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A method for preparing fosaprepitant dimeglumine

The technology of fosaprepitant dimeglumine and step 2 is applied in the field of preparing fosaprepitant dimeglumine, and can solve the problem of being unsuitable for pilot scale scale-up and mass production, having too many monobenzyl esters and low product yield. And other issues

Active Publication Date: 2016-06-15
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] CN1075812C discloses a kind of 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy-3-(S)-(4-fluoro)phenyl -The preparation method of 4-(3-(1-phosphoryl-5 oxo-4H-1,2,4-triazolyl)methyl)morpholine bis(N-methyl-D-glucosamine) salt , it has been verified that the product yield of this method is low
[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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  • A method for preparing fosaprepitant dimeglumine
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  • A method for preparing fosaprepitant dimeglumine

Examples

Experimental program
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preparation example Construction

[0037] Example 2 Preparation of compound of formula III

[0038] Add the compound of formula II (13.4g, 30mmol) and tetrahydrofuran (15ml) into a 250ml four-neck flask, stir and cool to 15°C, add 4-fluorophenyl magnesium bromide (1.0M THF solution, 40ml, 40mmol) dropwise, dropwise Stir at room temperature for 40min, add this solution dropwise to ice-cooled methanol (30ml), stir for 15min, add p-toluenesulfonic acid (10.4g, 54.7mmol) in methanol (20ml) solution, 10% Pd / C (0.4g ) And ammonium formate (3.8 g, 60 mmol) until the reaction is complete. Filter, wash with methanol, and concentrate to dryness. Add methyl isobutyl ketone (90 ml), stir, and add a solution of sodium carbonate (9.0 g) / sodium citrate (10.8 g) in water (120 ml). Separate the liquids, extract the aqueous layer with methyl isobutyl ketone (40 ml), combine the organic layers, and wash with water (50 ml). Add concentrated hydrochloric acid (5ml), filter, and evaporate the filtrate to dryness under normal pressur...

Embodiment 3

[0039] Example 3 Synthesis of raw material A

[0040]

[0041] Dissolve sodium (0.23g, 10mmol) in methanol (30ml), add it dropwise to chloroacetonitrile (26.3g, 0.348mol) in methanol (150ml) cooled to 0°C, stir at room temperature for 30min, and add methyl carbazate Ester (30.8g, 0.342mol) and acetic acid (0.6g) were stirred at room temperature for 40min. Concentrate to dry light yellow solid, add ether (150ml), stir under reflux for 30min, stir and cool, filter, wash with ether, and dry to obtain light yellow solid raw material A (56.3g, 99.4%).

Embodiment 4

[0042] Example 4 Preparation of compound of formula IV

[0043] Add the compound of formula III (10.0g), sodium carbonate (10.2g), dimethyl sulfoxide (20ml), toluene (20ml) into a 250ml reaction flask, stir for 5min in an ice water bath, add raw material A (3.9g) and stir until TLC display After the reaction was complete, toluene (50ml) and water (50ml) were added to separate the layers. The aqueous layer was extracted with toluene (40ml), the organic layers were combined and washed with hot water (50ml) at 50°C. Dry, filter, concentrate to dryness, and directly use in the next reaction.

[0044]

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Abstract

The invention relates to a method for preparing fosaprepitant. The fosaprepitant is shown as a formula (I). The method comprises steps 1, 2, 3 and 4, finally, a compound shown as the formula (I) is obtained through hydrogenation reduction; in the step 1, a compound in a formula (II) reacts with a Grignard reagent to generate a compound shown as a formula (III) in the presence of palladium carbon and ammonium formate. The method for preparing is simple in production step, has high reaction yield and less side products, is easy in control of the reaction conditions and is suitable for medical industrial production.

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, in particular to a preparation method of fosapitan and meglumine. Background technique [0002] Since platinum, doxorubicin and other anti-tumor drugs will produce severe vomiting during use, acute and severe nausea and vomiting may cause 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 their compliance is significantly reduced. As a result, the dose of chemotherapy is reduced or the treatment is discontinued, which seriously affects the therapeutic effect. Therefore, antiemetic drugs are important adjuvant therapy drugs for anti-tumor therapy, especially The use of drugs for the treatment of moderate and severe vomiting is also mainly concentr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6558C07C215/10C07C213/08
Inventor 徐士伟袁阜平
Owner JIANGSU HANSOH PHARMA CO LTD
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