CN104177356A - Method for synthesizing palonosetron metabolite - Google Patents
Method for synthesizing palonosetron metabolite Download PDFInfo
- Publication number
- CN104177356A CN104177356A CN201410459410.2A CN201410459410A CN104177356A CN 104177356 A CN104177356 A CN 104177356A CN 201410459410 A CN201410459410 A CN 201410459410A CN 104177356 A CN104177356 A CN 104177356A
- Authority
- CN
- China
- Prior art keywords
- palonosetron
- acid
- metabolite
- formula
- type iii
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- RCOFGDSGMTUPNB-DAFXYXGESA-N O=C(c1c(C(CCC2)C3)c2ccc1)N3[C@@H]1C(CC2)CCN2CC1 Chemical compound O=C(c1c(C(CCC2)C3)c2ccc1)N3[C@@H]1C(CC2)CCN2CC1 RCOFGDSGMTUPNB-DAFXYXGESA-N 0.000 description 1
- NMSKJVHLBOAIPC-VQIMIIECSA-N O=C(c1c([C@](C2)(C=CC3)I)c3ccc1)N2[C@H]1C(CC2)CCN2C1 Chemical compound O=C(c1c([C@](C2)(C=CC3)I)c3ccc1)N2[C@H]1C(CC2)CCN2C1 NMSKJVHLBOAIPC-VQIMIIECSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to the technical field of medicines, and in particular relates to a novel method for synthesizing palonosetron metabolite (3aS, 3'S)-2-[-1-aza-bicyclo-[2.2.2]cyn-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1H-benzo[de] isoquinoline nitric oxide. According to the method, the compound as shown in the formula I and/or a derivative of the compound is adopted as a raw material, and the compound or the derivative is reacted in an inert organic solvent in the presence of an oxidant as shown in the formula IV, thereby obtaining the palonosetron metabolite as shown in the formula III. Compared with the prior art, the method has the advantages that the used raw materials and oxidant are easily available, the reaction condition is gentle, the operation is simple, the yield is high, the nitric oxide can be massively prepared, and thus great pharmaceutical research significance and pharmaceutical industrial values are achieved.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to a kind of synthetic Palonosetron metabolite (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4, the novel method of 5,6-, six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 oxynitride.
Background technology
The nausea and vomiting side effect of anticancer chemotherapy and radiation is general and long-term problem.PalonosetronHydrochloride (formula V) is resisted moderate or highly caused the nausea and vomiting causing after the acute and Delayed onset nausea and vomiting of vomitting property chemotherapy initiation, operation has very effective effect.PalonosetronHydrochloride chemical name (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4,5,6-, six hydrogen-1-oxygen-1H-benzo [de] isoquinoline hydrochloride (No. CAS: 119904-90-4), its empirical formula is C
19h
24n
2o ﹒ HCL, molecular weight is 332.87, is developed by Hlesinm company of Switzerland, goes on the market in the U.S. in September, 2003, PalonosetronHydrochloride in the U.S. as trade mark is
aseptic parenteral solution sell, form is to contain 0.075 or the sterile unit dose bottle of 0.25mg PalonosetronHydrochloride.PalonosetronHydrochloride is also sold with the soft gel formulation that contains 0.5mg PalonosetronHydrochloride of oral administration.The chemical structural formula of PalonosetronHydrochloride is as shown in the formula shown in V:
Palonosetron is thanked as new compound (3aS giving Age of Mammals, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4,5,6-six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 oxynitride (Palonosetron oxynitride), according to bibliographical information (WO2011058427, Palonosetron Metabolites), oxynitride is as the important meta-bolites of Palonosetron, for the metabolic process of research Palonosetron, and finds the molecule tool with higher pharmaceutical activity and is of great significance; Meanwhile, the degradation process that it also can support study dies Palonosetron, is of great significance for the same tool of quality product of controlling Palonosetron.Therefore, exploitation (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4,5, the synthetic method of 6-six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 oxynitride, is the work that extremely has drug research to be worth, simultaneously for controlling drug quality and ensureing that drugs consumption person's drug safety is significant.
