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Preparation method of fosaprepitant dimeglumine

A technology of glucosamine and methyl, which is applied in the field of preparation of nausea and vomiting and postoperative nausea and vomiting compounds, can solve the problems of low yield of final product, high amount of monobenzyl ester, low product yield and the like

Active Publication Date: 2013-03-20
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] CN1075812C embodiment 97 discloses a kind of 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy-3-(S)-(4-fluoro )phenyl-4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolyl)methyl)morpholine bis(N-methyl-D-glucosamine) salt The preparation method, this method is with 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy-3-(S)-(4-fluoro) Phenyl-4-(3-(3-,4H-5 oxo-1,2,4-triazolyl)methylmorpholine and tetrabenzyl pyrophosphate were added NaHMDS, methanol and N-methyl-D-glucosamine, and use palladium carbon catalyst and hydrogen to carry out hydrogenation reduction, the product yield of this method is low, and reaction conditions are harsh
[0006] CN101056672A discloses a preparation method of fosaprepitant, but the method is complicated to operate and the reaction conditions are harsh, so it can still be tried in a small laboratory test, and is not suitable for pilot scale-up and mass production
In addition, the preparation method disclosed in this patent has a low yield of the final product, and there are many by-products of monobenzyl ester, which is not suitable for the production of the pharmaceutical industry

Method used

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

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Experimental program
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Embodiment 1

[0022] step one

Embodiment 1

[0024] 5-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4 -Morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (5.3g, 10mmol), tetrabenzyl pyrophosphate (7.0g, 13mmol) were dissolved in THF (60ml), cooled in an ice-water bath, was added dropwise with 2.0M sodium hexamethyldisilazane (NaHMDS, 12ml, 24mmol), and the reaction temperature was controlled at about -3°C. After dropping, stir for 2 hours until the reaction is complete, add methyl tert-butyl ether (150ml) and saturated sodium bicarbonate solution (150ml), separate the layers, saturated sodium bicarbonate solution (150ml), sodium bisulfate solution (150ml), water ( 150ml), concentrated to dryness, and dried to give 5.8g of white solid, yield 82.3%.

[0025] step two

[0026] The product (5.8g, 8.3mmol) and N-methyl-D-glucosamine (2.2g, 11.3mmol) obtained in the previous step were dissolved in methanol (25ml) / water (1ml), and 10% Pd / C (0.1 g), atmospheric pressure hydrogenation 4h until ...

Embodiment 2

[0031] step one

[0032] 5-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4 -Morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (5.3g, 10mmol), tetrabenzyl pyrophosphate (7.0g, 13mmol) were dissolved in THF (60ml) was cooled in an ice-water bath, 2.0M NaHMDS (12ml, 24mmol) was added dropwise, and the reaction temperature was controlled at about -3°C. After dropping, stir for 2 hours until the reaction is complete, add methyl tert-butyl ether (150ml) and saturated sodium bicarbonate solution (150ml), separate the layers, saturated sodium bicarbonate solution (150ml), sodium bisulfate solution (150ml), water ( 150ml), concentrated to dryness, and dried to give 5.9g of white solid, yield 86.7%.

[0033] step two

[0034] The product (5.9g, 8.4mmol) and N-methyl-D-glucosamine (2.2g, 11.3mmol) obtained in the previous step were dissolved in methanol (25ml) / water (1ml), and 10% Pd / C (0.1 g), atmospheric pressure hydrogenation 4h until the reaction...

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Abstract

The invention relates to a preparation method of fosaprepitant dimeglumine. Fosaprepitant dimeglumine is a compound shown in the formula I. The preparation method is characterized in that a compound shown in the formula II reacts with tetrabenzyl pyrophosphate in the presence of a steric hindrance alkali; and reaction products undergo a hydrogenation-reduction reaction in the presence of N-methyl-D-glucosamine to produce the compound shown in the formula I. The preparation method has simple processes, a high reaction yield, few by-products, and controllable reaction conditions, and is suitable for industrial large-scale production of medicines.

Description

technical field [0001] The invention relates to a preparation method of a compound for treating chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting, especially a preparation method of fosaprepitant dimeglumine. Background technique [0002] Because platinum, doxorubicin and other anti-tumor drugs will cause severe vomiting during the use, acute and severe nausea and vomiting may lead to dehydration, electrolyte imbalance, and malnutrition in patients, and severe cases may be caused by damage to the digestive tract mucosa. Bleeding, infection, and even death make patients fearful of chemotherapy and significantly reduce their compliance, resulting in reduced chemotherapy or suspension of treatment, which seriously affects the therapeutic effect. Therefore, antiemetic drugs are important adjuvant drugs for antitumor therapy, especially The use of drugs for the treatment of moderate and severe vomiting is also mainly concentrated in the field of adjuv...

Claims

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Application Information

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IPC IPC(8): C07F9/6558C07C215/10C07C213/00
Inventor 徐士伟杨宝海
Owner JIANGSU HANSOH PHARMA CO LTD
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