Preparation method for fosaprepitant dimeglumine

A technology of fosaprepitant dimeglumine and methanol, applied in the field of drug preparation, can solve the problems of long reaction time, high cost of industrial production, low yield, etc., and achieve the effects of simple operation, low cost and high yield

Inactive Publication Date: 2013-07-03
YANGZIJIANG PHARMA GROUP SHANGHAI HAINI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] This process adopts step-by-step method to obtain intermediate 2, but its yield is relatively low (78%), and Pd / C, H 2 When reducing, the reaction time is long, and the cost of industrial production is too high

Method used

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  • Preparation method for fosaprepitant dimeglumine
  • Preparation method for fosaprepitant dimeglumine
  • Preparation method for fosaprepitant dimeglumine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1 prepares two-O-phenyl phosphate

[0027]

Embodiment 2

[0029] Embodiment 2 prepares mono-O-phenyl phosphate

[0030]

[0031] In a 500mL single-necked flask, add methanol (150mL) to dissolve 40g of bis-O-phenyl phosphate in Example 1, raise the temperature to 45°C, and react for 4h. A large amount of white precipitate precipitates, which is tracked by TLC until the bis-O-phenyl The base phosphoric acid ester reacted completely, stopped the reaction, and filtered to obtain a white solid, which was mono-O-phenyl phosphoric acid ester (25.1 g, total yield of Examples 1 and 2: 95%). Purity > 98%;

[0032] 1 H NMR (DMSO-d6, 500MHz, ppm) δ7.86(s, 1H), 7.52(brs, 2H), 7.34~7.29(m, 7H), 7.08(t, J=8.5, 2H), 5.01~4.94 (m, 2H), 4.36(s, 1H), 4.13(t, J=15.0, 2H), 3.63(s, 1H), 3.54(d, J=20.0, 2H), 3.17(s, 1H), 2.82 (t, J=15.0, 2H), 1.43 (d, J=6.6, 3H). ESI-MS 705.1 (M+H, 100%).

Embodiment 3

[0033] Embodiment 3 prepares fosaprepitant dimeglumine

[0034]

[0035] In a 2L catalytic hydrogenation reactor, add 2.0g 10% Pd / C, at 0.4MPa, at room temperature (28°C), hydrogenate for 0.5h, then add the mono-O-phenyl phosphate (20.0 g, 28.4mmol), N-methyl-D-glumine (11.1g, 56.9mmol), methanol (200mL), water (10mL), make its solid dissolve completely; ), hydrogenation reaction 4h, TLC analysis, raw material reaction is complete, stop reaction. Diatomaceous earth was used to filter out Pd / C, methanol (400 mL) was used to wash diatomaceous earth, the filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo at 35°C to obtain the crude product fosaprepitant dimeglumine. The crude product was completely dissolved in methanol (100 mL), quickly dropped into isopropanol (600 mL), and a large amount of white precipitate was precipitated, which was filtered with air isolation to obtain a white filter cake, which was dried under reduce...

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Abstract

The invention provides a preparation method for fosaprepitant dimeglumine. The method comprises the steps of condensation reacting aprepitant and tetrabenzyl pyrophosphate in tetrahydrofuran in presence of bis(trimethylsilyl)sodamide to obtain bis-O-phenyl phosphate; then temperature reacting with methanol to obtain mono-O-phenyl phosphate; and finally obtaining the fosaprepitant dimeglumine through a hydrogenation reaction. The method is simple in operations, mild in conditions, low in cost and high in yield, is suitable for industrialized production and has relatively large application value.

Description

technical field [0001] The invention relates to medicine preparation, in particular to a method for preparing medicine fosaprepitant dimeglumine for treating nausea and vomiting caused by tumor chemotherapy. Background technique [0002] Chemotherapy is one of the commonly used methods for the treatment of malignant tumors. However, the adverse reactions of nausea and vomiting (CINV) caused by chemotherapy drugs are relatively serious, and the side effects of chemotherapy have become a serious clinical problem; if the control of these adverse reactions is not ideal, it will It will affect the quality of life of patients and further reduce the compliance of treatment. [0003] Fosaprepitant dimeglumine and aprepitant are human substance P / neurokinin 1 (NK-1) selective high-affinity receptor blockers, which mainly block the nausea and vomiting signals of the brain. Mechanism of Action An antiemetic effect occurs. If combined with other antiemetic drugs for intravenous inject...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558
Inventor 何春生陶元志陆宇伟刘文虎高苇姚书扬徐赟冯志祥
Owner YANGZIJIANG PHARMA GROUP SHANGHAI HAINI PHARMA
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