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159351-69-6

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159351-69-6 Usage

Overview

Everolimus is a derivative of Rapamycin(sirolimus), and works similarly to Rapamycin as an mTOR(mammalian target of rapamycin) inhibitor[1-3]. It is currently used as an immunosuppressant to prevent rejection of organ transplants. In a similar fashion to other mTOR inhibitors, Everolimus takes effect solely on the mTORC1 protein and not on the mTORC2 protein[1]. In transplantation medicine, it is marketed under the trade names Zortress(USA) and Certican(Europe)[4]. It has been also used for the treatment of tumors, being marketed as Afinitor(general tumours)?and Votubia(tumours as a result of TSC)?in oncology[5, 6].

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].

Mode of action

The mammalian target of rapamycin(mTOR)?pathway is one of the most clinically important molecular signalling networks to emerge over the past decade. It is the protein kinase at the core of this intricate and continually evolving pathway, controls cellular growth and behavior, impacting vital processes from immune reactivity to cancer progression[17, 18]. Everolimus is an mTOR inhibitor that binds with high affinity to the FK506 binding protein-12(FKBP-12), thereby forming a drug complex that inhibits the activation of mTOR[19-20]. This inhibition reduces the activity of effectors downstream, which leads to a blockage in the progression of cells from G1 into S phase, and subsequently inducing cell growth arrest and apoptosis. Everolimus also inhibits the expression of hypoxia-inducible factor, leading to a decrease in the expression of vascular endothelial growth factor[19, 20]. The result of everolimus inhibition of mTOR is a reduction in cell proliferation, angiogenesis, and glucose uptake. Since highly expression of mTOR is an important factor that promoting the cancer, blocking mTOR by Everolimus can effectively treat some kinds of cancer and the organ rejection due to immune response during/after organ transplantation[21, 22].

Pharmacokinetics

Oral everolimus is absorbed rapidly, and reaches peak concentration after 1.3–1.8 hours. Steady state is reached within 7 days, and steady-state peak and trough concentrations, and area under the concentration-time curve (AUC), are proportional to dosage. In adults, everolimus pharmacokinetic characteristics do not differ according to age, weight or sex, but bodyweight-adjusted dosages are necessary in children.

Adverse reactions

Some serious adverse reactions associated with Everolimus include non-infection pneumonitis, infections, severe hypersensitivity reactions, angioedema with concomitant use of ACE inhibitors, stomatitis, renal failure, impaired wound healing, metabolic disorders and myelosuppression[10]. Various common side effects include Bloating or swelling of the face, arms, hands, lower legs, or fee bloody nose, chest pain or tightness, chills, cough, decreased weight, diarrhea, difficult or labored breathing, difficulty with swallowing, fever, general feeling of discomfort or illness, hoarseness, lower back or side pain, painful or difficult urination, rapid weight gain, sores, ulcers, or white spots on the lips, tongue, or inside the mouth and tingling of the hands or feet[23]. Less common side effects include bleeding gums, bloody urine, blurred vision, burning, crawling, itching, numbness, prickling, or tingling feelings, coughing up blood, extreme tiredness or weakness, fast, pounding, or irregular heartbeat or pulse, increased thirst or urination, irregular breathing, loss of appetite, nausea, nervousness, nosebleeds, prolonged bleeding from cuts, red or black, tarry stools, red or dark brown urine, slow heartbeat, stomach ache, sweating, unusual tiredness or weakness and vomiting[23].

Warning and precautions

People who are allergic to Everolimus should be disabled. Since it can increase your risk of serious infections or getting certain cancers, such as lymphoma or skin cancer. The patients should ask their doctor about the specific risk[10, 23]. Patients who have the following conditions should consult for doctor for advice before administration: problem in digesting lactose or galactose(sugar); high cholesterol or triglycerides; liver disease; a heart transplantation; or skin cancer in them or their family members[23]. Since it may harm the unborn baby as well as affect fertility(the capability to have children), women should take effective birth control during administration of Everolimus and for at least eight weeks after stopping drugs. Should consult the doctor for advice if you want to or has become pregnant. It may also affect the fertility of men as well. It is generally not recommended to have breast-feed during the administration of Everolimus for women[10, 23].

