- A short total synthesis of palonosetron using catalytic hydrogenation
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The 5-HT3 receptor antagonists (1) and (2) (palonosetron) were synthesized by an efficient new route. The critical hydrogenation of imide (4) was carried out with either Pd/C catalyst or PtO2 catalyst.
- Kowalczyk, Bruce A.
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Read Online
- Hydrochloric acid palonosetron and intermediate preparation method (by machine translation)
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The invention discloses hydrochloric acid palonosetron and intermediate preparation method. The invention provides a preparation method of palonosetron intermediate I, comprises the following steps: in the organic solvent, the presence of a reducing agent, the compound III with the S - 3 - amino quinine cyclic amine reaction of intermediate I Sparrow division of the agar. The invention palonosetron preparation method of the midbody mild reaction conditions, post-processing step is simple, safe operation, the total yield is high, the prepared product has high purity, low production cost, the atom utilization rate is high, and is suitable for industrial production; and palonosetron intermediates of the present invention can be prepared in accordance with the raw materials of the standard of the hydrochloric acid palonosetron. (by machine translation)
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- Preparation method of high-purity palonosetron hydrochloride
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The invention discloses a preparation method of high-purity palonosetron hydrochloride. A synthesis method is as follows: taking 1,2,3,4-tetrahedro-naphthoic acid as a starting raw material, taking quinine as a resolving agent to obtain chiral(S)-1,2,3,4-tetrahedro-naphthoic acid, acylating the chiral(S)-1,2,3,4-tetrahedro-naphthoic acid by using oxalyl chloride, and then reacting with (S)-3-aminoquinuclidine ammonia salt to obtain amide compound; concentrating, adding water to dilute, adding alkali to adjust pH value to obtain (R)-N-((S)-3-quinine)-1,2,3,4-tetralyl-1-formamide; performing reduction reaction on an intermediate under the existence of the sodium borohydride and boron trifluoride diethyl etherate so as to obtain (R)-N-(1-((S)-1,2,3,4-tetralyl)methyl)-3-quinine amine, continuously reacting with the triphosgene and boron trifluoride diethyl etherate, salting, extracting and regulating the pH value to obtain a crude product of the Palonosetron after the reaction is completed; and salting and refining the crude product in isopropanol so as to obtain the Palonosetron Hydrochloride with high purity. The preparation method not only solves the problem that the palonosetron hydrochloride is low in yield and unstable in process for a long time, but also adopts class-three solvent ethyl acetate to extract in the synthesis of each step, the invention is in favor of the environmental protection, and convenient for solvent recycling and cost saving, and is suitable for industrial production.
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- Synthesis process of palonosetron hydrochloride hydrochloride
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The invention discloses a synthesis process of palonosetron hydrochloride hydrochloride. The synthesis process comprises the following steps: S1, performing condensation reduction on 3,4-dihydro-1-naphthalenemethylamine hydrochloride and 3-quinuclidinone hydrochloride which serve as raw materials, thus obtaining a n-butanol solution of N-[(3,4-dihydronaphthalene-1-yl) methyl]-(S)-1-azabicyclo [2.2.2] octane-3-amine; S2, directly adding a catalyst into the n-butanol solution of the N-[(3,4-dihydronaphthalene-1-yl) methyl]-(S)-1-azabicyclo [2.2.2] octane-3-amine for hydrogenation reduction, thus obtaining N-[(1,2,3,4-tetrahydronaphthalene-1-yl) methyl]-(S)-1-azabicyclo [2.2.2] octane-3-amine; S3, performing cyclization on the N-[(1,2,3,4-tetrahydronaphthalene-1-yl) methyl]-(S)-1-azabicyclo [2.2.2] octane-3-amine to form salt, thus obtaining the palonosetron hydrochloride hydrochloride. The synthesis process provided by the invention is mild in condition, simple in step and high in yield and has advantages superior to the prior art.
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- A hydrochloric acid palonosetron synthesis method
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The invention relates to a new synthetic method of palonosetron hydrochloride, and belongs to the field of pharmaceutical organic synthesis. The synthetic method adopts racemized tetrahydro naphthoic acid as a raw material; a reaction is carried out with thionyl chloride and (S)-3-aminoquinuclidine; after repeated washing, (S,S)-quinuclidine tetrahydronaphthalene carboxamide is obtained; the amide is reacted with sodium borohydride and boron trifluoride diethyl etherate; the product is added into a hydrochloric acid aqueous solution to obtain the palonosetron hydrochloride. According to the method, in the amide synthetic process, ethyl acetate is used as a solvent, which reduces the generation of by-products. In addition, according to the method, in the post-treatment process, impurities are removed by phase transfer, which increases product optical purity; through repeated washing, other impurities generated in the reaction are removed, and high-purity product is obtained.
