Synthetic method of ziprasidone

A technology of ziprasidone and dioxolane, applied in the field of drug synthesis, can solve the problems of low reaction yield and high cost

Active Publication Date: 2009-06-10
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] After careful examination of the known above-mentioned methods, it is found that: method one uses triethylsilane to reduce the carbonyl group in trifluoroacetic acid, and the cost of this step is quite high, resulting in a relatively high cost
And method 2 although the cost of raw materials is relatively low, but wherein there are several step reaction yields too low, especially the final step with sodium bisulfite reduction ring closure yield is only 40%. Therefore, to find a more convenient, efficient production way is very important

Method used

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  • Synthetic method of ziprasidone
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  • Synthetic method of ziprasidone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1: Preparation and synthesis of 2,5-dichloro-4-nitrotoluene

[0065]

[0066] Add 100 g of 2,5-dichlorotoluene and 50 ml of concentrated sulfuric acid to a 500 ml flask equipped with a thermometer with mechanical stirring and a condenser, and start stirring to cool to 10°C. Measure 80ml of concentrated sulfuric acid in another beaker, weigh fuming nitric acid 43.2g (95%), add dropwise in the beaker, and pay attention to cooling. Add the mixed acid into a 100ml dropping funnel and then slowly drop it into a 500ml flask. At the beginning, control the temperature at 10-15°C, and slowly rise to about 25°C when the solid precipitates. Keep adding at this temperature. After the addition, continue to stir at 35°C for 2 hours, then pour into ice water to freeze. The precipitated solid was suction filtered, and the obtained solid was recrystallized with 150 ml of ethanol. The product (80 g, yield 63%) was obtained. 1 H NMR (400MHz, CDCl 3 )δ: 2.44(s, 3H, CH 3 ),...

Embodiment 2

[0067] Example 2: Preparation of 2-(2,5-dichloro-4-nitrobenzene)-N,N-dimethylethyleneamine

[0068]

[0069] In a 300ml flask equipped with a thermometer with mechanical stirring and condenser, add 2,5-dichloro-4-nitrotoluene 33.8g, dimethoxy-N,N-dimethylmethylamine (29.3g , 1.5eq), DMF70ml, after the addition, the stirring and reflux temperature was maintained at about 120 degrees, and the reaction was carried out for 4 hours. Stop heating, cool to 100°C, pour the reaction solution into 150ml of water for washing, and a purple-brown solid precipitates out. The filtered cake was washed with water and pressed dry. The solids were oven dried at 90 degrees. The product (40 g, yield 93%) was obtained. 1 H NMR (400MHz, CDCl 3 )δ: 3.00 (s, 6H, 2NCH 3 ), 5.29(d, J=13.2Hz, 1H, CH=), 7.07(d, J=13.2Hz, 1H, NCH=), 7.34(s, 1H, ArH), 8.03(s, 1H, ArH); 13 C NMR (100MHz, d-DMSO) δ: 42.1, 42.6, 88.3, ​​122.2, 124.5, 125.6, 127.5, 138.0, 145.3, 148.5; Ms: M=260, Found (260, M + ), (2...

Embodiment 3

[0070] Example 3: Preparation of 2-(2,5-dichloro-4-nitrobenzyl)-1,3-dioxolane

[0071]

[0072] Add 2-(2,5-dichloro-4-nitrobenzene)-N,N-dimethylethyleneamine (40g), toluene 80ml successively in a 300ml flask equipped with a thermometer with mechanical stirring and condenser Oxalic acid (38.6g, 2eq), ethylene glycol 38g. Stir and reflux for 8 hours after addition. After the reaction was completed, the reaction liquid was added to 100 ml of water to wash, and then extracted with 200 ml of ethyl acetate, and the organic layer was collected, and the organic layer was washed with 100 ml of water. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized with a mixed solvent of 50ml ethyl acetate and 100ml of n-hexane to obtain the product (22g, yield 52%). 1 H NMR (400MHz, CDCl 3 )δ 3.16 (d, J=4.6Hz, 2H, CH 2 ), 3.86-3.90 (m, 2H, OCH 2 ), 3.95-3.99 (m, 2H, OCH 2 ), 5.15(t, J=4.6Hz, 1H, CH), 7.58(s, 1H, ArH...

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Abstract

The invention provides a new method for synthesizing ziprasidone. The method comprises the following steps: 2,5-dichlorotoluene is taken as a starting material to be condensed with N,N-dimethyldimethoxymethylamine after being nitrified; an obtained intermediate is converted to an acetal compound in the presence of oxalic acid and glycol; and the acetal compound is reacted with ethyl malonate and then is subjected to decarboxylation, reduction and cyclization to form a key intermediate 7; the compound 7 is subjected to deprotection under an acidic condition to from an aldehyde 8; and the aldehyde 8 is reacted with 3-piperazinyl-1,2-benzisothiazole in the presence of sodium triacetoxyborohydride to form the ziprasidone. The invention has the advantages of easy and simple control, readily available raw materials and convenient operation.

Description

Technical field: [0001] The present invention relates to a kind of synthetic method of medicine, more specifically, the present invention relates to the synthetic method of ziprasidone. Background technique: [0002] Ziprasidone is a potent antipsychotic and is used to treat a variety of disorders including schizophrenia, anxiety disorders, and migraines. Ziprasidone hydrochloride (Ziprasidone) is the latest atypical broad-spectrum antipsychotic drug developed by Pfizer. It is used for the treatment of schizophrenia. It is a 5-hydroxytryptamine and dopamine receptor antagonist, especially for 5-HT A2 / DA D2 Strong receptor affinity. The oral dosage form and intramuscular injection dosage form of the drug were launched in Sweden in September 1998 and 2000, respectively. It has a good curative effect on acute or chronic, initial or recurrent schizophrenia; it is effective on schizophrenia-related symptoms (including audiovisual hallucinations, delusions, lack of motivation an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12A61P25/00
Inventor 王亚平郑国君唐方辉高建明徐雨航蔡刚华许德州
Owner ZHEJIANG HISUN PHARMA CO LTD
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