References

Different sources of media describe the References of 159351-69-6 differently. You can refer to the following data:
1. https://www.drugbank.ca/drugs/DB01590 https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm488028.htm https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022334s036lbl.pdf Junge, G., et al. "EVEROLIMUS, MTORC1 INHIBITION, AND IMPACT ON HEPATOCELLULAR CARCINOMA RECURRENCE AFTER LIVER TRANSPLANTATION-12, 24, AND 36 MONTHS DATA FROM 719 LTX RECIPIENTS." Transplant International 27(2014]: 23-23. Yao, J. C., et al. "Everolimus for advanced pancreatic neuroendocrine tumors. " New England Journal of Medicine 364.6(2011]: 514-23. Motzer, Robert J, et al. "Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma." Lancet Oncology 17.7(2016]: 917-927. Nachtnebel, A. "Everolimus[Afinitor] for advanced/metastatic kidney cancer."[2009]. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254350.htm https://www.reuters.com/article/2012/07/20/novartis-afinitor-idUSL2E8IKD8B20120720 https://www.rxlist.com/afinitor-drug.htm#indications_dosage Matin, Surena F. "Everolimus for the treatment of TSC-associated tumors." Community Oncology 9.12(2012]:361–362. Cappellano, A. M., et al. "Successful everolimus therapy for SEGA in pediatric patients with tuberous sclerosis complex." Childs Nervous System Chns Official Journal of the International Society for Pediatric Neurosurgery 29.12(2013]:2301-2305. Bilbao, Itxarone, et al. "Multiple indications for everolimus after liver transplantation in current clinical practice." World Journal of Transplantation 4.2(2014]: 122-132. Ganschow, Rainer, et al. "The role of everolimus in liver transplantation." Clinical & Experimental Gastroenterology 7.default(2014]:329-343. Dunn, C, and K. F. Croom. "Everolimus: a review of its use in renal and cardiac transplantation. " Drugs 66.4(2006]:547-570. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm488028.htm Geissler, Edward K., H. J. Schlitt, and G. Thomas. "mTOR, Cancer and Transplantation." American Journal of Transplantation 8.11(2010]:2212-2218. Young, D. A., and C. L. Nickersonnutter. "mTOR--beyond transplantation. " Current Opinion in Pharmacology 5.4(2005]: 418-423. Anandappa, G., A. Hollingdale, and T. Eisen. "Everolimus – a new approach in the treatment of renal cell carcinoma." Cancer Management & Research 2.1(2010]:61. Raimondo, L., et al. "Everolimus induces Met inactivation by disrupting the FKBP12/Met complex:" Oncotarget 7.26(2016]:40073-40084. Sabatini, David M. "mTOR and cancer: insights into a complex relationship." Nature Reviews Cancer 6.9(2006]:729. Efeyan, Alejo, and D. M. Sabatini. "mTOR and cancer: many loops in one pathway." Current Opinion in Cell Biology 22.2(2010]:169-176. https://www.drugs.com/mtm/everolimus.html
2. 1) Schuurman et al. (1997), SDZ RAD, a new rapamycin derivative: synergism with cyclosporine; Transplantation, 64 32 2) Neuhaus et al. (2001), mTOR inhibitors: an overview; Liver Transpl., 7 473 3) Kahan et al. (2002), Therapeutic drug monitoring of immunosuppressant drugs in clinical practice; Clin. Ther., 24 330

Description

Different sources of media describe the Description of 159351-69-6 differently. You can refer to the following data:
1. 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.
2. 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.

Chemical Properties

Off White Solid

Originator

Novartis (Switzerland)

Uses

Different sources of media describe the Uses of 159351-69-6 differently. You can refer to the following data:
1. Macrolide immunosuppressant; derivative of Rapamycin. Inhibits cytokine-mediated lymphocyte proliferation
2. 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.
3. Everolimus Macrolide immunosuppressant; Everolimus is a derivative of Rapamycin. Everolimus inhibits cytokine-mediated lymphocyte proliferation.

Definition

ChEBI: A macrocyclic lactone that is rapamycin in which the hydroxy group attached to the cyclohexyl moiety has been converted to the corresponding 2-hydroxyethyl ether. It is an immunosuppressant and antineoplastic agent.

