- Preparation method of irinotecan hydrochloride
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The invention relates to a preparation method of irinotecan hydrochloride. The preparation method comprises the following steps: a) enabling 4-piperidylpiperidine and N, N'-carbonyldiimidazole to react with 7-ethyl-10-hydroxycamptothecine in an aprotic solvent containing a hemp and cotton resin compound to generate an irinotecan monomer, and b) adding water to dissolve the irinotecan monomer, adding a hydrochloric acid solution to adjust the pH value to 2-3, adding acetone of which the volume is 3-5 times that of the water, carrying out crystallizing, filtering and recrystallizing with a mixedsolvent of acetone and water, and carrying out vacuum drying to obtain the irinotecan hydrochloride finished product. Compared with the prior art, according to the invention, in preparatuion of irinotecan hydrochloride, no high-toxicity dangerous reagent is used, the N, N-dimethylformamide with relatively stable commercial easy-to-obtain property is used, a carbonyl group is introduced into N, N'-carbonyldiimidazole, an irinotecan monomer is obtained through a one-step reaction, the harsh condition that N, N'-carbonyldiimidazole needs to be anhydrous is avoided through cooperation with a hempand cotton resin compound, the reaction process is greatly simplified, the production period is shortened, and the preparation method has obvious industrial production advantages.
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Paragraph 0019; 0022; 0025; 0028; 0031
(2020/05/30)
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- A preparation method of irinotecan hydrochloride (by machine translation)
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The invention relates to a preparation method of irinotecan hydrochloride. Its steps are: parent ring to camptothecin as raw material generated by the reaction with the aldehyde 7 - ethyl camptothecin; hydrogen peroxide oxidation then N - oxide - 7 - ethyl camptothecin; by the illumination rearrangement 7 - ethyl - 10 - hydroxy camptothecin; 4 - piperidyl with dimethyl carbonate reaction to produce 4 - piperidyl carbonic acid methyl ester; 7 - ethyl - 10 - hydroxy camptothecin with 4 - piperidyl carbonic acid methyl ester reaction generating irinotecan monomer; irinotecan monomers with hydrochloric salt to obtain the finished product of the irinotecan hydrochloride. Compared with the prior art, the present invention avoid the use of phosgene in the reaction process, chloroform poisonous substance, in production with safe, convenient, less pollution and the like; in addition, the synthetic method avoids the need of the prior process in the defects of the chromatographic column separation and purification, reduces the production cost of the irinotecan, has great economic benefit. (by machine translation)
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- Visible-Light-Induced Radical Cascade Cyclization: Synthesis of (20S)-Camptothecin, SN-38 and Irinotecan
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(20S)-Camptothecin, irinotecan and SN-38 were successfully synthesized by a photocatalyzed radical cascade cyclization from an N-propargyl iodopyridinone and an arylisonitrile under visible light with a ruthenium catalyst. This synthetic method provided a useful entry into composing camptothecin family of antitumor agents in good yields under mild reaction conditions without the use of heavy metal reagents.
- Yuan, Yao,Dong, Wuheng,Gao, Xiaoshuang,Xie, Xiaomin,Curran, Dennis P.,Zhang, Zhaoguo
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p. 1035 - 1040
(2018/09/25)
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- Irinotecan-cholesterol succinic acid simple lipid ion pair, liposome and preparation method and application thereof
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The invention discloses an irinotecan-cholesterol succinic acid simple lipid ion pair, a liposome and a preparation method and application thereof. The cholesterol succinic acid simple lipid is used as a counter-ionic agent, and the active proton of carboxyl in the cholesterol succinic acid simple lipid structure transfers to the nitrogen of irinotecan amino group, a coordination bond is formed, an ion pair is formed with irinotecan, so that the lipid solubility of irinotecan is improved, and the simple preparation method is easily used for packaging the drug on a phospholipid layer of the liposome, and the drug loading and packaging efficiency are improved. According to the irinotecan-cholesterol succinic acid simple lipid ion pair, the liposome and the preparation method and applicationthereof, the hydrophobic ion pair technology is combined with the nano drug delivery system, the lipid solubility of the insoluble drugs is improved, nano-preparations are developed, the complexity ofthe preparation process is simplified, and the irinotecan-cholesterol succinic acid simple lipid ion pair, the liposome and the preparation method and application thereof is conducive to expanding the industrial production. In addition, irinotecan ion pair and the liposome releases faster in the meta-acid environment, certain pH sensitivity is achieved, good antitumor effect and safety are achieved, and good application is achieved.