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- A hydrochloric acid palonosetron production method
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The invention belongs to the field of organic synthesis, and particularly relates to a production method of high-purity and high-yield palonosetron hydrochloride. Chiral compounds, namely, (S)-(-)-1,2,3,4-tetrahedro-naphthoic acid and S-3-aminoquinuclidine, are taken as raw materials, and an intermediate is obtained; the intermediate has a reduction reaction in the presence of NaBH4 and BF3*CH3OH, a product is added to a hydrochloric acid aqueous solution for a reflux reaction after the reaction, and a transparent oily substance is obtained through extraction after the reflux reaction; toluene is added to the substance, a toluene solution of triphosgene is dropwise added again at the temperature ranging from 10 DEG C to 15 DEG C, white solids are separated out, a reaction is performed under the condition of heating reflux, and the toluene solution of the triphosgene is dropwise added again under the reflux condition; then a system is cooled to the temperature ranging from 10 DEG C to 15 DEG C, BF3*CH3OH is added, the system is added to water and the hydrochloric acid aqueous solution at the reflux temperature after addition, then a reflux reaction is performed at the heating reflux temperature, and then a crude product is obtained through washing, extraction and crystallization; the crude product is dissolved in acetone, repeated crystallization is performed after dissolution, and the refined palonosetron hydrochloride is obtained. Steps are simple and convenient, reaction conditions are mild, and the production method is easy to operate and suitable for industrial production.
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- METHOD FOR PRODUCING HYDROBENZ ISOQUINOLINE COMPOUND
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PROBLEM TO BE SOLVED: To provide a novel method for producing a hydrobenz isoquinoline compound. SOLUTION: A method for producing a hydrobenz isoquinoline compound represented by formula (7) includes subjecting an amine compound represented by formula (4) to carbamate reaction and cyclization reaction (where X is a chlorine atom, a bromine atom and others, R1 is a phenyl group and others, R2 is an isopropyl group, an ethyl group and others). SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0059
(2017/04/14)
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- Synthesis and Pharmacological Evaluation of [11C]Granisetron and [18F]Fluoropalonosetron as PET Probes for 5-HT3 Receptor Imaging
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Serotonin-gated ionotropic 5-HT3 receptors are the major pharmacological targets for antiemetic compounds. Furthermore, they have become a focus for the treatment of irritable bowel syndrome (IBS) and there is some evidence that pharmacological modulation of 5-HT3 receptors might alleviate symptoms of other neurological disorders. Highly selective, high-affinity antagonists, such as granisetron (Kytril) and palonosetron (Aloxi), belong to a family of drugs (the "setrons") that are well established for clinical use. To enable us to better understand the actions of these drugs in vivo, we report the synthesis of 8-fluoropalonosetron (15) that has a binding affinity (Ki = 0.26 ± 0.05 nM) similar to the parent drug (Ki = 0.21 ± 0.03 nM). We radiolabeled 15 by nucleophilic 18F-fluorination of an unsymmetrical diaryliodonium palonosetron precursor and achieved the radiosynthesis of 1-(methyl-11C)-N-granisetron ([11C]2) through N-alkylation with [11C]CH3I, respectively. Both compounds [18F]15 (chemical and radiochemical purity >95%, specific activity 41 GBq/μmol) and [11C]2 (chemical and radiochemical purity ≥99%, specific activity 170 GBq/μmol) were evaluated for their utility as positron emission tomography (PET) probes. Using mouse and rat brain slices, in vitro autoradiography with both [18F]15 and [11C]2 revealed a heterogeneous and displaceable binding in cortical and hippocampal regions that are known to express 5-HT3 receptors at significant levels. Subsequent PET experiments suggested that [18F]15 and [11C]2 are of limited utility for the PET imaging of brain 5-HT3 receptors in vivo.
- Mu, Linjing,Müller Herde, Adrienne,Rüefli, Pascal M.,Sladojevich, Filippo,Milicevic Sephton, Selena,Kr?mer, Stefanie D.,Thompson, Andrew J.,Schibli, Roger,Ametamey, Simon M.,Lochner, Martin
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p. 1552 - 1564
(2016/11/29)
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- A hydrochloric acid palonosetron compound (by machine translation)
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The present invention provides a process for preparing high-purity hydrochloric acid palonosetron, prepared by the following method: raw material (S)-N - (( (S) - 1, 2, 3, 4-tetrahydronaphthalen-1-yl) methyl) - 3-amino-Quinuclidines after reaction with the three poly phosgene, by adding boron trifluoride tetrahydrofuran solution to reflux reaction, the salt forming, extraction, systems free alkali, and become the salt in ethanol, crystallization, refined to obtain high-purity hydrochloric acid palonosetron, the purity 99.9% or more, the maximum shan Za in 0.1% the following. The method of the present invention solves the problems of the prior art low yield of the product, removal of impurities can't be efficient and the like, provided by the simple and convenient synthesis process operation, is easy to control, has no special requirement on the equipment, it is easy to realize industrial. (by machine translation)
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Paragraph 0036; 0037; 0038; 0039
(2016/12/01)
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- PROCESSES FOR THE PREPARATION OF PALONOSETRON
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The present invention relates to novel processes for the preparation of N-[(3S)-1- azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide of Formula I. The present invention further relates to processes for the preparation of palonosetron or its salts thereof using N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8- tetrahydronaphthalene-1-carboxamide of Formula I as an intermediate.