Brand name

Certican

General Description

Everolimus, sold under trade names including Zortress?, Certican, and Afinitor?, is an immunosuppressant drug used to prevent rejection of organ transplants and to treat renal cell cancer and other tumors. This Certified Spiking Solution? is suitable as starting material for calibrators, controls, or linearity standards for therapeutic drug monitoring or clinical and diagnostic testing of everolimus in patient whole blood samples by LC-MS/MS.

Biochem/physiol Actions

Everolimus, the 40-O-(2-hydroxyethyl) derivative of rapamycin (sirolimus), is a potent and selective inhibitor of mechanistic target of rapamycin (mTOR). Everolimus is selective for the mTORC1 protein complex. Everolimus exhibit potent immunosuppressive and anticancer activities.

Clinical Use

#N/A

Synthesis

Everolimus (IX) was discovered by Sandoz (Novartis) scientists by modifying rapamycin drug in the 40-hydroxyl position. Thus, treatment of rapamycin (84) with t-butyldimethylsilyloxy ethyl triflate in the presence of 2,6-lutidine at 60°C for 3.5 hrs gave ether 85. Deprotection of the silyl group was done by treating silyloxy ether 85 in methanol with 2N HCl to give the product IX (everolimus), which was purified by chromatography. No yields were given for the reactions.

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.

Metabolism

Everolimus is metabolised in the liver and to some extent in the gastrointestinal wall, and is a substrate of P-glycoprotein and the cytochrome P450 isoenzyme CYP3A4. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ringopened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were shown to have approximately 100 times less activity than everolimus itself. Following the administration of a single dose of radiolabelled everolimus, 80% of the radioactivity was recovered from the faeces, while 5% was excreted in the urine. The parent substance was not detected in urine or faeces.

Check Digit Verification of cas no

The CAS Registry Mumber 159351-69-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,5,9,3,5 and 1 respectively; the second part has 2 digits, 6 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 159351-69:
(8*1)+(7*5)+(6*9)+(5*3)+(4*5)+(3*1)+(2*6)+(1*9)=156
156 % 10 = 6
So 159351-69-6 is a valid CAS Registry Number.
InChI:InChI=1/C53H83NO14/c1-32-16-12-11-13-17-33(2)44(63-8)30-40-21-19-38(7)53(62,68-40)50(59)51(60)54-23-15-14-18-41(54)52(61)67-45(35(4)28-39-20-22-43(66-25-24-55)46(29-39)64-9)31-42(56)34(3)27-37(6)48(58)49(65-10)47(57)36(5)26-32/h11-13,16-17,27,32,34-36,38-41,43-46,48-49,55,58,62H,14-15,18-26,28-31H2,1-10H3/b13-11-,16-12+,33-17+,37-27-/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1

159351-69-6SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 15, 2017

Revision Date: Aug 15, 2017

1.Identification

1.1 GHS Product identifier

Product name everolimus

1.2 Other means of identification

Product number -
Other names SDZRAD

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:159351-69-6 SDS

159351-69-6Synthetic route

42-O-trityl-everolimus

42-O-trityl-everolimus

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With hydrogenchloride In methanol; water Solvent; Reagent/catalyst;88%
With 1,1,1,3',3',3'-hexafluoro-propanol at 58℃; for 3.5h;
28-O-TES-42-O-THDMS everolimus

28-O-TES-42-O-THDMS everolimus

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With sulfuric acid In tetrahydrofuran at 0 - 10℃; for 1h;71%
With sulfuric acid In tetrahydrofuran at 0 - 10℃; for 1h; Reagent/catalyst;3.72 g
28-O-TMS-42-O-TBS everolimus

28-O-TMS-42-O-TBS everolimus

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With hydrogenchloride In water; acetone at 0 - 5℃; for 1h;68.3%
With hydrogenchloride In water; acetonitrile at -10 - 0℃; for 0.5h;20.4 g
With hydrogenchloride In acetone at 0 - 5℃; for 1h;3.58 g
42-O-[2-(1-methyl-1-methoxyethoxy)ethyl]rapamycin

42-O-[2-(1-methyl-1-methoxyethoxy)ethyl]rapamycin

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With hydrogenchloride In methanol; water at 5℃; pH=3 - 4;68%
42-O-[2(tetrahydrofuran-2-oxy)ethyl]rapamycin