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Paragraph 0045; 0046; 0047
(2018/10/11)
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- Method for producing irinotecan
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PROBLEM TO BE SOLVED: To provide a novel method for producing irinotecan using amines.SOLUTION: A method of producing irinotecan represented by the chemical formula (1) includes reacting 7-ethyl-10-hydroxycamptothecin with 1-chlorocarbonyl-4-piperidinopiperidine or hydrochloride thereof in the presence of a nonaromatic tertiary amine having 5 or less carbon atoms.
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Paragraph 0041
(2018/10/10)
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- Method for the synthesis of irinotecan
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The present invention relates to a method for the synthesis of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (i.e. iriniotecan), comprising: (a) preparing 10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptotecin; and (b) selectively ethylating the compound of step (a) at the 7-position, thus resulting in the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin. The present invention is further directed to a method for the synthesis of 10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (i.e. 7-des-ethyl-irinotecan) which is used as an intermediate in the synthesis of irinotecan.
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Paragraph 0050-0052; 0053-0055
(2015/06/17)
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- Scalable synthetic route to 2-amino-5-hydroxypropiophenone: Efficient formal synthesis of irinotecan
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2-Amino-5-hydroxypropiophenone, a key precursor in the total synthesis of irinotecan, has been synthesized. Regioselective nitration and a SNAr displacement are the key steps involved in this strategy, which is high yielding, is economical, and has been performed on a plant scale. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications1 to view the free supplemental file. Copyright Taylor & Francis Group, LLC.
- Rao, A. V. Rama,Rao, Ramakrishna,Yadav,Khagga, Mukkanti
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p. 1661 - 1667
(2013/05/21)
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- NOVEL POLYMORPH OF IRINOTECAN HYDROCHLORIDE
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The present invention provides a novel crystalline form of irinotecan hydrochloride, process for its preparation and pharmaceutical compositions comprising it. Thus, for example, irinotecan hydrochloride trihydrate was dissolved in a mixture of methanol and methylene dichloride, the solvent was distilled off and then added acetone, and stirred for 18 hour at room temperature, filtered and dried to obtain irinotecan hydrochloride crystalline form H1.
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Page/Page column 5-6
(2012/02/02)
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- PROCESS FOR THE MANUFACTURE OF IRINOTECAN HYDROCHLORIDE BY TOTAL SYNTHESIS
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Disclosed herein is a highly safe and easily scalable process for the production of 7-Ethyl- 10-hydroxycamptothecin and its conversion to Irinotecan hydrochloride by total synthesis.
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- PROCESS FOR THE PREPARATION OF 7-ETHYL-10-[4- (1-PIPERIDINO)- 1-PIPERIDINO] CARBONYLOXY-CAMPTOTHECIN HYDROCHLORIDE TRIHYDRATE
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The present invention relates to process for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin hydrochloride trihydrate and process for the isolation of 1-chlorocarbonyl-4-piperidinopiperidine and novel crystalline form of 1-chlorocarbonyl-4-piperidinopiperidine and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin.
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Page/Page column 7
(2011/06/26)
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- Process for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin hydrochloride trihydrate
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The present invention relates to process for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin hydrochloride trihydrate and process for the isolation of 1-chlorocarbonyl-4-piperidinopiperidine and novel crystalline form of 1-chlorocarbonyl-4-piperidinopiperidine and 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin.
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Page/Page column 9
(2011/07/30)
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- THERAPEUTIC FOR HEPATIC CANCER
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A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
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- Simultaneous determination of irinotecan hydrochloride and its related compounds by high performance liquid chromatography using ultraviolet detection
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A new simple, precise and accurate high performance liquid chromatography (HPLC) method was developed and validated for the simultaneous determination of irinotecan (CPT-11) and two related compounds viz., 7-ethyl-10-hydroxycamptothecin (SN-38) and camptothecin (CPT) in pharmaceutical dosage forms. Chromatography was accomplished using a reversed-phase C18 column and ultraviolet (UV) detection and an isocratic mobile phase consisting of 3% v/v triethylammonium acetate buffer (pH 3) and acetonitrile (70:30 v/v). The linear range of quantitation for all the compounds was 0.1-10 μg/mL. The limit of quantitation for all the compounds ranged between 0.01-0.05 μg/mL. The method has the requisite accuracy, selectivity, sensitivity and precision to assay of CPT-11 and related compounds in pharmaceutical dosage forms and bulk API.