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Page/Page column 16
(2011/02/24)
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- Process for the Preparation of Substantially Pure Palonosetron and its Acid Salts
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This invention relates to an improved and scalable process for the preparation of substantially pure palonosetron and its acid addition salts, in particular hydrochloride (I) which comprises of, (a) converting intermediate (IIa) as such or as its freebase (II) to a crude mixture of diastereomeric palonosetrons (VIII) or (VIIIa) contaminated with varying amounts of unconverted intermediate (II) or (IIa) via hydrogenation under pressure with an appropriately chosen hydrogenation catalyst in an suitable organic solvent.(b) making the resulting crude mixture of diastereomeric palonosetrons (VIII) or (VIIIa) contaminated with varying amounts of unconverted intermediate (II) or (IIa) substantially free from (II) or (IIa) via halogenation reaction.(c) Finally, converting the resulting diastereomeric palonosetron (VIII) or its hydrochloride (VIIIa) substantially free from intermediate (II) or (IIa) to the desired palonosetron hydrochloride (I) in substantially pure form via selective crystallization from a suitable single or mixture of organic solvents.
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Page/Page column 5
(2011/02/18)
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- PREPARATION OF CRYSTALLINE PALONOSETRON HYDROCHLORIDE
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Processes for the preparation of palonosetron hydrochloride and its crystalline forms.
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Page/Page column 23-24
(2010/06/15)
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- HIGH PURITY PALONOSETRON BASE AND ITS SOLID STATE CHARACTERISTICS
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The present invention describes the process for the preparation of pure enantiomeric form of palonosetron base of formula (I), and its solid-state characteristics of said compound.
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Page/Page column 11-12
(2010/01/29)
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- NOVEL CRYSTALLINE FORMS OF PALONOSETRON HYDROCHLORIDE
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The present invention relates to novel crystalline forms, designated as Form (I) and Form (II) of Palonosetron Hydrochloride ((3as)-2[(3s)-1-Azabicyclo[2.2.2]Oct-3-yl]-2,3,3a,4,5,6- hexahydro-1H-benz[de]isoquinoline-1-one mono hydrchloride) and processes for their preparation. Palonosetron Hydrochloride is useful as anti-emetic agent during the chemotherapy of treatment of cancer patients. It is marketed globally under the brand names 'Aloxi' and 'Onicit'.
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Page/Page column 9
(2009/09/04)
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- PALONOSETRON FREE BASE AND PROCESS FOR ITS PREPARATION
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The present invention provides novel palonosetron free base in an amorphous form and crystalline form-G and processes for their preparation. The present invention also provides a process for the preparation of palonosetron hydrochloride from the novel palonosetron free base in an amorphous form and/or in crystalline form-G.
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Page/Page column 23-24
(2009/09/04)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF PURE PALONOSETRON HYDROCHLORIDE
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The present invention relates to an improved and industrially viable process for the preparation of high purity >99.8% chemical and >99.8% chiral of palonosetron hydrochloride of formula-I ((3as)-2[(3s)-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinoline-1-one monohydrochloride) obtained from reduction of 2-[(S)-1-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-1H-benz[de]iso-quinolin-1-one hydrochloride of formula-VI. In the prior art compound of formula-VI or its base are used in the catalytic hydrogenation. But the selection of solvents like acetic acid or THF rendered them commercially not viable due to low yield and low purity of palonosetron hydrochloride. In the present process simple solvent like methanol and readily available palladium-on-carbon were used to increase the yield and purity of palonosetron hydrochloride. Palonosetron Hydrochloride is useful as anti-emetic agent during the chemotherapy of treatment of cancer patients and is marketed under the brand names 'Aloxi' and 'Onicit'.
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Page/Page column 7
(2009/03/07)
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- Processes for preparing palonosetron salts
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The present invention provides processes for preparing Palonosetron salts, especially, the hydrochloride salt and intermediates used to prepare Palonosetron salts.
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Page/Page column 12
(2008/12/08)
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- PROCESS FOR THE PURIFICATION OF PALONOSETRON OR ITS SALT
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The present application relates to a process for purification of palonosetron or its salt substantially free of its R-isomer and structure related impurities.
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Page/Page column 5
(2008/06/13)
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- Process for preparing 2-(1-azabicyclo 2.2.2!oct-3-yl)-2,3,3A,4,5,6-hexahydro-1H-benz de!isoquinolin-1-one
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This invention relates to a process for preparing 2-(1-azabicyclo 2.2.2!oct-3-yl)-2,3,3a,4,5,6-tetrahydro-1H-benz de!isoquinolin-1-one, particularly 2-(1-azabicyclo 2.2.2!oct-3S-yl)-2,3,3aS,4,5,6-tetrahydro-1H-benz de!isoquinolin-1-one, and to intermediates useful in such process.
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