42-O-[2(tetrahydrofuran-2-oxy)ethyl]rapamycin

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With hydrogenchloride In methanol; water at 5℃;67%
42-O-[2-(1-ethoxyethoxy)ethyl]rapamycin

42-O-[2-(1-ethoxyethoxy)ethyl]rapamycin

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With hydrogenchloride In methanol; water at 5℃;65%
42-O-[2(tetrahydro-2H-furan-2-oxy)ethyl]rapamycin

42-O-[2(tetrahydro-2H-furan-2-oxy)ethyl]rapamycin

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With hydrogenchloride In methanol; water at 5℃;61%
42-O-[2-(methoxymethoxy)ethyl]rapamycin

42-O-[2-(methoxymethoxy)ethyl]rapamycin

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With hydrogenchloride In methanol; water at 5℃;55%
40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin
159351-68-5

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

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With triethylamine tris(hydrogen fluoride) In tetrahydrofuran at 20℃; for 2h;54%
With pyridine hydrogenfluoride In tetrahydrofuran at 0 - 45℃; for 1.5h;2.96 g
With hydrogenchloride In methanol; water at 0 - 25℃; for 1h; pH=1-3; pH-value; Time;
40-O-[2-(t-butyldiphenylsilyl)oxy]ethyl-rapamycin
1314705-20-8

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

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With pyridine; hydrogen fluoride In tetrahydrofuran at 0 - 20℃; for 4h;15%
With pyridine hydrogenfluoride In tetrahydrofuran at 0 - 20℃; for 4h;15%
With pyridine hydrogenfluoride In tetrahydrofuran at 0 - 45℃; for 3.5h; Temperature;6.81 g
With hydrogenchloride In water; acetonitrile at -10 - 0℃; for 0.5h;
40-O-[2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl] rapamycin
1392400-31-5

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

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With hydrogenchloride In methanol; water at 0℃; for 1.5h;
With hydrogenchloride In methanol; water at -10℃; Inert atmosphere;
C74H101NO16

C74H101NO16

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With 1,1,1,3',3',3'-hexafluoro-propanol at 50℃; for 1.5h; Reagent/catalyst;621 mg
sirolimus
53123-88-9

sirolimus

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: (1-ethylpropyl)diisopropylamine / toluene / 30 °C
2: pyridine hydrogenfluoride / tetrahydrofuran / 3.5 h / 0 - 45 °C
View Scheme
Multi-step reaction with 2 steps
1.1: 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride / dichloromethane / 0.5 h / -40 °C
1.2: -40 - 40 °C
2.1: hydrogenchloride / methanol; water / 1 h / 0 - 25 °C / pH 1-3
View Scheme
Multi-step reaction with 2 steps
1: N-ethyl-N,N-diisopropylamine / toluene / 12 h / 60 °C
2: hydrogenchloride / methanol; water / 5 °C
View Scheme
40-O-[2-(triisopropylsilyl)oxy]ethyl-rapamycin

40-O-[2-(triisopropylsilyl)oxy]ethyl-rapamycin

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With hydrogenchloride; phosphoric acid; water In n-heptane; acetonitrile at 20℃; for 24h;64 %Chromat.
31,42-bis(trimethylsilylether)rapamycin
331810-13-0

31,42-bis(trimethylsilylether)rapamycin

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: hydrogenchloride / tetrahydrofuran / 5 h / Cooling with ice
2: hydrogenchloride / toluene; water / 6 h / 0 - 10 °C
3: hydrogenchloride / water; methanol / 4.5 h / Cooling with ice
View Scheme
Multi-step reaction with 3 steps
1: hydrogenchloride / ethyl acetate; water / Cooling with ice
2: N-ethyl-N,N-diisopropylamine / 1,2-dimethoxyethane; toluene / 4 h / 60 °C
3: hydrogenchloride / water; acetone / 1 h / 0 - 5 °C
View Scheme
Multi-step reaction with 3 steps
1: hydrogenchloride / water / Cooling with ice
2: N-ethyl-N,N-diisopropylamine / toluene; 1,2-dimethoxyethane / 4 h / 60 °C
3: hydrogenchloride / acetone / 1 h / 0 - 5 °C
View Scheme
C56H91NO14Si

