Preparation method of fosaprepitant dimeglumine pharmaceutical salt

A fosaprepitant and intermediate technology, applied in a new field of preparation of fosaprepitant dimeglumine, to achieve the effects of enlarged production scale, good appearance and improved safety

Active Publication Date: 2018-12-07
QILU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Patent WO2006010110 (Chinese equivalent CN101056672A) has improved the route of patent WO9523798, and treated the obtained aprepitant phosphoryl dibenzyl ester with methanol to obtain aprepitant phosphoryl monobenzyl ester, but it still needs palladium carbon catalytic hydrogenation Preparation of Fosaprepitant Diglumine

Method used

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  • Preparation method of fosaprepitant dimeglumine pharmaceutical salt
  • Preparation method of fosaprepitant dimeglumine pharmaceutical salt
  • Preparation method of fosaprepitant dimeglumine pharmaceutical salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: [3-[2(R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorobenzene Base)-4-morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl]dibenzyl phosphate (IIa) preparation of

[0026] 300ml of tetrahydrofuran, 14.0g of aprepitant, and 22.3g of tetrabenzyl pyrophosphate were sequentially added into the reaction flask, protected by nitrogen, and cooled to 0-10°C. Add 33.6 kg of sodium hexamethyldisilazane solution while controlling the temperature at 0-10°C. After the addition was completed, the reaction was incubated for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with methyl tert-butyl ether. The organic layer was washed with 0.5M potassium bisulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filter and concentrate to obtain a yellow oil. Add 300ml of cyclohexane and stir at 5-15°C for 2-3 hours. After filtra...

Embodiment 2

[0027] Example 2 [3-[2(R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl )-4-morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl]monobenzyl phosphate (IIIa) preparation

[0028] Add 50ml of methanol and 10.0g of intermediate IIa to the reaction flask, stir at 40-50°C for 8 hours, cool to 0-5°C, keep stirring for 2-3 hours, filter, and vacuum-dry the filter cake for 2-3 hours to obtain White solid 8.0g, yield 89.8%.

Embodiment 3

[0029] The preparation of embodiment 3 fosaprepitant dimeglumine crude product

[0030] Add 5.0g of intermediate IIa, 2.8g of N-methyl-D glucamine, 0.5g of 10% palladium carbon, 1.9g of triethylsilane and 50ml of methanol into the reaction flask, and stir at room temperature for 2 hours. After the reaction, remove the palladium carbon by filtration, add 150ml of isopropanol to the filtrate, stir and crystallize, filter, and vacuum-dry the filter cake for 5-6 hours to obtain 5.1 g of white solid, with a yield of 80.7%. HPLC purity 99.5%;

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Abstract

The invention belongs to the technical field of medicine chemistry, and particularly relates to a novel preparation method of fosaprepitant dimeglumine. According to the preparation method, triethyl silane is used for replacing hydrogen, and high-pressure equipment can be prevented from being used, so that the safety is improved, and the obtained product is good in appearance, high in purity and suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a new preparation method of fosaprepitant dipglumine. The preparation method uses triethylsilane instead of hydrogen, can avoid the use of high-pressure equipment, improves safety, and the obtained product has good appearance and high purity, and is suitable for large-scale industrial production. Background technique [0002] Fosaprepitant Diglumine is a water-soluble phosphoryl prodrug of Aprepitant. After intravenous injection, it can be quickly converted into Aprepitant through phosphorylation in the body. It is suitable for patients who cannot be taken orally, Patients with difficulty swallowing or poor digestion. Fosaprepitant dimglumine and aprepitant belong to a group of selective high-affinity receptor blockers called human substance P / neurokinin 1 (NK-1), which mainly block nausea and vomiting signals in the brain The novel mechanism of action p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558C07C213/02C07C215/10
CPCC07C213/02C07F9/65583C07C215/10
Inventor 张红卫田振平庄红伟李国峰房金海程世强
Owner QILU PHARMA
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