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The synthetic method of ziprasidone intermediate

A synthesis method and technology of ziprasidone, applied in the field of medicine, can solve the problems of high toxicity, difficult to obtain raw materials and high cost

Active Publication Date: 2015-10-07
CHONGQING SHENGHUAXI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Using 6-chloro-2,3-indoledione as a raw material to synthesize intermediate 6-chloro-2-indolinone in one step, but the raw material is not easy to obtain, and a large amount of hydrazine hydrate is used, which is highly toxic
[0011] Route 2-2 uses o-nitro-p-chlorotoluene as the starting material (Journal of Wuhan Engineering University 2012, 32 (11), 25-28), and synthesizes the intermediate 6-chloro-2-indolone through 5 steps. The synthetic route Long, low yield, high cost synthetic route as shown below

Method used

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  • The synthetic method of ziprasidone intermediate
  • The synthetic method of ziprasidone intermediate
  • The synthetic method of ziprasidone intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: compound II reduction preparation compound III

[0027] Example 1-1 Add 200 mL of water to the reaction flask, heat to 40°C, add 17.0 g (143 mmol) of tin powder and adjust the pH to 3 with concentrated hydrochloric acid, continue to heat up to 60°C, add 9.0 g (57.1 mmol) and 23.9 g (201 mmol) of tin powder, after adding, react at 60~80°C for 8 hours, then add 10% sodium hydroxide solution, adjust the pH to 8~9, and stir for 30 minutes. After suction filtration, the filtrate was acidified with concentrated hydrochloric acid to pH 4~5, and a yellow solid precipitated out. The solid was collected and vacuum-dried to obtain 6.7 g of compound IV yellow solid, with a yield of 91.2%.

[0028] Example 1-2 Add 150 mL of water to the reaction flask, heat to 40°C, add 9.3 g (143 mmol) of zinc powder and 150 mL of acetic acid, continue to heat up to 60°C, add 9.0 g (57.1 mmol) of compound II in batches ) and 13.1 g (201 mmol) of iron powder, after adding, react at 60...

Embodiment 2

[0036] Embodiment 2: Preparation of compound IV by acylation of compound III

Embodiment 2-1

[0037] Example 2-1 Dissolve 10.2 g (80 mmol) of compound III and 13.2 mL (96 mmol) of triethylamine in 80 mL of dichloromethane, cool to 0°C, and slowly add 7.6 mL (96 mmol) of chloroacetyl chloride dropwise , After the dropwise addition, return to 25°C and stir for 20h. Evaporate to dryness under reduced pressure, wash the solid with water (80 mL×3), and suction filter to obtain a white solid, which was further recrystallized with ether to obtain 15.7 g of compound IV as a white solid, with a yield of 96.3%.

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Abstract

The invention discloses a novel synthetic method of a ziprasidone intermediate. The synthetic method comprises following steps: m-chloronitrobenzene is taken as an initial raw material, and is subjected to nitroreduction so as to obtain m-chloroaniline; m-chloroaniline is subjected to aminoacylation so as to obtain 3-chloroacetyl amino-chloro-benzene; and finally 3-chloroacetyl amino-chloro-benzene is subjected to Friedel-Crafts alkylation, and 6-chloro-2-indolone is obtained after cyclization. The raw materials of the synthetic method are cheap and easily available, synthetic route is short, yield is high, operation is convenient, cost is low, and the synthetic method is suitable for industrialized application.

Description

technical field [0001] The invention relates to a method for synthesizing a ziprasidone intermediate, belonging to the technical field of medicine. Background technique [0002] Ziprasidone hydrochloride (Ziprasidone) is a new atypical broad-spectrum antipsychotic drug developed by Pfizer, the chemical name is 5-(2-(4-(1,2-benzisothiazol-3-yl)-1 -piperazinyl)ethyl)-6-chloro-1,3-dihydro-2(1H)-indol-2-one hydrochloride monohydrate, the chemical structure is shown below. [0003] [0004] The oral dosage form and the intramuscular injection dosage form of this product were first launched in Sweden in 1998 and September 2000, respectively, with the trade names Zeldox and Geodon, and were subsequently marketed in the United States, Australia, and many European countries, mainly for the treatment of schizophrenia (Ann Pharmacother , 2002, 36(5), 839-851). [0005] This product is a 5-hydroxytryptamine (5-HT) and dopamine receptor (DA) antagonist, especially to the 5-HT2A rece...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/34
CPCC07D209/34
Inventor 周艳婷王庆
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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