C56H91NO14Si

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With hydrogenchloride In methanol; water for 4.5h; Cooling with ice;3.8 g
oxirane
75-21-8

oxirane

sirolimus
53123-88-9

sirolimus

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With trifluorormethanesulfonic acid In toluene at 70℃; under 7500.75 Torr; for 8h; Reagent/catalyst; Temperature; Pressure; Solvent; Autoclave;6.9 g
ethylene glycol
107-21-1

ethylene glycol

sirolimus
53123-88-9

sirolimus

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
Stage #1: ethylene glycol With trifluoroacetic anhydride In tetrahydrofuran at 10℃; for 1.5h; Inert atmosphere; Large scale;
Stage #2: sirolimus With boron trifluoride diethyl etherate In tetrahydrofuran at 10℃; for 2h; Temperature; Large scale;
5.7 kg
C56H91NO14Si

C56H91NO14Si

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With hydrogenchloride In water; acetonitrile at -10 - 0℃; for 0.5h;
C59H97NO14Si

C59H97NO14Si

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
With hydrogenchloride In water; acetonitrile at -10 - 0℃; for 0.5h;
31-(trimethylsilylether)rapamycin
331810-10-7

31-(trimethylsilylether)rapamycin

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: N-ethyl-N,N-diisopropylamine / 1,2-dimethoxyethane; toluene / 4 h / 60 °C
2: hydrogenchloride / water; acetone / 1 h / 0 - 5 °C
View Scheme
Multi-step reaction with 2 steps
1: N-ethyl-N,N-diisopropylamine / toluene; 1,2-dimethoxyethane / 4 h / 60 °C
2: hydrogenchloride / acetone / 1 h / 0 - 5 °C
View Scheme
31,42-bis(triethylsilylether)rapamycin
155435-45-3

31,42-bis(triethylsilylether)rapamycin

everolimus
159351-69-6

everolimus

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: sulfuric acid / acetone / 0 - 10 °C
2: N-ethyl-N,N-diisopropylamine / toluene / 4 h / 53 °C
3: sulfuric acid / tetrahydrofuran / 1 h / 0 - 10 °C
View Scheme
Multi-step reaction with 3 steps
1: sulfuric acid / acetone / 0 - 10 °C
2: N-ethyl-N,N-diisopropylamine / toluene; hexane / 2 h / 60 °C
3: sulfuric acid / tetrahydrofuran / 1 h / 0 - 10 °C
View Scheme
vinyl bromoacetate
5309-70-6

vinyl bromoacetate

everolimus
159351-69-6

everolimus

everolimus 42-bromoacetate
159351-81-2

everolimus 42-bromoacetate

Conditions
ConditionsYield
Novozym 435TM lipase In tert-butyl methyl ether at 35℃; for 10h; Molecular sieve;96%
at 20℃; for 4h; Enzymatic reaction;
everolimus
159351-69-6

everolimus

42-O-(2-fluoroethyl)rapamycin
1422173-29-2

42-O-(2-fluoroethyl)rapamycin

Conditions
ConditionsYield
With 1,3-bis(2,6-diisopropylphenyl)-2,2-difluoro-2,3-dihydro-1h-imidazole; N-ethyl-N,N-diisopropylamine In dichloromethane at 23℃; for 5h; Inert atmosphere;83%
Iodoacetic acid
64-69-7

Iodoacetic acid

everolimus
159351-69-6

everolimus

SDZ-RAD-iodoacetate ester

SDZ-RAD-iodoacetate ester

Conditions
ConditionsYield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; Inert atmosphere; Darkness;73%
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2.66667h;
2-{[tert-butyl(diphenyl)silyl]oxy}ethyl trifluoromethansulphonate

2-{[tert-butyl(diphenyl)silyl]oxy}ethyl trifluoromethansulphonate

everolimus
159351-69-6

everolimus

(35E,37E,39E,40E,48R,49S,50R,51R,53S,55S,57S,58S,59R,60R,69R)-58-[(1R)-2-[(1S,3R,4R)-4-[2-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]ethoxy]-3-methoxy-cyclohexyl]-1-methyl-ethyl]-59,69-dihydroxy-57,60-dimethoxy-48,49,50,51,61,62-hexamethyl-79,80-dioxa-71-azatricyclohexatriaconta-35,37,39(61),40(62)-tetraene-63,64,65,66,67-pentone