Application number is that 201080051504.6 patent of invention discloses metabolite of a kind of Palonosetron and preparation method thereof, and syntheti c route is as follows:
By the synthetic preparation easily of two steps; described synthesizing comprises that (1) makes the acid of formula X or the condensed ring dicyclic compound of acid derivative or formula Xa be converted into the substituted amide of formula XI; and (2) make described acid amides react under the existence of highly basic with formylation reagent; then acidifying, to form the compound (having the compound of key selectable) of formula XII, is passed through H subsequently
2reduction prepares the metabolite (not having the compound of key selectable) of Palonosetron, but the method operation is more complicated.
Document (WO2011058427, Palonosetron Metabolites) in point out, can adopt the starting raw material that contains rubane oxide structure (shown in VII), four step synthetic methods with reference to Palonosetron are prepared, but clearly do not provide synthetic method and the operation steps of concrete oxynitride.
For preparing rubane oxide structure (shown in VI and VII), (Tetrahedron in document, 1998,54,7831-7842.) reported use fluorine-containing nitrogen oxirane oxygenant, at low temperature-60 DEG C, can carry out selective oxidation to rubane, but the preparation complexity of the oxygenant using in the method, severe reaction conditions, temperature is low, not easy to operate, therefore many drawbacks limit of the method its application.
In document, (Chemical Communications, 2006,43,4545-4547.) also reported by the amino method on ozone oxidation rubane, can obtain associated products with higher yields.But in the method, ozone preparation and use all need special device, and complicated operation, is not easy to amplify preparation.
At present, the method of the acquisition rubane oxide compound of reporting in document all requires harsher, and available technology adopting rubane oxide compound synthesizes 3aS as starting raw material, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4,5, the common shortcoming that 6-six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 oxynitride exists is: raw material is not easy to obtain, step is long, can not amplify cost costliness.
Summary of the invention
In order to address the above problem, the unforeseeable discovery of contriver, by (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2, 3, 3a, 4, 5, 6-six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 is dissolved in inert organic solvents, under the oxygenizement of the oxygenant shown in formula IV, can carry out selective oxidation to rubane, synthetic Palonosetron metabolite (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2, 3, 3a, 4, 5, 6-six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 oxynitride, the oxygenant that the method is used directly can obtain by commercial sources, do not need to prepare through special synthesis step, in addition, this oxygenant is to 3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2, 3, 3a, 4, 5, 6-six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 is oxidized within the scope of-20-100 DEG C and all can carries out, need to not react as the condition of-60 DEG C at extremely low temperature, this reaction does not need special device yet, only need single step reaction, simple to operate, be convenient to amplify preparation, based on above-mentioned discovery, thereby complete the present invention.
Therefore, the object of the present invention is to provide a kind of synthetic Palonosetron metabolite (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, the novel method of 4,5,6-, six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 oxynitride.
For achieving the above object, technical scheme of the present invention is:
The method of the Palonosetron metabolite shown in a kind of synthesis type III, taking the compound shown in formula I and/or its derivative as raw material, in inert organic solvents, under the oxygenizement of the oxygenant shown in formula IV, reaction obtains the Palonosetron metabolite shown in formula III;
Wherein: the R in formula IV is H, F, Cl, Br or I.
Preferably, the derivative of the compound shown in formula I is that general formula is suc as formula the salt shown in II;
Wherein: X is sour acid group.
The chemical equation that general formula is raw material suc as formula the salt shown in II is as follows:
Wherein: in formula, X is sour acid group.
General formula is to be formed by compound and acid-respons shown in formula I suc as formula the preparation method of the salt shown in II, and described acid is mineral acid, is selected from such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc., described acid also can be organic acid, be selected from for example acetic acid, propionic acid, caproic acid, enanthic acid, cyclopentanepropanoiacid acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, succinic acid, oxysuccinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, o-(4-hydroxy benzoyl) phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, 1, 2-ethionic acid, 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthene sulfonic acid, tosic acid, camphorsulfonic acid, 4-methyl bicycle [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4, 4 '-methylene-bis (3-hydroxyl-2-alkene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert.-butylacetic acid, dodecyl sulphate, gluconic acid, L-glutamic acid, naphthoic acid, Whitfield's ointment, stearic acid, muconic acid etc.General formula is preferably hydrochloride suc as formula the salt shown in II, hydrobromate, hydriodate, phosphoric acid salt, vitriol, benzene sulfonate, mesylate.
Preferably, described acid is one or more in hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, sulfuric acid, Phenylsulfonic acid and methylsulfonic acid.
