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Dihalide impurity in ziprasidone hydrochloride intermediate and preparation method of dihalide impurity

A technology for ziprasidone hydrochloride and intermediates, which is applied in the field of ziprasidone hydrochloride impurity research, can solve problems such as carry-in and generation of impurities, and achieve the effects of strong controllability, mild conditions, and reduced drug risk

Active Publication Date: 2021-04-30
HAINAN XINOPEN SOURCE MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, in the actual reaction process, impurities may be produced in the raw materials, intermediates and the preparation process, which are finally brought into the ziprasidone product

Method used

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  • Dihalide impurity in ziprasidone hydrochloride intermediate and preparation method of dihalide impurity
  • Dihalide impurity in ziprasidone hydrochloride intermediate and preparation method of dihalide impurity
  • Dihalide impurity in ziprasidone hydrochloride intermediate and preparation method of dihalide impurity

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preparation example Construction

[0086] In the present invention, the ziprasidone is preferably prepared by the following steps:

[0087] Using 6-chloroindol-2-one as the starting material, introduce chloroacetyl chloride or bromoacetyl bromide through Friedel-Crafts reaction to obtain 5-(2-chloroacetyl)-6-chloro-1,3-di Hydrogen-indol-2-one or 5-(2-bromoacetyl)-6-chloro-1,3-dihydro-indol-2-one, followed by reduction of the carbonyl to give 5-(2-chloroethyl )-6-chloro-1,3-dihydro-indol-2-one or 5-(2-bromoethyl)-6-chloro-1,3-dihydro-indol-2-one, then in In the presence of a base, react with 3-piperazinyl-1,2-benzisothiazole hydrochloride to obtain ziprasidone.

[0088] The present invention provides a kind of preparation method of the dihalogen impurity in the ziprasidone hydrochloride intermediate, preferably comprises the following steps:

[0089] 1) After mixing the base and the first solvent, under a protective atmosphere, add dimethyl malonate, and then add 1-halo-2-nitrobenzene for nucleophilic substitu...

Embodiment 1

[0138] step 1:

[0139] Tetrahydrofuran (100mL, 10V) was put into a 250mL three-neck reaction flask, cooled to 0°C in an ice-water bath, sodium hydride (4.7g, 118.4mmol, 60%) was added in batches, and the temperature was controlled below 10°C. Under the protection of nitrogen, dimethyl malonate (10.4 g, 70.9 mmol) was started to be added dropwise, and the temperature was controlled below 15°C for 20 minutes. After the dropwise addition was completed, the mixture was stirred at 0-5°C for half an hour, and then compound 2 (10.0 g, 70.9 mmol) was added. The ice-water bath was removed, the temperature was raised to reflux (68° C.), and the mixture was stirred at reflux for 16 hours. TLC detection shows that the raw material still has a small amount of residue. Pour the reaction solution into 200g of crushed ice, add 300mL of dichloromethane, stir, dissolve and separate for extraction, then extract the aqueous phase once with 300mL of dichloromethane, combine the organic phases...

Embodiment 2

[0156] The difference from Example 1 is that the equivalent ratio of compound 4 and aluminum trichloride in step 4 is 1.0:2.5.

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Abstract

The invention provides a dihalide impurity in a ziprasidone hydrochloride intermediate. The dihalide impurity has a structure shown as a formula 1. On the basis that the ziprasidone hydrochloride intermediate can bring in the dechlorination impurity or the preparation process contains the dechlorination step, the dechlorination impurity with a specific structure is obtained, and the preparation steps of the corresponding impurity are provided, so a corresponding technical support is provided for preparation of ziprasidone hydrochloride. The synthesis method provided by the invention has the advantages of simple process, strong controllability and mild conditions, can be used for quality standard establishment and quality control links of ziprasidone hydrochloride process research and development, production and the like, and provides technical support for ziprasidone hydrochloride medication safety. The method can be used for quality research such as qualitative and quantitative analysis of impurities in ziprasidone hydrochloride synthesis, so that the quality of ziprasidone hydrochloride can be improved, 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 ziprasidone hydrochloride impurity research, in particular to a dihalogen impurity in a ziprasidone hydrochloride intermediate 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, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34
CPCC07D209/34
Inventor 赵宇郭照珊张丽杰
Owner HAINAN XINOPEN SOURCE MEDICAL TECH CO LTD
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