159351-69-6

Basic information

• Product Name: Everolimus
• Synonyms: 23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine, rapamycin deriv;Everolimus solution ;Everolimus, >=98%;42-O-(2-Hydroxyethyl)-rapamycin;Certica;RAD-001;SDZRAD;Rapamycin, 42-O-(2-hydroxyethyl)-
• CAS NO: 159351-69-6
• Molecular Formula: C₅₃H₈₃NO₁₄
• Molecular Weight: 958.232
• EINECS: 1806241-263-5
• Product Categories: Akt;mTOR;PI3K;All Inhibitors;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Inhibitor;Antineoplastic protein kinase inhibitors;mTOR inhibitor;Certican, Zortress, Afinitor;Anti-cancer&immunity;PI3K/Akt/mTOR;Everolimus
• Mol File: 159351-69-6.mol

Chemical Properties

• Melting Point: NA
• Boiling Point: 998.7 °C at 760 mmHg
• Flash Point: 2℃
• Appearance: off white solid
• Density: 1.18 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.548
• Storage Temp.: −20°C
• Solubility: Soluble in DMSO (up to 100 mg/ml) or in Ethanol (up to 100 mg/ml).
• PKA: 10.40±0.70(Predicted)
• Water Solubility: Soluble in dimethysulfoxide,ethanol and chloroform. Slightly soluble in water.
• Stability: Hygroscopic
• CAS DataBase Reference: Everolimus(CAS DataBase Reference)
• NIST Chemistry Reference: Everolimus(159351-69-6)
• EPA Substance Registry System: Everolimus(159351-69-6)

Safety Data

• Hazard Codes: T,Xn,F
• Statements: 48/25-36-20/21/22-11
• Safety Statements: 45-36/37-26-16
• RIDADR: UN 1648 3 / PGII
• WGK Germany: 2
• F: 10
• Hazardous Substances Data: 159351-69-6(Hazardous Substances Data)

Usage

Uses

Used in Transplantation Medicine:
Everolimus is used as an immunosuppressant to prevent rejection of organ transplants. It is marketed under the trade names Zortress (USA) and Certican (Europe) and is often used in conjunction with cyclosporin.
Used in Oncology:
Everolimus is used for the treatment of various types of tumors, including renal cell cancer. It is marketed under the trade names Afinitor (general tumors) and Votubia (tumors as a result of TSC). It inhibits cytokine-mediated lymphocyte proliferation and has shown to reduce the incidence of efficacy failure and cardiac allograft vasculopathy (CAV) in transplant patients.
Used in Drug Development:
Everolimus is a starting material for calibrators, controls, or linearity standards for therapeutic drug monitoring or clinical and diagnostic testing in patient whole blood samples by LC-MS/MS.
Used in Pharmaceutical Formulation:
The 40-O-(2-hydroxyethyl) group in Everolimus alters the physico-chemical properties of the macrolide, allowing for galenic formulation and improved pharmacokinetics compared to Rapamycin.
Everolimus is extensively metabolized, primarily by CYP3A4, and is well-tolerated in transplant patients. However, it may cause adverse events such as thrombocytopenia, leucopenia, and elevated serum lipids and creatinine.

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

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

References

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

Originator

Novartis (Switzerland)

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.

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

Synthetic route

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

Conditions	Yield
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 → everolimus (159351-69-6)

Conditions	Yield
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 → everolimus (159351-69-6)

Conditions	Yield
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 → everolimus (159351-69-6)

Conditions	Yield
With hydrogenchloride In methanol; water at 5℃; pH=3 - 4;	68%

42-O-[2(tetrahydrofuran-2-oxy)ethyl]rapamycin → everolimus (159351-69-6)

Conditions	Yield
With hydrogenchloride In methanol; water at 5℃;	67%

42-O-[2-(1-ethoxyethoxy)ethyl]rapamycin → everolimus (159351-69-6)

Conditions	Yield
With hydrogenchloride In methanol; water at 5℃;	65%

42-O-[2(tetrahydro-2H-furan-2-oxy)ethyl]rapamycin → everolimus (159351-69-6)