In above-mentioned method, described inert organic solvents can select arbitrarily raw material and oxygenant to have the inert organic solvents of solubility, can be also the mixture of this kind solvent.
Preferably, described inert organic solvents is the halogenated alkane of a tool 1-3 carbon atom or the mixture of this kind solvent.
Preferred, described inert organic solvents is methylene dichloride and/or trichloromethane.
Particularly, described inert organic solvents is methylene dichloride.
Further, described oxygenant and the mass ratio of raw material are 0.1-10, and preferred, described oxygenant and the mass ratio of raw material are 1-2.
Further, described inert organic solvents and the mass ratio of raw material are 1-30, and preferred, described inert organic solvents and the mass ratio of raw material are 5-10.
Further, the method of the Palonosetron metabolite shown in described a kind of synthesis type III, compound shown in described formula I and/or its derivative are in inert organic solvents, under the effect of the oxygenant shown in formula IV, the temperature of reaction is-20-100 DEG C, preferably, described temperature of reaction is 0-25 DEG C.
In the method for the invention, compound shown in formula I and/or its derivative are in inert organic solvents, under the effect of the oxygenant shown in formula IV, after completion of the reaction, can obtain the Palonosetron metabolite of solid through follow-up processing, follow-up processing is: reaction solution after filtration, saturated sodium carbonate washing, anhydrous magnesium sulfate drying, filters, is concentrated into anhydrous, obtains the Palonosetron metabolite shown in the formula III of white solid.
Beneficial effect of the present invention is: one of the present invention is synthesized Palonosetron metabolite
(3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2, 3, 3a, 4, 5, the method of 6-six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 oxynitride compared with prior art, advantage have following some: (1) the method use oxygenant directly can obtain by commercial sources, do not need to prepare through special synthesis step, raw material 3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2, 3, 3a, 4, 5, 6-six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 also can facilitate acquisition by commercial sources, raw material used and oxygenant all do not need to be prepared through other special reactions, (2) the present invention's oxygenant used is to 3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4,5,6-, six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 is oxidized within the scope of-20-100 DEG C and all can carries out, and need to not react as the condition of-60 DEG C at extremely low temperature, this reaction does not need special device yet, only need single step reaction, simple to operate, be convenient to amplify preparation.
Brief description of the drawings
Fig. 1 is Palonosetron metabolite (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl that embodiment 1 obtains]-2,3,3a, the HPLC assay result of 4,5,6-, six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 oxynitride;
Fig. 2 is Palonosetron metabolite (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl that embodiment 5 obtains]-2,3,3a, the HPLC assay result of 4,5,6-, six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 oxynitride.
Embodiment
Illustrated embodiment is in order better content of the present invention to be described, but is not that content of the present invention only limits to illustrated embodiment.So those of ordinary skill in the art carry out nonessential improvement and adjustment according to foregoing invention content to embodiment, still belong to protection scope of the present invention.
In following examples, pertinent instruments used and testing conditions are as follows:
Performance liquid chromatographic column: Shim-pack VP-ODS, specification 250*4.6mm;
Mass spectrograph: instrument model: AccuTOF CS/CADM-YQ-003
The chromatographic condition that HPLC analyzes:
Detect wavelength: 215nm;
Flow velocity: 1.0ml/min;
Column temperature: 45 degree;
Sample size: 10ul;
Thinner: acetonitrile: containing the aqueous solution (with phosphorus acid for adjusting pH value to 3.0 ± 0.1)=35:65 of 0.04mol/L Potassium Hexafluorophosphate and 0.06mol/L sodium perchlorate.
Mobile phase A: containing the aqueous solution (with phosphorus acid for adjusting pH value to 3.0 ± 0.1) of 0.04mol/L Potassium Hexafluorophosphate and 0.06mol/L sodium perchlorate
Mobile phase B: acetonitrile
Gradient elution timetable is as follows:
| Time (min) | A(％) | B(％) |
| 0 | 75 | 25 |
| 40 | 65 | 35 |
| 50 | 65 | 35 |
| 50.1 | 75 | 25 |
| 60 | 75 | 25 |
Embodiment 1
In tri-mouthfuls of reaction flasks of 250ml, add (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4,5,6-, six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 5g (0.017mol), 25ml methylene dichloride, then under agitation condition, splash into the metachloroperbenzoic acid 2.5g (0.029mol) dissolving with 25ml methylene dichloride; After having added, 25 DEG C are reacted 2 hours, and sampling is monitored.
