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Preparation method of landiolol hydrochloride

A technology for landiolol hydrochloride and salt formation, applied in the field of preparation of landiolol hydrochloride, can solve problems such as affecting product quality and yield, malodorous thioether, insufficient alkali stability and the like

Active Publication Date: 2018-11-06
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] CN104003973A discloses that the compound landiolol is very easy to undergo transesterification or alcoholysis with alcohol solvents under alkaline conditions, thus bringing risks to the safety and effectiveness of the drug
CN101012217A discloses that Landyrolol is easily decomposed in methanol to produce by-products, and has chosen to avoid using methanol in the process, but still adopts isopropanol / water as the reaction solvent to carry out the epoxy ring-opening reaction in its synthesis process, Unavoidable isopropyl transesterification impurities
However, these solvents are easily decomposed in aqueous sodium hydroxide solution
Dimethyl sulfoxide is not stable enough to alkali, and it is easy to decompose and produce its own disproportionation reaction, resulting in a foul-smelling sulfide taste; in addition, the oxidative property of dimethyl sulfoxide itself will affect the easily oxidizable groups of landyrolol such as hydroxyl , the amine group is affected by the formation of oxidized impurities such as ketones, nitrogen oxides, etc. Therefore, this solvent is also an unsuitable solvent
In addition, CN102232930A discloses that landyrolol is easy to hydrolyze and isomerize under acidic and alkaline conditions, especially under alkaline conditions, the ester hydrolysis reaction is more likely to occur, resulting in alkali hydrolysis impurities shown in formula V, thus affecting the quality of the product. quality and yield

Method used

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  • Preparation method of landiolol hydrochloride
  • Preparation method of landiolol hydrochloride
  • Preparation method of landiolol hydrochloride

Examples

Experimental program
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Effect test

specific Embodiment approach

[0049] The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

[0050] Test equipment used in the experiment:

[0051] Chromatographic column: Octadecylsilane bonded silica gel as filler

[0052] Detection wavelength: 223nm

[0053] Flow rate: 0.8ml / min

[0054] Mobile phase A: Phosphate solution (take 0.5g sodium heptanesulfonate and 3.9g sodium dihydrogen phosphate, add water 1000mL to dissolve)-methanol (60:40)

[0055] Mobile Phase B: Methanol

[0056] Carry out gradient elution according to the following table:

[0057]

[0058] The experimental methods not indicating specific conditions in the examples of the present invention are generally in accordance with conventional conditions, or in accordance with the conditions suggested by raw material or commodity manufacturers. Reagents without specific sources indicated are conventional reagents purchased in the market.

Embodiment 1、4

[0059] Example 1, 4-[(2S)-3-cyclopropoxy]phenylpropanoic acid [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl ester ( The preparation of formula 1)

[0060]

[0061] Add acetonitrile (9.0kg) in reactor, 600g 4-hydroxyphenylpropionic acid [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl] methyl ester and 566g (S )-glycidyl m-nitrobenzenesulfonate, then add potassium carbonate (1.18kg). Then the reaction system was raised to 62-70°C for reaction. After the reaction, the reaction system was cooled down to room temperature. After filtration, the filtrate was concentrated to dryness to obtain an oil, which was directly used in the next reaction.

Embodiment 2

[0062] Embodiment 2, the preparation of N-(2-aminoethyl)-4-morpholine formamide (formula 2 compound)

[0063]

[0064] After adding 30 kg of dichloromethane and 3.0 kg of N-(2-aminoethyl)-4-morpholine formamide oxalate into the reaction kettle, 5.0 kg of anhydrous sodium sulfate and 1.14 kg of sodium hydroxide were added. React at 30°C for 15-18h. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain about 1.97 kg of light yellow oil, with a yield of 99.5%.

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Abstract

The invention relates to a preparation method of landiolol hydrochloride, in particular to the selection of a reaction solvent 1,4-dioxane. The landiolol hydrochloride prepared by means of the methodcan prevent the generation of ester exchange impurities, the operation is simple, the reaction yield is high, the method is suitable for industrial large-scale production, and a crude drug and the preparation of the crude drug have better safety performance, effectiveness and stability, and have significant use in preparing drugs used for urgently treating arrhythmia and postoperative dynamic monitoring abnormality.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of landisolol hydrochloride. Background technique [0002] Landiolol hydrochloride (Landiolol hydrochloride, CAS: 133242-30-5), trade name: Onoact; chemical Chinese name: 4-[(2S)-2-hydroxy-3-[[2-[(4-morpholine Carbonyl)amino]ethyl]amino]propoxy]phenylpropanoic acid [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl ester hydrochloride, which has Chemical structure as shown in formula II, [0003] [0004] Landiolol is a selective β1-receptor blocking drug with a broad-spectrum effect, and exists in the form of hydrochloride in specific applications. It mainly antagonizes the β1 receptor present in the heart and inhibits the increase in heart rate caused by catecholamines. The drug was first developed by Japan's Ono (Ono) Pharmaceutical Industry Co., Ltd., and was first listed in Japan in September 2002. It is used for tachycardia arrhythmias (including atrial fib...

Claims

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Application Information

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IPC IPC(8): C07D317/24A61K31/5377A61P9/06
CPCA61P9/06C07D317/24
Inventor 文利斌陈昱李长松何飚薛州洋
Owner JIANGSU HENGRUI MEDICINE CO LTD
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