- 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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- 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 0020; 0023; 0026; 0029; 0032
(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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- Preparation method of irinotecan hydrochloride
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The invention discloses a preparation method of irinotecan hydrochloride. The preparation method comprises following steps: 1, chemical raw materials of racemic indolizine derivatives are taken as initial raw materials, ring closing reaction and alkali ring-opening reaction are carried out so as to obtain an organic acid intermediate; 2, a chiral amine and the organic acid intermediate are subjected to salt forming resolution so as to obtain a chiral intermediate; 3, the chiral intermediate is subjected to acid ring-opening reaction so as to remove the chiral amine; 4, esterification with a piperidine derivative, and salt forming are carried out so as to obtain the target product irinotecan hydrochloride. The preparation method is used for total synthesis of irinotecan hydrochloride, large scale production is realized, reaction conditions are mild, the preparation method is easy to control, product purity is 98% or higher, and the largest individual impurity content is lower than 0.1%.
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- A method for preparation of irinotecan of hydrochloric acid
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The present invention provides a method for preparation of irinotecan of hydrochloric acid. The method, through intermediate 7-ethyl -10-hydroxy camptothecin and 4-piperidyl formyl chloride or its salt, in the 4-dimethylamino-pyridine or its salt, or its analogs in the presence of a reaction, after concentration, washing, salt and other steps to a final product. The method of the invention avoid the use of regulating, easy to change pyridine take part in the reaction, reduced side reaction, has improved the purity of the product and the yield, the improvement of color and luster of the product at the same time, easy large-scale production.
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Paragraph 0045; 0046; 0047; 0048; 0049; 0050; 0051
(2017/01/09)
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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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- 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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- Crystalline irinotecan hydrochloride and methods for the preparation thereof
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Disclosed is a crystalline form of irinotecan hydrochloride (I) and processes for the preparation thereof from crude irinotecan hydrochloride or another polymorphic form of irinotecan. Said crystalline form is particularly suitable for industrial use, bec
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Page/Page column 4-5
(2010/06/15)
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- CRYSTALLINE IRINOTECAN HYDROCHLORIDE AND METHODS FOR ITS PREPARATION
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Disclosed is a crystalline form of irinotecan hydrochloride (I) and processes for the preparation thereof from crude irinotecan hydrochloride or another polymorphic form of irinotecan. Said crystalline form is particularly suitable for industrial use, bec
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Page/Page column 3
(2010/08/03)
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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 8; 9; 10
(2008/06/13)
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- Novel crystal forms of irinotecan hydrochloride
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The present invention provides for novel crystalline forms of irinotecan hydrochloride and processes for their preparation, pharmaceutical compositions containing the novel forms and methods for treating metastatic carcinoma of the colon or rectum using s
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Page/Page column 4
(2008/06/13)
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- ACID ADDITION SALT OF IRINOTECAN
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The present invention is directed to an irinotecan acid addition salt which is formed through addition of an acid selected from the group consisting of sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, citric acid, maleic acid, and succin
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Page/Page column 4
(2008/06/13)
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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 9
(2008/06/13)
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- PROCESS FOR PRODUCING [1,4'] BIPIPERIDINYL-1'-CARBONYL CHLORIDE OR HYDROCHLORIDE THEREOF
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The present invention is related to a process for the preparation of [1,4'] bipiperidinyl-1' -carbonyl chloride or its hydrochloride using methylene chloride as a solvent in the reaction of 4-piperidinopiperidine with phosgene and removing the reaction so
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Page/Page column 5-6
(2008/06/13)
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- PROCESS FOR THE MANUFACTURING OF 7-ETHYL-10-HYDROXY CAMPTOTHECIN
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The invention discloses the preparation method of 7-ethyl-l0-hydroxycamptothecin from 4-ethyl-7, 8-dihydro-4-hydroxy-lH-pyrano [3,4-f ] indolizine-3, 6,10 (4H) -trione and 1- (2-amino-5-hydroxyphenyl) -propan-1-one using high reaction temperature and fast heating to that temperature .
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Page/Page column 6-7
(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 11
(2010/10/20)
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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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- METHOD FOR PREPARING POLYMORPHISM OF IRINOTECAN HYDROCHLORIDE
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A method for preparing a novel crystalline polymorphic irinotecan hydrochloride which is excellent in the solubility in water and reduced in the content of impurities is provided. A method for preparing c-type crystals of irinotecan hydrochloride having d
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Page/Page column 5
(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 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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- Kinetic studies of the hydrolysis and lactonization of camptothecin and its derivatives, CPT-11 and SN-38, in aqueous solution
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The effect of pH and temperature on the reaction rate of the hydrolysis and lactonization of camptothecin and its derivatives, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and 7-ethyl-10-hydroxycamptothecin (SN-38), in aqueous solution was studied by high-performance liquid chromatography or two-wavelength spectrophotometry. Hydrolysis and lactonization of each compound progressed according to pH- and temperature-dependent pseudo-first-order kinetics. The ratio of the lactone form of each compound to its hydroxy-acid form was determined mainly by the pH of the solution and was not influenced by temperature. Half-lives of the lactone and hydroxy-acid forms of CPT-11 at 37°C and pH 7.4 were 13.7 min and 4.25 h, respectively.
- Akimoto,Kawai,Ohya
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p. 2135 - 2138
(2007/10/02)
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