Aftertreatment: stopped reaction, filter, saturated sodium carbonate washed twice, anhydrous magnesium sulfate drying, filters, is concentrated into dry, obtains off-white color solid 4.8g, yield 91.1%.
HPLC content: 98.4%; (referring to table 1 and accompanying drawing 1);
Mass spectrum: instrument model: AccuTOF CS/CADM-YQ-003
According to Theoretical Calculation, its [M+]=312.18378, [M+H]=313.19160; Low Resolution Mass Spectra shows its [M+H]=313.2, [M+Na]=335.2, and [M+K]=351.2, this is consistent with the molecular structure of this oxynitride.
High resolution mass spectrum shows its accurate mass number [M+H]=313.19062, and experimental result error, in experiment allowed band, conforms to its theoretical value.
Hydrogen spectrum: δ=7.25 (m, 2H), δ=7.84 (t, 1H) is for fragrant hydrogen and can be confirmed to be three replacements adjacent phenyl ring from peak shape analysis; δ=5.11 (t, 1H) are the CH being connected with amino in 3-amino quinine structure; In molecule, also contain in addition 20 non-aromatic H (δ=0.86～3.85), wherein 9 is CH2 structure, and part is to be directly connected with N atom, and this conforms to the theoretical molecular structure of this oxynitride.
Table 1 embodiment 1HPLC assay result
| Peak# | Ret.Time | Height | Area | Area％ |
| 1 | 8.214 | 642 | 14754 | 0.240 |
| 2 | 10.577 | 215 | 3522 | 0.057 |
| 3 | 13.448 | 103 | 1937 | 0.032 |
| 4 | 16.919 | 137 | 2175 | 0.035 |
| 5 | 20.388 | 633 | 13208 | 0.215 |
| 6 | 20.869 | 851 | 16713 | 0.272 |
| 7 | 24.220 | 190 | 3986 | 0.065 |
| 8 | 29.178 | 285 | 6387 | 0.104 |
| 9 | 31.027 | 1287 | 33714 | 0.0548 |
| 10 | 32.346 | 224220 | 6050473 | 98.432 |
| Total | ? | 228563 | 6146869 | 100.00 |
The impact that embodiment 2 differential responses temperature condition are synthetic on isoquinoline 99.9 oxynitride
According to the method in embodiment 1, inquire into differential responses temperature condition (as shown in table 1) to Palonosetron metabolite (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4,5, the impact (be temperature of reaction difference, other are all identical) that 6-six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 oxynitride is synthetic, the results are shown in Table shown in 2.
The impact that table 2 differential responses temperature condition is synthetic on isoquinoline 99.9 oxynitride
| Temperature of reaction (DEG C) | Output (g) | Yield (%) |
| -20 | 3.6 | 68.3 |
| -10 | 3.7 | 70.2 |
| 0 | 4.2 | 79.7 |
| 5 | 4.5 | 85.4 |
| 15 | 4.7 | 89.2 |
| 25 | 4.8 | 91.1 |
| 35 | 4.7 | 89.2 |
| 45 | 4.6 | 87.3 |
The impact that the different oxygenants of embodiment 3 are synthetic on isoquinoline 99.9 oxynitride
According to the method in embodiment 1, inquire into different oxygenants (as shown in table 2) to Palonosetron metabolite (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4,5, the synthetic impact of 6-six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 oxynitride, the results are shown in Table shown in 3.