(35E,37E,39E,40E,48R,49S,50R,51R,53S,55S,57S,58S,59R,60R,69R)-58-[(1R)-2-[(1S,3R,4R)-4-[2-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]ethoxy]-3-methoxy-cyclohexyl]-1-methyl-ethyl]-59,69-dihydroxy-57,60-dimethoxy-48,49,50,51,61,62-hexamethyl-79,80-dioxa-71-azatricyclohexatriaconta-35,37,39(61),40(62)-tetraene-63,64,65,66,67-pentone

Conditions
ConditionsYield
With N-ethyl-N,N-diisopropylamine In toluene at 45℃; for 18h;59%
everolimus
159351-69-6

everolimus

C53H83NO14

C53H83NO14

Conditions
ConditionsYield
With zinc(II) chloride In tetrahydrofuran at 60℃; for 2h; Reagent/catalyst;45%
everolimus
159351-69-6

everolimus

(22E,24E,26E,27E,31R,32S,33R,34R,36S,38S,40S,41S,42S,43R,52R)-42,52-dihydroxy-41-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-40,43-dimethoxy-31,32,33,34,44,45-hexamethyl-62,63-dioxa-53-azatricyclohexatriaconta-22,24,26(44),27(45)-tetraene-46,47,48,49,50-pentone

(22E,24E,26E,27E,31R,32S,33R,34R,36S,38S,40S,41S,42S,43R,52R)-42,52-dihydroxy-41-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-40,43-dimethoxy-31,32,33,34,44,45-hexamethyl-62,63-dioxa-53-azatricyclohexatriaconta-22,24,26(44),27(45)-tetraene-46,47,48,49,50-pentone

Conditions
ConditionsYield
With titanium(IV) isopropylate In dichloromethane at 20℃;38%
everolimus
159351-69-6

everolimus

2,2'-[1,2-ethanediylbis(oxy)]bisethanol
112-27-6

2,2'-[1,2-ethanediylbis(oxy)]bisethanol

(21E,23E,25E,26E,36R,37S,38R,39R,41S,43S,46S,47R,48R,57R)-47,57-dihydroxy-45-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]-46-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-48-methoxy-36,37,38,39,49,50-hexamethyl-68,69-dioxa-58-azatricyclohexatriaconta-21,23,25(49),26(50)-tetraene-51,52,53,54,55-pentone

(21E,23E,25E,26E,36R,37S,38R,39R,41S,43S,46S,47R,48R,57R)-47,57-dihydroxy-45-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]-46-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-48-methoxy-36,37,38,39,49,50-hexamethyl-68,69-dioxa-58-azatricyclohexatriaconta-21,23,25(49),26(50)-tetraene-51,52,53,54,55-pentone

Conditions
ConditionsYield
With toluene-4-sulfonic acid In tetrahydrofuran; water at 20℃; for 2h;28%
everolimus
159351-69-6

everolimus

diethylene glycol
111-46-6

diethylene glycol

(21E,23E,25E,26E,34R,35S,36R,37R,39S,41S,44S,45R,46R,55R)-45,55-dihydroxy-43-[2-(2-hydroxyethoxy)ethoxy]-44-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-46-methoxy-34,35,36,37,47,48-hexamethyl-66,67-dioxa-56-azatricyclohexatriaconta-21,23,25(47),26(48)-tetraene-49,50,51,52,53-pentone

(21E,23E,25E,26E,34R,35S,36R,37R,39S,41S,44S,45R,46R,55R)-45,55-dihydroxy-43-[2-(2-hydroxyethoxy)ethoxy]-44-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-46-methoxy-34,35,36,37,47,48-hexamethyl-66,67-dioxa-56-azatricyclohexatriaconta-21,23,25(47),26(48)-tetraene-49,50,51,52,53-pentone

Conditions
ConditionsYield
With toluene-4-sulfonic acid In tetrahydrofuran; water at 20℃; for 2h;19%
Tetraethylene glycol
112-60-7

