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Method for synthesizing palonosetron metabolite

A technology of palonosetron and metabolites, which is applied in the field of medicine, can solve the problems of complex operation, high cost, and long steps, and achieve the effect of simple operation

Inactive Publication Date: 2014-12-03
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the preparation and use of ozone in this method requires special equipment, the operation is complicated, and it is not convenient for scale-up preparation.
[0012] At present, the methods for obtaining quinine epoxides reported in the literature are relatively demanding, and in the prior art, quinine epoxides are used as starting materials to synthesize 3aS, 3'S)-2-[-1-azabicyclo [2.2.2] Oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1H-benzo[de]isoquinoline nitrogen oxides have the following common disadvantages: Raw materials are not easy to obtain, the steps are long, cannot be scaled up, and the cost is expensive

Method used

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  • Method for synthesizing palonosetron metabolite
  • Method for synthesizing palonosetron metabolite
  • Method for synthesizing palonosetron metabolite

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] In a 250ml three-necked reaction flask, add (3aS,3'S)-2-[-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro- 1-Oxygen-1H-benzo [de] isoquinoline 5g (0.017mol), 25ml dichloromethane, then under stirring condition, drop 2.5g (0.029g) m-chloroperoxybenzoic acid dissolved in 25ml dichloromethane mol); after the addition is complete, react at 25°C for 2 hours, and take samples for monitoring.

[0055] Post-processing: stop the reaction, filter, wash twice with saturated sodium carbonate, dry over anhydrous magnesium sulfate, filter, and concentrate to dryness to obtain 4.8 g of off-white solid with a yield of 91.1%.

[0056] HPLC content: 98.4%; (see Table 1 and attached figure 1 );

[0057] Mass spectrometry: Instrument model: AccuTOF CS / CADM-YQ-003

[0058] According to theoretical calculation, its [M+]=312.18378, [M+H]=313.19160; low-resolution mass spectrum shows its [M+H]=313.2, [M+Na]=335.2, [M+K]=351.2, which is consistent with The nitrogen oxides have the same ...

Embodiment 2

[0063] The influence of embodiment 2 different reaction temperature conditions on the synthesis of isoquinoline nitrogen oxides

[0064] According to the method in Example 1, explore different reaction temperature conditions (as shown in Table 1) to palonosetron metabolite (3aS, 3'S)-2-[-1-azabicyclo[2.2.2]octyl- The influence of 3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1H-benzo[de]isoquinoline nitrogen oxide synthesis (that is, the reaction temperature is different, and the others are the same) , the results are shown in Table 2.

[0065] Table 2 Effects of different reaction temperature conditions on the synthesis of isoquinoline nitrogen oxides

[0066] Reaction temperature (°C)

Embodiment 3

[0067] The influence of embodiment 3 different oxidants on the synthesis of isoquinoline nitrogen oxides

[0068] According to the method in Example 1, explore the effect of different oxidants (as shown in Table 2) on palonosetron metabolite (3aS, 3'S)-2-[-1-azabicyclo[2.2.2]octane-3- base]-2,3,3a,4,5,6-hexahydro-1-oxo-1H-benzo[de]isoquinoline nitrogen oxide synthesis, the results are shown in Table 3.

[0069] Table 3 Effects of different oxidants on the synthesis of isoquinoline nitrogen oxides

[0070] Reaction material

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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 [0001] The invention belongs to the technical field of medicines, in particular to a synthetic palonosetron metabolite (3aS,3'S)-2-[-1-azabicyclo[2.2.2]oct-3-yl]-2,3, New method for 3a,4,5,6-hexahydro-1-oxo-1H-benzo[de]isoquinoline nitroxide. Background technique [0002] Nausea and vomiting side effects of chemotherapy and radiation therapy against cancer are common and chronic problems. Palonosetron hydrochloride (formula V) has a very effective effect on acute and delayed nausea and vomiting caused by moderate or highly emetogenic chemotherapy, and nausea and vomiting caused after surgery. Palonosetron hydrochloride chemical name (3aS,3'S)-2-[-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro- 1-Oxo-1H-benzo[de]isoquinoline hydrochloride (CAS No.: 119904-90-4), its empirical formula is C 19 h 24 N 2 O. HCL, with a molecular weight of 332.87, was developed by the Hlesinm company in Switzerland and was launched in the U.S. in September 2003. Palonose...

Claims

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Application Information

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IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 张波毛启良张霄
Owner CHONGQING HUABANGSHENGKAI PHARM
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