Conditions	Yield
With hydrogenchloride In methanol; water at 5℃;	61%

42-O-[2-(methoxymethoxy)ethyl]rapamycin → everolimus (159351-69-6)

Conditions	Yield
With hydrogenchloride In methanol; water at 5℃;	55%

40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (159351-68-5) → everolimus (159351-69-6)

Conditions	Yield
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) → everolimus (159351-69-6)

Conditions	Yield
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) → everolimus (159351-69-6)

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

C74H101NO16 → everolimus (159351-69-6)

Conditions	Yield
With 1,1,1,3',3',3'-hexafluoro-propanol at 50℃; for 1.5h; Reagent/catalyst;	621 mg

sirolimus (53123-88-9) → everolimus (159351-69-6)

Conditions	Yield
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 → everolimus (159351-69-6)

Conditions	Yield
With hydrogenchloride; phosphoric acid; water In n-heptane; acetonitrile at 20℃; for 24h;	64 %Chromat.

31,42-bis(trimethylsilylether)rapamycin (331810-13-0) → everolimus (159351-69-6)

Conditions	Yield
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 → everolimus (159351-69-6)

Conditions	Yield
With hydrogenchloride In methanol; water for 4.5h; Cooling with ice;	3.8 g

oxirane (75-21-8) + sirolimus (53123-88-9) → everolimus (159351-69-6)

Conditions	Yield
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) + sirolimus (53123-88-9) → everolimus (159351-69-6)

Conditions	Yield
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 → everolimus (159351-69-6)

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

C59H97NO14Si → everolimus (159351-69-6)

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

31-(trimethylsilylether)rapamycin (331810-10-7) → everolimus (159351-69-6)

Conditions	Yield
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) → everolimus (159351-69-6)

Conditions	Yield
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) + everolimus (159351-69-6) → everolimus 42-bromoacetate (159351-81-2)

Conditions	Yield
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) → 42-O-(2-fluoroethyl)rapamycin (1422173-29-2)

Conditions	Yield
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) + everolimus (159351-69-6) → SDZ-RAD-iodoacetate ester

Conditions	Yield
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 + everolimus (159351-69-6) → (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	Yield
With N-ethyl-N,N-diisopropylamine In toluene at 45℃; for 18h;	59%

everolimus (159351-69-6) → C53H83NO14

Conditions	Yield
With zinc(II) chloride In tetrahydrofuran at 60℃; for 2h; Reagent/catalyst;	45%

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

everolimus (159351-69-6) + 2,2'-[1,2-ethanediylbis(oxy)]bisethanol (112-27-6) → (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	Yield
With toluene-4-sulfonic acid In tetrahydrofuran; water at 20℃; for 2h;	28%

everolimus (159351-69-6) + diethylene glycol (111-46-6) → (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	Yield
With toluene-4-sulfonic acid In tetrahydrofuran; water at 20℃; for 2h;	19%

Tetraethylene glycol (112-60-7) + everolimus (159351-69-6) → (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	Yield
With toluene-4-sulfonic acid In tetrahydrofuran; water at 20℃; for 2h;	17%

heptaethylene glycol (5617-32-3) + everolimus (159351-69-6) → (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	Yield
With toluene-4-sulfonic acid In tetrahydrofuran; water at 22℃; for 18h; Inert atmosphere;	14%

everolimus (159351-69-6) → 40-O-(2-hydroxy)ethyl rapamycin

Conditions	Yield
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) + everolimus (159351-69-6) → everolimus (2'-pyridyldisulfanyl)ethyl carbonate (1312678-90-2)

Conditions	Yield
With dmap In dichloromethane for 0.5h; Inert atmosphere;

malonic acid (141-82-2) + everolimus (159351-69-6) → C54H83NO15

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

Upstream product

• 1392400-31-5 40-O-[2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl] rapamycin 
• 53123-88-9 sirolimus 
• 159351-68-5 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin 
• 331810-13-0 31,42-bis(trimethylsilylether)rapamycin 
• 75-21-8 oxirane 
• 331810-10-7 31-(trimethylsilylether)rapamycin 
• 155435-45-3 31,42-bis(triethylsilylether)rapamycin 
• 107-21-1 ethylene glycol 

Downstream Products

• 159351-81-2 everolimus 42-bromoacetate 
• 159351-68-5 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin 
• 1314705-20-8 40-O-[2-(t-butyldiphenylsilyl)oxy]ethyl-rapamycin 

Relevant articles and documents

Preparation method and intermediate of everolimus

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.