- Mohammadi, Ali,Esmaeili, Farnaz,Dinarvand, Rassoul,Atyabi, Fatemeh,Walker, Roderick B.
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scheme or table
p. 3966 - 3972
(2010/11/18)
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- Multifunctional Forms of Polyoxazoline Copolymers and Drug Compositions Comprising the Same
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The present disclosure provides copolymers of 2-substituted-2-oxazolines possessing two or three reactive functional groups which are also chemically orthogonal. The copolymers described may be random copolymers, block copolymers or a mixture of random and block copolymer configurations. Furthermore, the present disclosure provides novel methods for synthesizing the above polymers and for conjugating to molecules such as targeting, diagnostic and therapeutic agents.
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- Therapeutic use of at least one botulinum neurotoxin in the treatment of pain induced by at least one anti-neoplastic agent
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The present invention relates to a method of treating or preventing pain or pains induced by an anti-neoplastic agent, comprising the step of administering an effective amount of at least one botulinum neurotoxin to a patient in need thereof.
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- Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
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Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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- PROCESS FOR PRODUCTION OF CAMPTOTHECIN DERIVATIVE
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Disclosed is a process for production of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycampto thecin from a camptothecin composition containing 18,19-dehydrocamptothecin without producing any vinyl form of the compound. The process is characterized by catalytically reducing at least one compound selected from a compound (1) and others in the process of producing a compound (5) from a composition containing the compound (1).
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Page/Page column 8-9
(2009/01/24)
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- NOVEL INTERMEDIATES FOR THE PREPARATION OF CAMPTOTHECIN ANALOGUES
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The present invention relates to novel intermediate compounds of formula (Ia) and its salts thereof, wherein R is an amino protecting group, R1 is selected from the group consisting of hydrogen, an alkyl, araalkyl, hydroxymethyl, carboxymethyl, acyloxymethyl, trialkylsilyl or an N-substituted alkyl amine where nitrogen forms the linking atom. The invention also relates to the use of these novel intermediate compounds of formula (Ia) for the preparation of camptothecin analogues and its salts, more particularly the anti-cancer drug irinotecan and its pharmaceutically accepted salts.
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Page/Page column 10
(2008/06/13)
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- METHODS FOR PREPARING IRINOTECAN
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Methods for manufacturing 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy-camptothecin are described comprising I. reacting a mixture of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride and 7-ethyl-10-hydroxycamptothecin in a polar aprotic solvent with a base in the presence of catalytic amounts of a N-containing cyclic organic compound having 3 to 20 carbon atoms and optionally in the presence of a water binding agent in an amount which effectively binds any water present in the above reactants and solvents; or II. reacting: (a) 7-Ethyl-10-hydroxycamptothecin in a polar aprotic solvent with phosgene, trichlormethyl-chloroformate, bis(trichloromethyl)carbonate or a alternative to phosgene and a base in the presence of catalytic amounts of a N-containing cyclic organic compound having 3 to 20 carbon atoms; and (b) subsequently with piperidinopiperidine and an amine base.
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Page/Page column 2-3
(2010/11/27)
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- PROCESS FOR PREPARING IRINOTECAN
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The present invention relates to a process for the preparation of pure irinotecan or salts thereof, and a process for the preparation of intermediate compound 7-ethyl-10-hydroxycamptothecin.
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Page/Page column 7; 7-8
(2008/06/13)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF IRINOTECAN HYDROCHLORIDE TRIHYDRATE
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The invention relates to an improved process for the preparation of Irinotecan hydrochloride trihydrate of formula (4) of enhanced yield, purity by contacting 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride with 7-ethyl-10 hydroxy-camptothecin [IRT-3 (synthetic)] to obtain crude Irinotecan which is subsequently purified by solvent treatment, obtaining purified irinotecan which is converted into irinotecan hydrochloride trihydrate and the invention also relates to a report of the compound 1-chlorocorbonyl-4-iperidinopiperidine hydrochloride of formula (1) and its process for preparation.
