Impurity in ziprasidone hydrochloride and preparation method thereof

A technology of ziprasidone hydrochloride and ziprasidone, which is applied in the field of ziprasidone hydrochloride impurity research, can solve problems such as the difficulty of impurity reference substances, and achieve the effects of reducing drug risk, simple method, and strong controllability

Pending Publication Date: 2021-06-15
HAINAN XINOPEN SOURCE MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the course of the research, it was found that using the synthetic method of the literature, when the impurity exists in a small amount (below 0.5%), it is difficult to obtain a sufficient amount of the impurity reference substance by separating the reaction solution

Method used

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  • Impurity in ziprasidone hydrochloride and preparation method thereof
  • Impurity in ziprasidone hydrochloride and preparation method thereof
  • Impurity in ziprasidone hydrochloride and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0070] The invention provides a kind of preparation method of the impurity in ziprasidone hydrochloride, comprises the following steps:

[0071] 1) After mixing the Lewis acid and the first solvent, under a protective atmosphere, after adding chloroacetyl chloride or bromoacetyl bromide, and then adding 1,3-dihydro-indol-2-one for Friedel-Crafts acylation reaction , to give 5-(2-chloro-acetyl)-1,3-dihydro-indol-2-one or 5-(2-bromo-acetyl)-1,3-dihydro-indol-2- ketone;

[0072] 2) The 5-(2-chloro-acetyl)-1,3-dihydro-indol-2-one or 5-(2-bromo-acetyl)-1,3-dihydro- After indol-2-one, reducing agent and second solvent carry out reduction reaction, obtain 5-(2-chloro-1-hydroxyl-ethyl)-1,3-dihydro-indol-2-one or 5- (2-Bromo-1-hydroxy-ethyl)-1,3-dihydro-indol-2-one;

[0073] 3) 5-(2-chloro-1-hydroxyl-ethyl)-1,3-dihydro-indol-2-one or 5-(2-bromo-1-hydroxyl-ethyl) obtained in the above steps -1,3-dihydro-indol-2-one, 3-piperazinyl-1,2-benzisothiazole hydrochloride, alkali and the thi...

Embodiment 1

[0113] step 1:

[0114]Add 100mL of dichloromethane into a 250mL three-necked flask, cool to 0°C in an ice-water bath, slowly add aluminum trichloride (30.0g, 225.3mmol) in batches while stirring, keep the temperature below 20°C, a yellow suspension, add Finished, nitrogen protection. Start to slowly add chloroacetyl chloride (10.2 g, 90.1 mmol) dropwise, keeping the temperature below 20°C. After the dropwise addition was completed, stir for 30 min. Compound 2 (10.0 g, 75.1 mmol) was added slowly, the temperature rose to 30° C. during the addition, and the yellow suspension turned into a black solution. Stir under nitrogen protection at room temperature for 24 hours. TLC monitors that the reaction raw materials have completely reacted, and slowly pours into 200 mL of ice water, keeping the temperature below 30°C. A large amount of solids precipitated, and 100 mL of water was added, stirred for 15 minutes, filtered, and the filter cake was slurried with 50 mL of methanol f...

experiment example 2

[0125] The difference from Example 1 is that the equivalent ratio of compound 4 and compound 4a in step 3 is 1:1.0.

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Abstract

The invention provides an impurity in ziprasidone hydrochloride. The impurity has a structure as shown in formula 1. The impurity with a specific structure is obtained on the basis that chlorine impurities are doped in the ziprasidone hydrochloride preparation process, or impurities are brought in and transferred into a final product in the dechlorination step in the acylation reaction process, and the corresponding impurity preparation steps are provided, so that corresponding technical support is provided for preparation of ziprasidone hydrochloride. The synthesis method provided by the invention is simple in process, strong in controllability and mild in condition, can be used for quality standard establishment and quality control links in ziprasidone hydrochloride process research and development, production and the like, and provides technical support for the medication safety of ziprasidone hydrochloride. The method can be used for quality research such as qualitative and quantitative analysis of impurities in ziprasidone hydrochloride synthesis, so that improvement of the quality of ziprasidone hydrochloride is facilitated, and important guiding significance is provided for reducing the medication risk of ziprasidone hydrochloride.

Description

technical field [0001] The invention relates to the technical field of impurity research on ziprasidone hydrochloride, in particular to an impurity in ziprasidone hydrochloride and a preparation method thereof. Background technique [0002] Ziprasidone, marketed under the brand name Geodon among others, is an atypical antipsychotic (AAP; SGAs) used in the treatment of schizophrenia and acute mania and agitated depression associated with bipolar disorder . Its immediate-release intramuscular form is approved for acute psychomotor agitation in patients with schizophrenia. Ziprasidone can also be used for the treatment of depressive symptoms, bipolar disorder, and post-traumatic stress syndrome (PTSD) and other symptoms of off-label treatment drugs. [0003] Oral administration of ziprasidone is in the form of hydrochloride, ziprasidone hydrochloride and the like. On the other hand, intramuscular injection (IM) administration is in the form of mesylate, ziprasidone mesylate ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor 赵宇郭照珊张丽杰
Owner HAINAN XINOPEN SOURCE MEDICAL TECH CO LTD
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