Purification method of everolimus

The invention provides a purification method of everolimus. According to the method, derivatization, separation and hydrolysis are carried out on everolimus, the treated everolimus has greatly reducedimpurity rapamycin content, and further by means of one-time preparation of liquid phase for purification, a high purity product with high yield can be obtained, thereby reducing the industrial costof the purification steps. The invention also further provides a preparation method of everolimus. The method has the advantages of high yield and simple operation, and is suitable for industrial production.

Everolimus intermediate, and preparation method and application thereof

The invention discloses an everolimus intermediate, and a preparation method and an application of the everolimus intermediate. A structure of the everolimus intermediate C is shown as formula (1) asshown in the specification. The preparation method comprises the following step: allowing 28-monosilicon protected rapamycin (an everolimus intermediate B) to react with trifluoromethanesulfonic acidsingle-protection glycol ester in the presence of organic base. The invention further discloses the application of the everolimus intermediate C. The preparation method of the everolimus intermediateis simple and high in yield; everolimus prepared from the intermediate can reduce side reactions; a technical operation procedure is simplified; the total yield is increased; the product quality is ensured; and therefore, the preparation method has better industrial application and popularization prospects.

Preparation method of everolimus

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

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

A preparation method of not takes charge of according to uygur

The invention relates to a preparation method of everolimus. The preparation method of everolimus comprises the following step: carrying out one-step reaction on rapamycin and ethylene oxide in presence of strong acid, so that everolimus is obtained. The preparation method of everolimus has the advantages that the process is simple, the after-treatment is convenient, the product yield is high, and the quality is good, so that the preparation method of everolimus is applicable to industrial production.

A method of drying not takes charge of according to Uygur (by machine translation)

The invention discloses a not takes charge of according to Uygur post treatment method, in particular for the ivermectin Mo-division and crude drying method, the drying method to obtain ivermectin Mo after si Cupin, adding water, solid precipitation, filtration, solid taken out -20 °C storage, preparation, to obtain the pure product after dissolving with ethanol, is added to the purification in the water drop, separating out the filter, solid nitrogen gas at 0 °C under, dry 24 hours. (by machine translation)

Preparation method of everolimus

The invention relates to the technical field of medicine production, in particular to a preparation method of everolimus. Glycol and acid anhydride react to obtain a transient midbody (formula I), then, the midbody reacts with sirolimus (formula II) under the catalysis of lewis acid to generate a crude everolimus (formula III), and everolimus is obtained through refining. According to the technical scheme, the reaction cycle is short, operation is simple, and the everolimus is suitable mass production.

METHOD FOR THE SYNTHESIS OF RAPAMYCIN DERIVATIVES

The present invention relates to a method for the production of a rapamycin derivative of formula (I), the method comprising the preparation of a 2-(tri-substituted silyl)oxyethyl triflate by reacting ethylene oxide and a tri-substituted silyl triflate, reaction of the resulting 2-(tri-substituted silyl)oxyethyl triflate with rapamycin in the presence of a molar excess of organic base, and deprotection to obtain the rapamycin derivative of compound (I).

Method for preparing everolimus

The invention discloses a method for preparing everolimus. The method includes the following steps that rapamycin and trimethylchlorosilane react so as to achieve double protection of hydroxyl groups in positions 31 and 40, and acidic hydrolysis is conducted to obtain an intermediate 1 with the protected hydroxyl group in the position 31; the intermediate 1 and ethylene oxide have a condensation reaction to obtain an intermediate 2, the intermediate 2 is subjected to acidic hydrolysis to obtain an everolimus crude product, and the crude product is separated and purified by means of a preparation liquid phase to obtain everolimus.