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Page/Page column 10
(2010/10/20)
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- Process to prepare camptothecin derivatives and novel intermediate and compounds thereof
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New processes are disclosed for the preparation of camptothecin derivatives, such as, irinotecan and topotecan, as well as new intermediates and compounds related thereof.
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Page/Page column 13; 4/8
(2008/06/13)
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- Process to prepare camptothecin derivatives
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A process is provided for the preparation of camptothecin derivatives, such as irinotecan, in a one-pot operation.
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Page/Page column 6
(2008/06/13)
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- COMPOUNDS USEFUL IN PREPARING CAMPTOTHECIN DERIVATIVES
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Novel compounds are provided having the formula and salts thereof, where R1 is hydrogen, an alkyl, aralkyl, hydroxymethyl, carboxymethyl, acyloxymethyl or trialkylsilyl group, or a group —CH2NR3R4 where N is a linking nitrogen atom and where (a) R3 and R4 are independently selected from hydrogen and alkyl, alkenyl, hydroxyalkyl and alkoxyalkyl groups; (b) R3 is hydrogen or an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl group, and R4 is —COR5 where R5 is hydrogen or an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl group; or (c) R3 and R4 taken together with the linking nitrogen atom form a saturated 3- to 7-member heterocyclic group. These compounds are useful intermediates in a process to prepare camptothecin derivatives including the anti-cancer drug irinotecan.
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Page/Page column 3
(2008/06/13)
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- METHOD OF MANUFACTURING OF 7-ETHYL-10-[4-(1-PIPERIDINO)--1- PIPERIDINO]- CARBONYLOXYCAMPTOTHECIN
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The invention relates to the method of manufacturing of 7-ethyl-10-[4-(1-piperidino)--1-piperidino]-carbonyloxycamptothecin by condensation of 7-ethyl-l0-hydroxycamptothecin with 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride in a polar aprotic solvent in the presence of 4-dimethylaminopyridine.
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Page/Page column 4
(2008/06/13)
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- METHOD OF SYNTHESIZING CAMPTOTHECIN-RELATING COMPOUNDS
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The present invention is to prepare efficiently 2'-amino-5'-hydroxypropiophenone corresponding to the AB-ring part of camptothecin (CPT) skeleton and a tricyclic ketone corresponding to the CDE-ring part in order to provide efficiently CPT by the total synthesis, which is a starting material for irinotecan hydrochloride and various kinds of camptothecin derivatives, and to provide stably CPT and its derivatives.
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- PHARMACIA CORPORATION
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Novel compounds are provided having formula (I) and salts thereof, where R1 is hydrogen, an alkyl, aralkyl, hydroxymethyl, carboxymethyl, acyloxymethyl or trialkylsilyl group, or a group -CH2NR3R4 where N is a linking nitrogen atom and where (a) R3 and R4 are independently selected from hydrogen and alkyl, alkenyl, hydroxyalkyl and alkoxyalkyl groups; (b) R3 is hydrogen or an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl group, and R4 is -COR5 where R5 is hydrogen or an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl group; or (c) R3 and R4 taken together with the linking nitrogen atom form a saturated 3- to 7-member heterocyclic group. These compounds are useful intermediates in a process to prepare camptothecin derivatives including the anti-cancer drug irinotecan.
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Page/Page column 7
(2008/06/13)
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- Antiangiogenic combination therapy for the treatment of cancer
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The present invention provides combinations of a DNA topoisomerase I inhibiting agent and a selective COX-2 inhibiting agent for preventing, treating, and/or reducing the risk of developing a neoplasia disorder in a mammal.
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- A general synthetic approach to the (20s)-camptothecin family of antitumor agents by a regiocontrolled cascade radical cyclization of aryl isonitriles
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A general and efficient synthesis of (20S)-camptothecin (1a) is reported. A key common intermediate containing the pyridone and lactone (DE) rings of camptothecin and most derivatives was constructed from 2-trimethylsilyl-6-methoxypyridine by a series of metalation reactions and a Heck cyclization to provide an achiral bicyclic enol ether. Sharpless asymmetric dihydroxylation followed by lactol oxidation and iododesilylation produced the key intermediate in 94% enantiomeric excess. Alkylation with prop-argyl bromide and a cascade radical reaction with phenyl isonitrile then produced 1a. About 20 other penta-and hexacyclic analogues of camptothecin with differing single or multiple substituents at C7, C9, C10, C11, and/or C12 were made by changing the propargylating agent and the isonitrile. Included among these are several drug candidates and the approved drugs topotecan and irinotecan. The synthesis of the prodrug irinotecan is a direct one that does not pass through the active metabolite. The use of ortho-trimethylsilyl-substituted isonitriles allows the regioselective synthesis of camptothecin analogues in cases where isomeric mixtures are formed from the parent isonitriles. The synthesis of the derivatives relies on the broad scope and functional group tolerance of the key cascade radical reaction.
