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Olopatadine alpha methyl compound, and preparation method and application thereof

A technology for olopatadine and compound, which is applied in the field of olopatadine alpha methyl compound and preparation, and can solve problems such as unfavorable safe production, high safety risk and the like

Active Publication Date: 2020-10-23
唯智医药科技(北京)有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, because sodium hydride and other materials release flammable gas when they meet water, the safety risk is relatively large in the production process, which is not conducive to safe production. At present, some manufacturers have replaced it with safer bis(trimethylsilyl)amide Sodium (alias: sodium hexamethyldisilazide) or potassium bis(trimethylsilyl)amide is more conducive to safe production

Method used

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  • Olopatadine alpha methyl compound, and preparation method and application thereof
  • Olopatadine alpha methyl compound, and preparation method and application thereof
  • Olopatadine alpha methyl compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1 The method for preparing olopatadine α methyl compound:

[0035]

[0036] Take 20 g of isoket acid (compound 1) and add it to the reaction flask, add 50 ml of isopropanol, stir and cool down to 0-10°C, add 10 g of thionyl chloride dropwise, stir and heat up to reflux after the addition, TLC detects that the reaction is complete After cooling down, thionyl chloride and isopropanol were removed by concentration under reduced pressure, and then 40ml of isopropanol was added for recrystallization to obtain 22g of compound 2.

[0037]

[0038] Take 20g of compound 2, add 200ml of N,N-dimethylformamide, stir and dissolve completely, control the temperature below 10°C, add 8.47g of potassium tert-butoxide, stir and control the temperature below 10°C, add 10.26g of methyl iodide dropwise, and the reaction is complete at room temperature , drop 150ml of purified water to quench the reaction, then use dichloromethane to extract completely, use anhydrous sodium ...

Embodiment 2

[0043] Example 2 Confirmation of impurities

[0044] Multiple batches of the original drug olopatadine hydrochloride (trade name: Alloca) were tested using the following method: mobile phase A was potassium dihydrogen phosphate solution-acetonitrile (75:25), and mobile phase B was potassium dihydrogen phosphate Solution-Acetonitrile (40:60), AgelaVenusil MP C8 (4.6*250mm) chromatographic column, the detection wavelength is 299nm.

[0045] result figure 2 Shown, detect and separate and find the impurity compound of about 0.019% trace (see figure 2 36.682min place), the same separation environment, fully matched with the compound obtained in Example 1. It can be seen that the impurity is the olopatadine α-methyl compound prepared in Example 1.

Embodiment 3

[0047] Preparation system: prepare with reference to the method in CN1042211676:

[0048]

[0049] It is extremely difficult to separate during the separation and preparation of the mother liquor. It exists in a small amount in the mother liquor, and is similar in polarity to other impurities. The peak time in HPLC (high performance liquid chromatography) is relatively close, but it is not easy to prepare and separate. After using more methods for purification and separation (silica gel column chromatography, Sephadex, ODS reverse phase, HPTLC, HPLC, etc.), try to use HPLC for separation, and replace different chromatographic columns (Agela Venusil MP C8 (4.6*250mm), phenomenonex Ultracarb (4.6*150mm, etc.), changing the mobile phase ratio, buffer salt type and ratio, etc., finally found that adding a small amount of trifluoroacetic acid can be effectively separated, and then obtained trace amounts of the Impurities, for structural confirmation.

[0050] Specific process: ...

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PUM

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Abstract

The invention discloses an olopatadine alpha methyl compound, and a preparation method and application thereof, and belongs to the technical field of medicines. The impurity compound olopatadine alphamethyl compound in the olopatadine medicine is discovered for the first time, and the standard substance of the olopatadine alpha methyl compound can be used for qualitative analysis and quantitativedetection of impurities in the olopatadine hydrochloride medicine. Meanwhile, the invention also provides an emulsifiable paste based on the compound. The compound can be used as an active componentin the emulsifiable paste product for mainly treating main symptoms, and is mainly used for treating skin diseases such as mosquito bites and the like.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to olopatadine α-methyl compound, its preparation method and application. Background technique [0002] Olopatadine hydrochloride (olopatadine hydrochloride) is an antiallergic drug developed and marketed by Kyowa Hakko, Japan, and has been marketed in Europe, the United States, Japan and other countries. It has the dual functions of inhibiting the release of histamine and selectively antagonizing HI receptors, without the central nervous system depression and cardiotoxic side effects common to HI receptor antagonist antiallergic drugs. It is used orally for allergic rhinitis, skin irritation, polymorphic Treatment of exudative erythema and urticaria. Its eye drops are used to treat allergic conjunctivitis. The drug can not only inhibit the release of histamine from mast cells, but also selectively antagonize H1 receptors, and has no effect on α-adrenoceptors, dopamin...

Claims

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Application Information

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IPC IPC(8): C07D313/12A61K31/335A61P17/00A61K47/06A61K47/14A61K47/18
CPCA61K9/0014A61K9/06A61K47/06A61K47/14A61K47/18A61P17/00A61P17/04C07D313/12
Inventor 瞿鑫季子建左伟初野张建楼张佳祥
Owner 唯智医药科技(北京)有限公司
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