- Preparation method and intermediate of everolimus
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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.
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- Everolimus intermediate, and preparation method and application thereof
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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.
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- Preparation method of everolimus
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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.
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- Purification method of everolimus
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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.
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Paragraph 0081; 0087; 0088; 0089
(2019/01/24)
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- RAPAMYCIN ANALOGS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00349; 00352
(2020/01/08)
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- A preparation method of not takes charge of according to uygur
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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.
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Paragraph 0035-0050
(2017/12/06)
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- A method of drying not takes charge of according to Uygur (by machine translation)
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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)
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Paragraph 0023
(2017/08/23)
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- Preparation method of everolimus
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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.
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Paragraph 0037; 0038; 0039; 0040; 0041; 0042; 0043-0056
(2017/07/20)
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- Method for preparing everolimus
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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.
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Paragraph 0020; 0022; 0032; 0033; 0034; 0035
(2017/06/02)
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- METHOD FOR THE SYNTHESIS OF RAPAMYCIN DERIVATIVES
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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).
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Page/Page column 14
(2017/01/09)
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- Everolimus preparation method
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The present invention discloses an everolimus preparation method, which comprises: a) carrying out a reaction of rapamycin and ethylene glycol mono trifluoromethanesulfonate represented by a formula II and containing an acetal protection group under the effect of an organic alkali, and carrying out column chromatography to obtain an intermediate represented by a formula III; and b) carrying out an acetal protection group removing reaction on the intermediate represented by the formula III and obtained in the step a) under the acid condition of the pH value of 2-4, and carrying out column chromatography to obtain the everolimus represented by a formula I. According to the present invention, the inexpensive and easily-available ethylene glycol mono trifluoromethanesulfonate is used to react with the rapamycin, such that the advantages of convenient hydroxy protection and removal reactions, high reaction yield, low toxicity of the used reagents, easy intermediate and product separation, and the like; and the unreacted rapamycin can be recycled through the column chromatography treatment, the product quality is ensured, the yield is improved, the cost is reduced, and the industrial application values are provided.
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Paragraph 0052; 0056; 0057
(2017/01/17)
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- PROCESS FOR THE SYNTHESIS OF EVEROLIMUS AND INTERMEDIATES THEREOF
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The present invention relates to a novel process for the synthesis of everolimus of formula (I) and intermediates thereof.
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Page/Page column 22
(2016/04/09)
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- Process for preparing not takes charge of according to Uygur
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The invention provides a preparation technology for everolimus. The preparation method comprises the two steps of: 1) reacting sirolimus with 2-(tert-butyldiMethylsilyloxy) ethyl trifluoromethane sulfonate in the presence of proper solvent and organic base, to obtain an intermediate A; 2) reacting the intermediate A with inorganic acid in an organic solvent to obtain everolimus, wherein the organic base used in the step 1) is selected from large-steric hindrance or non-nucleophilic bases such as triethylamine, N,N-diisopropylethylamine, 1,8-diazabicycloundec-7-ene or N-methylmorpholine, acid used in the step 2) is hydrochloric acid, sulfuric acid or phosphoric acid. According to the technology, the total yield in the two steps and the purity of a final product are greatly improved as compared with those reported by the existing literature, the process route is short, the reaction conditions are mild, and the reaction result is also stable and reliable.