- Josien, Hubert,Ko, Sung-Bo,Bom, David,Curran, Dennis P.
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-
- Practical asymmetric synthesis of (S)-4,ethyl-7,8-dihydro-4-hydroxy-1H- pyrano[3,4-f]indolizine-3,6,10(4H)-trione, a key intermediate for the synthesis of Irinotecan and other camptothecin analogs
-
A practical asymmetric synthesis of (S) 4-ethyl-7,8-dihydro-4-hydroxy- 1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (1), a versatile intermediate for the synthesis of camptothecin analogs, was developed. Commercially available citrazinic acid is converted in four steps into the 2-chloro-6- methoxypyridine 5. An ortho-directed metalation followed by reaction with a formamide produces an aldehyde with the required 2,3,4,6-substituted pyridine (6) with high regioselectivity. After refunctionalization of the aldehyde, the chloropyridine is converted into an ester by a facile palladium-mediated carbonylation reaction. Wittig reaction and racemic osmylation produce the diol 16 which is resolved by an efficient lipase resolution to an ee > 99%, and a one-pot recycle of the unwanted diol enantiomer was developed. A series of high-yielding oxidation and deprotection steps convert (S)-16 into the pyridone 25, which is then converted into 1 with an ee > 99.6%.
- Henegar,Ashford,Baughman,Sih,Gu
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p. 6588 - 6597
(2007/10/03)
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- Synthesis and antitumor activity of 20(S)-camptothecin derivatives: Carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin
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Novel 36 derivatives (6), bonding the phenolic hydroxyl group of 7-ethyl-10-hydroxycamptothecin (4) with diamines through a monocarbamate linkage, were synthesized and their antitumor activity was evaluated in vivo. The derivatives were soluble in water as their HCl salts with the E lactone ring intact and exhibited significant antitumor activity. One of the derivatives, 6-27 showed excellent activity against L1210 leukemia and other murine tumors. The structure of its hydrochloride trihydrate (CPT-11) was determined by spectroscopic and crystallographic methods.
- Sawada,Okajima,Aiyama,Nokata,Furuta,Yokokura,Sugino,Yamaguchi,Miyasaka
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p. 1446 - 1454
(2007/10/02)
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- Camptothecin derivatives and process for preparing same
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New camptothecin derivatives possessing high anti-tumor activity with slight toxicity, represented by the general formula: STR1 wherein R1 is a hydrogen atom, a halogen atom or an alkyl group with 1-4 carbon atoms and X is a chlorine atom or --NR2 R3 where R2 and R3 are the same or different and each represents a hydrogen atom, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted carbocyclic or heterocyclic group, with the proviso that when both R2 and R3 are the substituted or unsubstituted alkyl groups, they may be combined together with the nitrogen atom, to which they are bonded, to form a heterocyclic ring which may be interrupted with --O--, --S-- and/or >N--R4 in which R4 is a hydrogen atom, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted phenyl group and wherein the grouping --O--CO--X is bonded to a carbon atom located in any of the 9-, 10- and 11-positions in the ring A of camptothecin, as well as an ammonium salt or an alkali metal salt thereof. These new camptothecin derivatives are prepared by reacting a 7-R1 -camptothecin derivative having a hydroxyl group in any of the 9-, 10- and 11-positions on the ring A thereof with phosgen and then reacting, if necessary, the resultant 7-R1 -camptothecin derivative having a chlorocarbonyloxy group in the same position on the ring A thereof with an amine HNR2 R3 or by reacting a 7-R1 -camptothecin derivative having a hydroxyl group in any of the 9-, 10- and 11-positions on the ring A thereof with a carbamoyl chloride Cl-CONR2 R3.
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