Preparation method of fosaprepitant dimeglumine

A technology for fosaprepitant dimeglumine and fosaprepitant, which is applied in the field of preparation of fosaprepitant dimeglumine, can solve the problems of being unsuitable for large-scale industrialized production, having a long reaction period and many production processes, and the like, Achieve the effect of shortening production cycle, low production cost and low equipment requirements

Active Publication Date: 2012-07-11
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that the reaction cycle is long, the production process is many, the yield is low, and it is not suitable for industrialized large-scale production.

Method used

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  • Preparation method of fosaprepitant dimeglumine
  • Preparation method of fosaprepitant dimeglumine
  • Preparation method of fosaprepitant dimeglumine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 {3-[2(R)-[(1R)-1-[3, 5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl )morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl}di-p-ethylbenzyl phosphate (intermediate ) preparation

[0029] Add 12g (22.4mmol) of aprepitant (22.4mmol), 21.9g (33.6mmol) of tetra-p-ethylbenzyl pyrophosphate and 150mL of THF into a 250mL three-necked flask, stir to dissolve, cool the temperature to 0~5°C in an ice-salt bath, and divide 4.3 g (44.8 mmol) of sodium tert-butoxide was added in batches, and the temperature was controlled below 5° C. during the addition, and monitored by TLC until the reaction was completed. Pour the reaction solution into 150 mL of saturated NaHCO 3 Then add 150mL of ether to the solution, separate the layers, wash the organic phase with 100mL of purified water until the pH is neutral, and concentrate to dryness under reduced pressure to obtain 16.2g of the product with a purity of 99.63% and a yield of 85.0%.

Embodiment 2

[0030] Example 2 {3-[2(R)-[(1R)-1-[3, 5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl )morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl}di-p-methylbenzyl phosphate (intermediate ) preparation

[0031] Add 12g (22.4mmol) of aprepitant, 20.0g (3.36mmol) of tetra-p-methylbenzyl pyrophosphate and 165mL of THF into a 250mL three-neck flask, stir to dissolve, cool the temperature to 0~5°C in an ice-salt bath, and add methanol Sodium 2.4g (44.8mmol), the temperature was controlled below 5°C during the addition process, and monitored by TLC until the reaction was completed. Pour the reaction solution into 120 mL of saturated NaHCO 3 Then add 180mL ether to the solution, separate the layers, wash the organic phase with 120mL of purified water twice until the pH is neutral, and concentrate to dryness under reduced pressure to obtain 16.1g of the product with a purity of 99.70% and a yield of 85.2%.

Embodiment 3

[0032] Example 3 {3-[2(R)-[(1R)-1-[3, 5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl )morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl}di-p-chlorobenzyl phosphate (intermediate) preparation of

[0033] Add 12g (22.4mmol) of aprepitant, 22.7g (33.6mmol) of tetra-p-chlorobenzyl pyrophosphate and 150mL of THF into a 250mL three-neck flask, stir to dissolve, cool the temperature in an ice-salt bath to 0~5°C, and add in batches 4.9 g (44.8 mmol) of sodium tert-amylate, the temperature was controlled below 5°C during the addition process, and monitored by TLC until the reaction was completed. Pour the reaction solution into 150 mL of saturated NaHCO 3 Then add 150mL ether to the solution, separate the layers, wash the organic phase with 150mL of purified water twice until the pH is neutral, and concentrate to dryness under reduced pressure to obtain 16.8g of the product with a purity of 99.55% and a yield of 87.1%.

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Abstract

The invention provides a preparation method of fosaprepitant dimeglumine. The preparation method is characterized in that aprepitant is used as a raw material, under an alkaline condition, dibenzyl ester intermediate compound is obtained by phosphonylation, the intermediate compound is further hydrogenated and catalyzed to obtain fosaprepitant, the fosaprepitant is further reacted with N-methyl-D-glucamine, and finally the fosaprepitant dimeglumine is obtained. The preparation method has the advantages of short reaction cycle, simpleness in operation, low production cost and good product quality; the purity of the finished product is more than 99.5 percent, and the content of single impurity is less than 0.1 percent; and the preparation method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine production, in particular to a preparation method of fosaprepitant dimeglumine. Background technique [0002] Fosaprepitant dimeglumine (fosaprepitant dimeglumine, trade name Emend), CAS number: 265121-04-8, the structural formula is shown in formula III: [0003] [0004] (Ⅲ) [0005] Fosaprepitant dimeglumine was developed by Merck, and another drug of the company, aprepitant, is used to treat acute and delayed nausea and vomiting induced by chemotherapy. Its mechanism of action is different from that of setron-type antiemetics, such as ondansetron from GlaxoSmithKline and granisetron from Roche, which belong to the antiemetic class of 5-hydroxytryptamine-3 receptor antagonists. Fosaprepitant dimeglumine and aprepitant belong to the neurokinin-1 (NK-1) receptor, that is, substance P antagonists, and they mainly work by blocking the novel mechanism of action of the brain's nausea and vomiti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558C07C215/10C07C213/08
Inventor 宗在伟张艳阳刘同根杜有国
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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