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Impurities of heterocyclic boronic acid compounds and their control methods

A quality, tartrate technology, applied in the preparation of organic compounds, organic chemistry methods, chemical instruments and methods, etc., can solve the difficulty of separation and identification, the large number of impurities in dudagliptin, and the difficulty of separation and identification of impurities, etc. problems, to achieve the effect of ensuring quality stability and drug safety, ensuring purity, and improving product quality

Active Publication Date: 2021-09-28
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Due to the many impurities produced during the synthesis of duogliptin, it is difficult to separate and identify each impurity
Since the amount of the RRT1.09 impurity produced is uncontrollable and has the same polarity as duxagliptin, it is very difficult to separate and identify this impurity, and it is necessary to find a suitable method for its identification and confirmation to further determine its content. control

Method used

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  • Impurities of heterocyclic boronic acid compounds and their control methods
  • Impurities of heterocyclic boronic acid compounds and their control methods
  • Impurities of heterocyclic boronic acid compounds and their control methods

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] The preparation of embodiment 1 impurity (II)

[0063]

[0064] Add 2 g of duagliptin L-tartrate and 100 mL of 0.1% hydrogen peroxide solution into the reaction bottle, and place it at room temperature for at least 90 h. The sample was lyophilized at -18°C to yield 1 g of impurity (II).

[0065] The impurity (II) is dissociated under alkaline conditions, and the L-tartaric acid therein is removed to obtain the impurity (I). During detection, impurity (I) and impurity (II) peak simultaneously.

[0066] Gained impurity (II) is carried out structural identification, obtains following data:

[0067] MS(ESI)m / z=214.1540(M+H) + , consistent with the molecular weight of impurity (II) free base 213.1477. Spectrum see attached figure 1 .

[0068] 1 H NMR (500MHz, D 2 O) δ5.75(s, 1H), 5.39(s, 1H), 4.27(s, 2H), 4.10-4.08(m, 1H), 4.06-4.02(m, 1H), 3.95(s, 1H), 3.72-3.68(m, 1H), 3.55-3.50(m, 3H), 3.38-3.27(m, 2H), 2.51-2.44(m, 1H), 2.18-2.14(m, 1H), 1.94-1.86(m , 3H), s...

Embodiment 2

[0071] The preparation of embodiment 2 high-purity Gliptin L-tartrate

[0072] 1), hydrogenation reaction

[0073]

[0074] Intermediate (2-I) (5.7Kg), 5% wet Pd / C (0.57Kg) and methanol (43L) were added to the reaction kettle. The air in the system was replaced three times with nitrogen, and then three times with hydrogen. Under the hydrogen pressure of 0.5MPa, react at room temperature, when the system pressure drops to 0.3MPa, add hydrogen to the pressure of 0.5MPa, replace the reaction system with hydrogen twice every hour, and react for 5h.

[0075] Fill the pressure filter with microcrystalline cellulose and anhydrous sodium sulfate, pressurize the reaction solution with nitrogen, rinse with methanol, combine the filtrates, concentrate under reduced pressure under nitrogen protection to a residual volume of about 10L, add 14L of ethyl acetate At this time, the mixture is a milky cloudy liquid, continue to concentrate to a remaining volume of about 10L, add 14L of eth...

Embodiment 3

[0080] Example 3 Large-scale preparation of high-purity Gliptin L-tartrate

[0081] 1), hydrogenation reaction

[0082]

[0083] Add intermediate (2-I) (70kg), 5% wet Pd / C (7Kg) and methanol (500L) into the reaction kettle. Replace the air in the system with nitrogen three times, then replace it with 0.5MPa hydrogen three times, stir the reaction at room temperature, add hydrogen to the pressure of 0.5MPa when the system pressure drops to 0.3MPa, replace the reaction system with hydrogen twice every hour, and react for 7h , to terminate the reaction.

[0084] Fill the pressure filter with microcrystalline cellulose and anhydrous sodium sulfate, filter the reaction liquid under pressure with nitrogen, and rinse with methanol. The filtrates were combined, concentrated under reduced pressure under nitrogen protection, and ethyl acetate (180 L) was added. At this time, the mixture was a milky turbid liquid, and the concentration was continued to a residual volume of about 140...

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Abstract

The invention provides impurities (I) and (II) of duogliptin L-tartrate and a preparation method thereof. (I) and (II) are the oxidation impurity of duoglitin L-tartrate, all can produce in duoglitin L-tartrate preparation and placement process. The present invention simultaneously provides the industrialized production of dulogliptin L-tartrate, while reducing the total impurity and controlling the method of impurity (I) and (II) content, has improved the quality standard of dulogliptin L-tartrate, To ensure its drug safety. In addition, impurities (I) and (II) can be used as reference standards or reference substances for the quality control and research of duxagliptin or its L-tartrate salt raw materials and / or preparations.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical analysis and preparation, in particular to impurities (I) and (II) of the heterocyclic boronic acid compound dulogliptin L-tartrate, a preparation method thereof, and a quality control method for (I) and (II) . Background technique [0002] Dutogliptin L-Tartrate (Dutogliptin L-Tartrate) is a selective DPP-IV inhibitor, which is currently in the clinical stage and can be used for glucose regulation in diabetic patients. Duogliptin L-tartrate is a heterocyclic boronic acid compound with the following structure: [0003] [0004] Duogliptin L-tartrate is a white to off-yellow solid powder, easily soluble in methanol and slightly soluble in isopropanol. Because of its strong water absorption, its solid raw material contains about 10% water. At the same time, duogliptin L-tartrate is unstable in nature, and is easily degraded to produce impurities under acidic and alkaline conditions. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/14C07C51/41C07C59/255C07F5/02
CPCC07B2200/07C07C51/412C07C59/255C07D207/14C07F5/025Y02P20/55
Inventor 朱云龙郑直周婷叶杉卿亚丽黄雪惠吕裕斌
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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