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Paragraph 0027; 0030; 0031
(2016/10/07)
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- METHOD FOR PREPARING EVEROLIMUS AND ITS INTERMEDIATES
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The present invention relates to a manufacturing method of everolimus and an intermediate thereof, and more specifically, to a manufacturing method comprising: a first step of manufacturing a compound of chemical formula 2 by reacting rapamycin of chemical formula 3 and 2-(trityl oxy)ethyl methane sulfonate; and a second step of manufacturing the everolimus of chemical formula 1 by deprotecting the manufactured compound of the chemical formula 2. The present invention is able to manufacture the everolimus with a high yield using a easier and simpler method compared to conventional methods. In the chemical formula 2, R1 is triphenyl methane.COPYRIGHT KIPO 2015
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Paragraph 0071-0072
(2016/12/22)
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- RAFAMYCIN ANALOGS AND METHODS FOR MAKING SAME
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A semi-synthetic rapamycin analog with a triazole moiety or a pharmaceutically acceptable salt or prodrug thereof, is a broad-spectrum cytostatic agent and a mTOR inhibitor, and is useful in the treatment of various cancers, or tumors in organs such as kidney, liver, breast, head and neck, lung, prostate, and restenosis in coronary arteries, peripheral arteries, and arteries in the brain, immune and autoimmune diseases. Also disclosed are fungal growth-, restenosis-, post-transplant tissue rejection- and immune- and autoimmune disease-inhibiting compositions and a method of inhibiting cancer, fungal growth, restenosois, post-transplant tissue rejection, and immune and autoimmune disease in a mammal. One particular preferred application of such triazole-moiety containing rapamycin analog is in treating renal carcinoma, lung cancer, colon cancer, and breast cancers wherein potency of the drug, its half-life, tissue distribution properties, and its pharmacokinetic properties including bioavailability through oral and intravenous routes are essential to the clinical outcomes.
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Paragraph 0086
(2015/02/25)
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- ALKYLATION WITH AN ALKYL FLUOROALKYL SULFONATE
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The present invention discloses a process for preparing a chemical compound comprising reacting a nucleophile with an alkyl fluoroalkyi sulfonate in the presence of a base of formula NR1 R2R3, wherein R1 and R2 are independently 2-methylpropyl or isopropyl and R3 is - CH(R4)(R5), wherein R4 and R5 are identical or different alkyls that are optionally connected to form a ring. The invention also relates to a process for preparing an alkyl fluoroalkyi sulfonate. The invention further relates to a use of the base in a chemical reaction comprising an alkyl fluoroalkyi sulfonate. The process and uses are suitable for preparing chemical compounds, reactants or intermediates thereof, and in particular for preparing API or reactants, like for example everolimus or reactants for its preparation.
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Page/Page column 21; 22
(2015/01/07)
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- RAFAMYCIN ANALOGS AND METHODS FOR MAKING SAME
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A semi-synthetic rapamycin analog with a triazole moiety or a pharmaceutically acceptable salt or prodrug thereof, is a broad-spectrum cytostatic agent and a m TOR inhibitor, and is useful in the treatment of various cancers, or tumors in organs such as kidney, liver, breast, head and neck, lung, prostate, and restenosis in coronary arteries, peripheral arteries, and arteries in the brain, immune and autoimmune diseases. Also disclosed are fungal growth-, restenosis-, post- transplant tissue rejection- and immune- and autoimmune disease- inhibiting compositions and a method of inhibiting cancer, fungal growth, restenosois, post-transplant tissue rejection, and immune and autoimmune disease in a mammal. One particular preferred application of such triazole-moiety containing rapamycin analog is in treating renal carcinoma, lung cancer, colon cancer, and breast cancers wherein potency of the drug, its half-life, tissue distribution properties, and its pharmacokinetic properties including bioavailability through oral and intravenous routes are essential to the clinical outcomes.
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Paragraph 50
(2014/06/23)
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- PROCESS FOR MAKING EVEROLIMUS
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An improved process of making the compound everolimus is disclosed. The process is based on a reaction of rapamycin with 2-(t-hexyldimethylsilyloxy)ethyl triflate of formula (3C) in an inert solvent in the presence of a base, to form 40-O-2-(t-hexyldimethylsilyloxy)ethylrapamycin which is deprotected by an acid to form everolimus.
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Page/Page column 18
(2012/08/27)
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- METHOD OF PURIFYING MACROLIDES
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Provided is a method of purifying a macrolide, especially tacrolimus, that includes loading macrolide onto a bed of sorption resin and elting with a suitable eluent such as a combination of water and tetrahydrofuran.
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- O-methylated rapamycin derivatives for alleviation and inhibition of lymphoproliferative disorders
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The present invention relates to methods of alleviating and inhibiting a lymphoproliferative disorder in a mammal, the method comprising administering one or more rapamycin derivatives (including rapamycin) to the mammal. Further, the invention provides a method for identifying agents which are useful for alleviating and inhibiting a lymphoproliferative disorders, as well as a method for identifying agents which are capable of inhibiting metastasis of lymphatic tumors in a mammal.
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