolimus is estimated between 1.5 to 2 hours, and steady state is achieved within 4 days. The terminal elimination half-life is 21 to 35 hours. By comparison, rapamycin has a longer elimination half-life (60 hours) and longer time to reach steady state (7 to 14 days). Consequently, rapamycin treatment requires a large loading dose, followed by once daily maintenance dose, whereas everolimus is administered twice daily but without the need of a loading dose. Everolimus is extensively metabolized, primarily by CYP3A4. Approximately 80% of the dose is excreted in the feces and about 5% in the urine. In clinical trials with adult cardiac transplant recipients, oral everolimus 0.75 or 1.5 mg twice daily significantly reduced the incidence of efficacy failure as well as cardiac allograft vasculopathy (CAV) up to 2 years after transplantation as compared with azathioprene 1–3 mg/kg/day. However, graft and patient survival rates at 1 year were similar in patients receiving everolimus and azathioprene. In trials involving renal transplant recipients, the combined incidence of biopsy-confirmed acute rejection, graft loss, death, or loss to follow-up was similar in patients receiving everolimus 1.5 or 3 mg/day or mycophenolate mofetil 2 g/day up to 3 years after transplantation. Everolimus was well tolerated in transplant patients. The incidence of viral infection including cytomegalovirus (CMV) was reduced in comparison to azathioprene and mycophenolate mofetil, but bacterial infections were more frequent. Main adverse events associated with everolimus were thrombocytopenia, leucopenia, and elevated serum lipids and creatinine.
• Uses: Macrolide immunosuppressant; derivative of Rapamycin. Inhibits cytokine-mediated lymphocyte proliferation Everolimus (IX) (SDZ-RAD), was developed by Novartis as an immunosuppressant to be used in conjunction with cyclosporin in transplantation allograft rejection and was recently approved in the US in 2003. Another natural product that had been approved for use in transplantation is rapamycin (sirolimus) as an inejectable agent. In an attempt to develop an orally bioavailable immunosuppressant agent, many companies attempted modification of rapamycin itself. Everolimus Macrolide immunosuppressant; Everolimus is a derivative of Rapamycin. Everolimus inhibits cytokine-mediated lymphocyte proliferation.
• Clinical Use: #N/A
• Drug interactions: Potentially hazardous interactions with other drugs ACE-Is: increased risk of angioedema. Antibacterials: erythromycin, clarithromycin and telithromycin increase everolimus levels - avoid with clarithromycin and telithromycin; rifampicin decreases everolimus levels by factor of 3. Antidepressants: St John’s wort decreases everolimus levels. Antifungals: concentration increased by ketoconazole and possibly itraconazole, posaconazole and voriconazole - avoid. Antipsychotics: increased risk of agranulocytosis with clozapine - avoid. Antivirals: concentration possibly increased by atazanavir, darunavir, indinavir, ritonavir and saquinavir - avoid; concentration significantly increased by dasabuvir and ombitasvir/paritaprevir/ ritonavir - avoid concomitant use. Calcium channel blockers: concentration of both drugs increased with verapamil. Ciclosporin: increases everolimus AUC by 168% and Cmax by 82%. Cytotoxics: concentration increased by imatinib - consider reducing everolimus dose. Grapefruit juice: increases everolimus levels.

Technology Process of (1R,9S,12S,15R,16E,18R,19R,21R,23R,24Z,26E,28E,30S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone

There total 26 articles about (1R,9S,12S,15R,16E,18R,19R,21R,23R,24Z,26E,28E,30S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone 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: 96.28%

C64H105NO16Si → everolimus (159351-69-6)

Guidance literature:

With hydrogenchloride; In water; acetone; at 5 ℃; pH=2 - 3; Reagent/catalyst; Solvent; Temperature;

Reference yield: 88.0%

42-O-trityl-everolimus → everolimus (159351-69-6)

Guidance literature:

With hydrogenchloride; In methanol; water; Solvent; Reagent/catalyst;

Reference yield: 71.0%

28-O-TES-42-O-THDMS everolimus → everolimus (159351-69-6)

Guidance literature:

With sulfuric acid; In tetrahydrofuran; at 0 - 10 ℃; for 1h;

upstream raw materials:

40-O-[2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl] rapamycin

40-O-[2-(t-butyldiphenylsilyl)oxy]ethyl-rapamycin

sirolimus

40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin

Downstream raw materials:

42-O-(2-fluoroethyl)rapamycin

40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin

40-O-[2-(t-butyldiphenylsilyl)oxy]ethyl-rapamycin

Refernces

• 1、 -. "Purification method of everolimus". Paragraph 0081; 0087; 0088; 0089. . Retrieved 2019/01/24.
• 2、 -. "Preparation method of everolimus". . . Retrieved 2019/06/13.