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Improved process for preparing thieno-benzodiazepine compounds

A technology of compound and cyclization reaction, applied in the direction of organic chemistry, can solve the problems of high purity and preparation cost, high price of stannous chloride, influence, and unsatisfactory effect

Inactive Publication Date: 2008-11-26
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since stannous chloride is used as a reducing agent in the process of preparing 4-amino-2-methyl-10H-thieno[2,3-b][1,5]-benzodiazepine or its hydrochloride, Affected the purity and preparation cost of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]-benzodiazepine or its hydrochloride (due to stannous chloride The price is higher, and it is not suitable for application in commercial manufacturing; ii unreacted stannous chloride is easy to form complexes that are difficult to separate with the product), and finally causes the finished product (such as olanzapine) to be difficult to commercialize
[0004] WO 2004094390 also relates to the preparation method of thieno-benzodiazepines, but it has been proved by practice that its effect is not satisfactory (mainly because the yield of the product is low)
[0005] In view of the fact that the existing methods for preparing thieno-benzodiazepines are difficult to commercialize, the present invention provides an easy-to-commercial method for preparing thieno-benzodiazepines

Method used

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  • Improved process for preparing thieno-benzodiazepine compounds

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preparation example Construction

[0018] The reaction equation of the method for compound shown in the said preparation formula (1) or its salt of the present invention is as follows:

[0019]

[0020] R in the reaction equation 1 , R 2 , R 3 , R 4 , R 5 and X have the same meanings as described above.

[0021] Said preparation method comprises the steps:

[0022] (a) the compound shown in formula (2) and the compound shown in formula (3) (see WO 2004094390 or US.Pat.No.5,229,382 for its preparation) in a phase transfer catalyst (quaternary ammonium salt compound, such as triethylbenzyl Ammonium chloride, etc.) and alkali (potassium or sodium carbonate, potassium or sodium hydroxide, or potassium or sodium hydride), with an aprotic polar solvent as the reaction solvent, at 0°C React at ~50°C for 1 hour to 10 hours to obtain the compound shown in formula (4), and recover the unreacted compound shown in formula (3) (the recovered compound shown in formula (3) can be recycled);

[0023] (b) react the co...

Embodiment 1

[0028] Potassium hydroxide (52.8g, 0.94mol), triethylbenzyl ammonium chloride (0.85g) and DMF (50ml) were successively added to a three-necked flask, and o-fluoronitrobenzene was added dropwise within 30 minutes at 25°C. (63.8g, 0.45mol), 2-amino-5-methylthiophene-3-carbonitrile (52g, 0.38mol) (see US. Hour. Pour the reaction solution into 400ml of crushed ice, stir the dark brown solid to precipitate out, and use CH 2 Cl 2 (200ml×3) extraction, and then CH 2 Cl 2 (200ml×2) to wash the aqueous layer. The organic phases were combined, washed with 100 ml of water, adjusted to pH 8-9 with 2N HCl solution, and finally washed with 400 ml of water. After separating the aqueous phase, the CH 2 Cl 2 Evaporate, recover the unreacted o-fluoronitrobenzene and use it mechanically, finally recrystallize with 200ml of absolute ethanol, and dry to obtain 81.3g of reddish-brown compound [2-(2-nitrophenylamino)-5-methylthiophene -3-carbonitrile], yield 83.3%, m.p.108.3℃~109℃.

[0029]...

Embodiment 2～15

[0031] Different products can be obtained with different raw materials and different catalysts with reference to Example 1, and the specific structure is shown in Table 1:

[0032] Table 1

[0033]

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Abstract

The invention relates to a method for preparing a thieno-benzodiazepine compound. The following main steps are that the thieno-benzodiazepine compound is prepared by a compound as shown in the formula (2) and a compound as shown in the formula (3) by carrying out condensation reaction, reduction reaction and cyclization reaction in sequence; the method is characterized in that i) the reducer adopted in the reduction reaction can be Fe, FeSO4, Zn, Na2S, Na2S2 or NaHS; ii) before the reduction reaction is carried out, the unreacted compound as shown in the formula (2) needs to be removed. The preparation method has the advantages of simple and easy operation (facilitating commercial preparation), moderate reaction conditions, low preparation cost of the products, high purity and yield of the products, and so on. The preparation method lays a foundation for the enhancement of the commercial preparation of the ultimate products which take the thieno-benzodiazepine compound prepared by the invention as an intermediate.

Description

technical field [0001] The invention relates to a preparation method of thieno-benzodiazepine (thieno-benzodiazepine) compounds. Background technique [0002] Thieno-benzodiazepine (thieno-benzodiazepine) compounds are a class of intermediates for pharmaceutical preparation. [0003] US. Pat. No. 5,229,382 reports the preparation of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]-benzodiazepine and its hydrochloride. The main steps are: 2-amino-5-methylthiophene-3-carbonitrile is reacted with o-fluoronitrobenzene under a strong base (such as sodium hydride, lithium hydroxide, etc.) to prepare 2-(2-nitrobenzene phenylamino)-5-methylthiophene-3-carbonitrile, then react with reducing agent stannous chloride and then cyclize to obtain 4-amino-2-methyl-10H-thieno[2,3-b][1 , 5]-benzodiazepine or its hydrochloride. Since stannous chloride is used as a reducing agent in the process of preparing 4-amino-2-methyl-10H-thieno[2,3-b][1,5]-benzodiazepine or its hydrochloride, Affected the pur...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 吴范宏袁文蛟杨先金
Owner EAST CHINA UNIV OF SCI & TECH
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