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A method for preparing 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2-(3h)-one

A technology of tetrahydrofuran and potassium hydroxide, applied in the field of pharmaceutical industry, can solve problems such as being unsuitable for industrialized production, having many by-products, and having a total yield of only 12.8%.

Active Publication Date: 2017-06-06
SHANGHAI TIANCI INT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Similar to Line 1 and Line 2, the highly toxic organic compound ethyl bromoacetate and extremely toxic and active cyanogen bromide are used as raw and auxiliary materials for preparation, and the large amount of waste acid produced in the first step is not conducive to environmental protection. It is easy to generate many and miscellaneous by-products, the total yield is only 12.8%, and the yield is low. It is still not suitable for industrial production

Method used

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  • A method for preparing 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2-(3h)-one
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  • A method for preparing 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2-(3h)-one

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preparation example Construction

[0125] The preparation of formula (V) compound

[0126] The present invention provides a kind of preparation method of formula (V) compound, it is characterized in that, comprises steps:

[0127]

[0128] (3) In an inert solvent, the compound of formula (IV) is reacted with a reducing agent to obtain the compound of formula (V).

[0129] In a preferred example of the present invention, in the step (3), the reducing agent is selected from the group consisting of 10% palladium carbon, sodium cyanoborohydride, sodium acetate borohydride, lithium aluminum hydride, trifluoro boron tetrahydrofuran complex, sodium borohydride, or a combination thereof; preferably sodium borohydride; and / or

[0130] In the step (3), the inert solvent is selected from the group consisting of methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, toluene, xylene, acetic acid, trifluoroacetic acid, formic acid, or combinations thereof; Preference is given to tetrahydrofuran.

[0131] In an...

Embodiment 1

[0174] (1) Preparation of 5,6-dichloroisatoic anhydride (Ⅲ):

[0175] 4,5-Dichloroisatin (II) (50.0g, 231.46mmol) was dissolved in dichloromethane (600ml), m-chloroperoxybenzoic acid (79.89g, 462.92mmol) was added in batches at room temperature, Stir the reaction for 2 h, and TLC detects that the reaction is complete. Suction filtration and washing with a small amount of dichloromethane gave 51.02 g of 5,6-dichloroisatoic anhydride (Ⅲ), with a yield of 95%.

[0176] (2) Preparation of compound (Ⅳ):

[0177] 5,6-dichloroisatoic anhydride (Ⅲ) (50.0g, 215.50mmol) in tetrahydrofuran (450ml), then added ethyl aminoacetate (24.4g, 237.05mmol), stirred at room temperature for 3h, then added triphosgene ( 63.95g, 215.50mmol) and sodium carbonate (45.68g, 431.0mmol), and continued to stir for 8h, and TLC detected that the reaction was complete. Add ammonium chloride reaction solution dropwise to quench, recover tetrahydrofuran, extract with ethyl acetate (3x200ml), combine organic p...

Embodiment 2

[0186] (1) Preparation of 5,6-dichloroisatoic anhydride (Ⅲ):

[0187] 4,5-Dichloroisatin (II) (50.0g, 231.46mmol) was dissolved in dichloromethane (600ml), m-chloroperoxybenzoic acid (59.91g, 347.19mmol) was added in batches at room temperature, The reaction was stirred for 2.5 h, and TLC detected that the reaction was complete. Suction filtration and washing with a small amount of dichloromethane gave 49.95 g of 5,6-dichloroisatoic anhydride (Ⅲ), with a yield of 93%.

[0188] (2) Preparation of compound (Ⅳ):

[0189] 5,6-dichloroisatoic anhydride (Ⅲ) (40.0g, 172.40mmol) in tetrahydrofuran (350ml), then added ethyl aminoacetate (19.52g, 189.64mmol), stirred at room temperature for 3h, then added triphosgene ( 51.16g, 172.40mmol) and sodium carbonate (27.41g, 258.60mmol), and continued to stir for 8h, and TLC detected that the reaction was complete. Add ammonium chloride reaction solution dropwise to quench, recover tetrahydrofuran, extract with ethyl acetate (3x150ml), comb...

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Abstract

The invention provides a novel method for preparing 6,7-dichloro-1,5-imidazolinyl [2,1-b] quinazoline-2-(3H)-one. The method comprises the following steps: preparing a compound with the structure shown as the formula (IV), and then preparing anagrelide by taking the compound shown as the formula (IV) as an intermediate. The method has the advantages of being simple to operate, moderate in reaction condition, low in overall cost, high in yield, high in anagrelide purity and the like. Thus, the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical industry, in particular, the invention relates to a preparation method of a novel oral platelet-lowering drug anagrelide. Background technique [0002] Anagrelide (Anagrelide AG) is a new oral platelet-lowering drug, belonging to imidazoquinoline chemical drugs, used for the treatment of thrombocythemia, including polycythemia vera, primary myelofibrosis, chronic myeloid autovascular disease , Essential thrombocythemia and other myeloproliferative diseases. [0003] AG is the only drug in the world approved by the US FDA to treat essential thrombocythemia, and its effect is amazing, with an effective rate of over 80%. The drug has strong selectivity, no leukopenia, anemia and serious side effects suspected of causing leukemia, significant curative effect and small side effects, etc., and has the characteristics of long-term use (3-5 years), so it was approved in 1997 After listing, it imm...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D239/96
CPCC07D239/96C07D487/04
Inventor 李新涓子李健之马西来池王胄刘海胡旭华郑肖利翟志军李建勋
Owner SHANGHAI TIANCI INT PHARMA
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