The impact that the different oxygenants of table 3 are synthetic on isoquinoline 99.9 oxynitride
| Reaction raw materials | Oxygenant | Output (g) | Yield (%) |
| Isoquinoline 99.9 | Benzoyl hydroperoxide | 4.2 | 79.7 |
| Isoquinoline 99.9 | Metachloroperbenzoic acid | 4.8 | 91.1 |
| Isoquinoline 99.9 | Between bromine benzoyl hydroperoxide | 3.9 | 74.0 |
| Isoquinoline 99.9 | To chloroperoxybenzoic acid | 4.6 | 87.3 |
| Isoquinoline 99.9 | 3,4-, bis-chloroperoxybenzoic acids | 4.5 | 85.4 |
| Isoquinoline hydrochloride | Benzoyl hydroperoxide | 3.0 | 56.9 |
| Isoquinoline hydrochloride | Metachloroperbenzoic acid | 3.2 | 60.7 |
| Isoquinoline hydrochloride | To chloroperoxybenzoic acid | 3.1 | 58.8 |
| Isoquinoline 99.9 phosphoric acid salt | Benzoyl hydroperoxide | 2.6 | 49.3 |
| Isoquinoline 99.9 phosphoric acid salt | Metachloroperbenzoic acid | 2.8 | 53.1 |
| Isoquinoline 99.9 benzene sulfonate | Benzoyl hydroperoxide | 2.7 | 51.2 |
| Isoquinoline 99.9 benzene sulfonate | Metachloroperbenzoic acid | 2.7 | 51.2 |
The impact that embodiment 4 different organic solvents are synthetic on isoquinoline 99.9 oxynitride
According to the method in embodiment 1, inquire into different organic solvents (as shown in table 3) to Palonosetron metabolite (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4,5, the synthetic impact of 6-six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 oxynitride, the results are shown in Table shown in 4.
The impact that table 4 different organic solvents is synthetic on isoquinoline 99.9 oxynitride
| Reaction raw materials | Organic solvent | Output (g) | Yield (%) |
| Isoquinoline 99.9 | Methylene dichloride | 4.8 | 91.1 |
| Isoquinoline 99.9 | Trichloromethane | 3.8 | 72.1 |
| Isoquinoline 99.9 | Ethylene dichloride | 3.6 | 68.3 |
| Isoquinoline 99.9 | Trichloroethane | 3.5 | 66.4 |
| Isoquinoline 99.9 | Trichloropropane | 3.3 | 62.6 |
| Isoquinoline hydrochloride | Methylene dichloride | 3.2 | 60.7 |
| Isoquinoline hydrochloride | Ethylene dichloride | 2.5 | 47.4 |
| Isoquinoline hydrochloride | Trichloropropane | 2.3 | 43.6 |
Embodiment 5
In tri-mouthfuls of reaction flasks of 250ml, add (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4,5,6-, six hydrogen-1-oxygen-1H-benzo [de] isoquinoline hydrochloride 5g (0.015mol), 25ml methylene dichloride, then under agitation condition, splash into the metachloroperbenzoic acid 2.5g dissolving with 25ml methylene dichloride; After having added, 25 DEG C are reacted 2 hours, and sampling is monitored
Aftertreatment: stopped reaction, filter, saturated sodium carbonate washed twice, anhydrous magnesium sulfate drying, filters, is concentrated into dry, obtains off-white color solid 3.2g, yield 68.2%.
HPLC content: 92.0%; (referring to table 5 and accompanying drawing 2);
Table 5 embodiment 5HPLC assay result
| Peak# | Ret.Time | Height | Area | Area％ |
| 1 | 2.830 | 16906 | 114510 | 0.290 |
| 2 | 3.469 | 21536 | 112134 | 0.284 |
| 3 | 3.985 | 9301 | 63995 | 0.162 |
| 4 | 5.612 | 13304 | 114875 | 0.291 |
| 5 | 6.109 | 5920 | 51905 | 0.132 |
| 6 | 7.874 | 9061 | 138374 | 0.351 |
| 7 | 9.314 | 3626 | 53956 | 0.137 |
| 8 | 10.172 | 37982 | 577125 | 1.463 |
| 9 | 13.039 | 3539 | 74371 | 0.189 |
| 10 | 19.348 | 12662 | 275309 | 0.698 |
| 11 | 20.366 | 3033 | 63451 | 0.161 |
| 12 | 27.574 | 4147 | 114224 | 0.290 |
| 13 | 28.056 | 2296 | 53067 | 0.135 |
| 14 | 30.183 | 24822 | 638711 | 1.619 |
| 15 | 31.042 | 1087500 | 36292416 | 92.002 |
| 16 | 33.979 | 2640 | 78634 | 0.199 |
| 17 | 37.943 | 19740 | 630366 | 1.598 |
| Total | ? | 1278015 | 39447424 | 100.000 |
Embodiment 6
In tri-mouthfuls of reaction flasks of 250ml, add (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4,5,6-, six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 5g (0.017mol), 25ml trichloromethane, then under agitation condition, splash into the metachloroperbenzoic acid 2.5g dissolving with 25ml trichloromethane; After having added, 25 DEG C are reacted 2 hours, and sampling is monitored.