Tetraethylene glycol

everolimus
159351-69-6

everolimus

(21E,23E,25E,26E,38R,39S,40R,41R,43S,45S,48S,49R,50R,59R)-49,59-dihydroxy-47-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-48-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-50-methoxy-38,39,40,41,51,52-hexamethyl-70,71-dioxa-60-azatricyclohexatriaconta-21,23,25(51),26(52)-tetraene-53,54,55,56,57-pentone

(21E,23E,25E,26E,38R,39S,40R,41R,43S,45S,48S,49R,50R,59R)-49,59-dihydroxy-47-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-48-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-50-methoxy-38,39,40,41,51,52-hexamethyl-70,71-dioxa-60-azatricyclohexatriaconta-21,23,25(51),26(52)-tetraene-53,54,55,56,57-pentone

Conditions
ConditionsYield
With toluene-4-sulfonic acid In tetrahydrofuran; water at 20℃; for 2h;17%
heptaethylene glycol
5617-32-3

heptaethylene glycol

everolimus
159351-69-6

everolimus

(21E,23E,25E,26E,44R,45S,46R,47R,49S,51S,54S,55R,56R,65R)-55,65-dihydroxy-53-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-54-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-56-methoxy-44,45,46,47,57,58-hexamethyl-76,77-dioxa-66-azatricyclohexatriaconta-21,23,25(57),26(58)-tetraene-59,60,61,62,63-pentone

(21E,23E,25E,26E,44R,45S,46R,47R,49S,51S,54S,55R,56R,65R)-55,65-dihydroxy-53-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-54-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-56-methoxy-44,45,46,47,57,58-hexamethyl-76,77-dioxa-66-azatricyclohexatriaconta-21,23,25(57),26(58)-tetraene-59,60,61,62,63-pentone

Conditions
ConditionsYield
With toluene-4-sulfonic acid In tetrahydrofuran; water at 22℃; for 18h; Inert atmosphere;14%
everolimus
159351-69-6

everolimus

40-O-(2-hydroxy)ethyl rapamycin

40-O-(2-hydroxy)ethyl rapamycin

Conditions
ConditionsYield
With triethylammonium acetate In 1,4-dioxane; water at 22 - 28℃; for 4h;
1H-benzo[d][1,2,3]triazol-1-yl (2-(pyridin-2-yldisulfaneyl)ethyl) carbonate
913168-10-2

1H-benzo[d][1,2,3]triazol-1-yl (2-(pyridin-2-yldisulfaneyl)ethyl) carbonate

everolimus
159351-69-6

everolimus

everolimus (2'-pyridyldisulfanyl)ethyl carbonate
1312678-90-2

everolimus (2'-pyridyldisulfanyl)ethyl carbonate

Conditions
ConditionsYield
With dmap In dichloromethane for 0.5h; Inert atmosphere;
malonic acid
141-82-2

malonic acid

everolimus
159351-69-6

everolimus

C54H83NO15

C54H83NO15

Conditions
ConditionsYield
In methanol at 20℃; for 10h;

159351-69-6Relevant articles and documents

Preparation method and intermediate of everolimus

-

, (2021/12/07)

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method and an intermediate of everolimus. The invention provides three new everolimus intermediate compounds and a new route for synthesizing everolimus, rapamycin is protected step by step by adopting two protecting groups, 31-site byproducts do not exist, the problem of excessive hydrolysis is effectively avoided, meanwhile, the product yield and purity are greatly improved, the operation controllable range is wide, and the method is suitable for industrial large-scale production.

Preparation method of everolimus

-

, (2019/06/13)

The invention discloses a preparation method of everolimus. The preparation method comprises the following step of performing deprotection reaction on an everolimus intermediate C. The preparation method of everolimus adopts a manner of regioselective protection of rapamycin 28-hydroxyl, so that the selectivity of a 40-hydroxyl alkylation reaction is improved; side reactions are reduced; a total yield of everolimus calculated from rapamycin can reach above 70%; compared with yields reported in available literatures, the yield is greatly increased; a technical operation procedure is simplified;the product quality is ensured; and the preparation method has better industrial application and popularization prospects.

RAPAMYCIN ANALOGS AND USES THEREOF

-

Paragraph 00349; 00352, (2020/01/08)

The present invention provides compounds, compositions thereof, and methods of using the same.

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