Aftertreatment: stopped reaction, filter, saturated sodium carbonate washed twice, anhydrous magnesium sulfate drying, filters, is concentrated into dry, obtains off-white color solid 3.6g, yield 68.3%.
Embodiment 7
In tri-mouthfuls of reaction flasks of 250ml, add (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4,5,6-, six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 5g (0.017mol), 25ml trichloromethane, then under agitation condition, splash into the metachloroperbenzoic acid 5g dissolving with 25ml methylene dichloride; After having added, 25 DEG C are reacted 2 hours, and sampling is monitored.
Aftertreatment: stopped reaction, filter, saturated sodium carbonate washed twice, anhydrous magnesium sulfate drying, filters, is concentrated into dry, obtains off-white color solid 4.1g, yield 77.8%.
Embodiment 8
In tri-mouthfuls of reaction flasks of 250ml, add (3aS, 3 ' S)-2-[-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3a, 4,5,6-, six hydrogen-1-oxygen-1H-benzo [de] isoquinoline 99.9 5g (0.017mol), 25ml trichloromethane, then under agitation condition, splash into the benzoyl hydroperoxide 2.5g dissolving with 25ml methylene dichloride; After having added, 25 DEG C are reacted 2 hours, and sampling is monitored.
Aftertreatment: stopped reaction, filter, saturated sodium carbonate washed twice, anhydrous magnesium sulfate drying, filters, is concentrated into dry, obtains off-white color solid 4.2g, yield 79.7%.
Finally explanation is, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although the present invention is had been described in detail with reference to preferred embodiment, those of ordinary skill in the art is to be understood that, can modify or be equal to replacement technical scheme of the present invention, and not departing from aim and the scope of technical solution of the present invention, it all should be encompassed in the middle of claim scope of the present invention.
Claims (10)
1. the method for the Palonosetron metabolite shown in a synthesis type III, it is characterized in that, taking the compound shown in formula I and/or its derivative as raw material, in inert organic solvents, under the oxygenizement of the oxygenant shown in formula IV, reaction obtains the Palonosetron metabolite shown in formula III;
Wherein: the R in formula IV is H, F, Cl, Br or I.
2. the method for the Palonosetron metabolite shown in a kind of synthesis type III according to claim 1, is characterized in that, the derivative of the compound shown in formula I is that general formula is suc as formula the salt shown in II;
Wherein: X is sour acid group.
3. the method for the Palonosetron metabolite shown in a kind of synthesis type III according to claim 2, is characterized in that, described acid is one or more in hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, sulfuric acid, Phenylsulfonic acid and methylsulfonic acid.
4. according to the method for the Palonosetron metabolite shown in a kind of synthesis type III described in claim 1-3 any one, it is characterized in that, described inert organic solvents is the halogenated alkane of a tool 1-3 carbon atom.
5. the method for the Palonosetron metabolite shown in a kind of synthesis type III according to claim 4, is characterized in that, described inert organic solvents is methylene dichloride and/or trichloromethane.
6. according to the method for the Palonosetron metabolite shown in a kind of synthesis type III described in claim 1-3 any one, it is characterized in that, described oxygenant and the mass ratio of raw material are 0.1-10.
7. according to the method for the Palonosetron metabolite shown in a kind of synthesis type III described in claim 1-3 any one, it is characterized in that, described inert organic solvents and the mass ratio of raw material are 1-30.
8. the method for the Palonosetron metabolite shown in a kind of synthesis type III according to claim 1, is characterized in that, described temperature of reaction is-20-100 DEG C.
9. the method for the Palonosetron metabolite shown in a kind of synthesis type III according to claim 8, is characterized in that, described temperature of reaction is 0-25 DEG C.
10. the method for the Palonosetron metabolite shown in a kind of synthesis type III according to claim 1, it is characterized in that, after completion of the reaction described, through filtering, saturated sodium carbonate washing, anhydrous magnesium sulfate drying, filters, is concentrated into anhydrous, obtains the Palonosetron metabolite shown in the formula III of white solid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410459410.2A CN104177356A (en) | 2014-09-10 | 2014-09-10 | Method for synthesizing palonosetron metabolite |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410459410.2A CN104177356A (en) | 2014-09-10 | 2014-09-10 | Method for synthesizing palonosetron metabolite |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104177356A true CN104177356A (en) | 2014-12-03 |
Family
ID=51958733
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410459410.2A Pending CN104177356A (en) | 2014-09-10 | 2014-09-10 | Method for synthesizing palonosetron metabolite |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104177356A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111205284A (en) * | 2020-01-20 | 2020-05-29 | 广州九植医药科技有限公司 | Synthetic method of palonosetron hydrochloride related substance A |
| CN111205283A (en) * | 2020-01-20 | 2020-05-29 | 广州九植医药科技有限公司 | Synthetic method of palonosetron hydrochloride related substance B |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010056656A2 (en) * | 2008-11-11 | 2010-05-20 | Dr. Reddy's Laboratories Ltd. | Preparation of crystalline palonosetron hydrochloride |
| WO2011058427A1 (en) * | 2009-11-13 | 2011-05-19 | Helsinn Healthcare S.A. | Palonosetron metabolites |
-
2014
- 2014-09-10 CN CN201410459410.2A patent/CN104177356A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010056656A2 (en) * | 2008-11-11 | 2010-05-20 | Dr. Reddy's Laboratories Ltd. | Preparation of crystalline palonosetron hydrochloride |
| WO2011058427A1 (en) * | 2009-11-13 | 2011-05-19 | Helsinn Healthcare S.A. | Palonosetron metabolites |
Non-Patent Citations (1)
| Title |
|---|
| 邢其毅 等: "胺的氧化和Cope消除", 《基础有机化学》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111205284A (en) * | 2020-01-20 | 2020-05-29 | 广州九植医药科技有限公司 | Synthetic method of palonosetron hydrochloride related substance A |
| CN111205283A (en) * | 2020-01-20 | 2020-05-29 | 广州九植医药科技有限公司 | Synthetic method of palonosetron hydrochloride related substance B |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wang et al. | Preparation of selenofunctionalized heterocycles via iodosobenzene-mediated intramolecular selenocyclizations of olefins with diselenides | |
| CN113717071A (en) | Preparation method of green visible light catalyzed acetamide compound | |
| CN111393350A (en) | Synthesis method of N-methyl-3-substituted benzylmercapto-4-morpholinyl maleimide compound | |
| EP4186915A1 (en) | Method for synthesizing c-nucleoside compound | |
| CN103172636B (en) | Pyridine-quinazolinone compound and preparation method thereof | |
| CN104177356A (en) | Method for synthesizing palonosetron metabolite | |
| CN108373453A (en) | Triazole derivatives and preparation method thereof | |
| CN102766092A (en) | Method for synthesizing optically active tetrahydroquinoline derivative in presence of chiral spiro phosphoric acid serving as catalyst | |
| CN108822014B (en) | Synthetic method of avibactam intermediate | |
| CN109467559B (en) | Fused bisindole derivatives and process for producing the same | |
| CN102627644A (en) | Method for preparing sapropterin dihydrochloride through direct chiral synthesis method | |
| CN107973755B (en) | Preparation method of 3-acetamido quinoxalinone derivative | |
| CN108218816A (en) | The method for synthesizing the pyran compounds of sulfonyl substitution | |
| CN113105385B (en) | Preparation method of levobupivacaine | |
| CN104059063A (en) | Preparation method of 7,7-difluoro-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine and derivatives of 7,7-difluoro-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine | |
| CN104447776A (en) | Novel heterocyclic organic compound and preparation method thereof | |
| Zhou et al. | Copper Nitrate Mediated Regioselective Difunctionalization of Alkenes with N-Fluorobenzenesulfonimide: A Direct Approach to β-Aminonitrates | |
| CN103951631A (en) | Synthetic method of benzoxazole derivative | |
| CN112266345B (en) | Preparation method of alpha, alpha-difluoro-beta-ketone sulfone compound | |
| CN105481860A (en) | Refinement technique of tadalafil I crystal | |
| CN103130702A (en) | Method for synthesizing 3-substituted indole and 2,3-disubstituted indole | |
| CN105272920B (en) | Bendamustine hydrochloride mannitol ester and preparation method and application thereof | |
| JPS5978164A (en) | 1,2,3,4-tetrahydro-1-aminomethyl-4- phenylisoquinoline and manufacture | |
| CN115650892A (en) | Method for preparing carbon-acyloxy substituted aziridine compound | |
| CN116789712A (en) | Synthesis method of ferrocene amide or sulfamide compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20141203 |