CN103787970A - Technology for preparing 6,9-difluoro benzisothiazol-5,10-diketone employing one-pot method - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry, and discloses a technology for preparing 6,9-difluoro benzisothiazol-5,10-diketone (I) employing a one-pot method. 6,9-difluoro benzisothiazol-5,10-diketone is an important midbody for pixantrone synthesis, and pixantrone is a new aza-anthraquinone drug, and used for treating multiple recurrent or intractable non-hodgkin lymphoma. The technology is simple in operation, low in cost and beneficial to large-scale synthesis.

Description

The legal system for the treatment of different things alike is for 6,9-difluoro benzisoquinoline-5, the technique of 10-diketone

Technical field

The invention belongs to pharmaceutical chemistry field, be specifically related to a China fir fine jade intermediate 6,9-difluoro benzisoquinoline-5, the synthetic technology of 10-diketone.

Background technology

China fir fine jade is a kind of new naphthazin(e) quinones medicine, is used for the treatment of the Aggressive Non-Hodgkin's of many recurrents or refractory, at present in the clinical study stage three phases.It both can reduce the cardiac toxic that anthracene nucleus medicament is relevant, can not reduce again anticancer therapeutic, was with a wide range of applications.

6,9-difluoro benzisoquinoline-5,10-diketone is a synthetic important intermediate of China fir fine jade, now only has a kind of disclosed synthetic route (CN1282738A, CN1145028, EP0503537A1).Reaction formula is as follows:

This technique obtains target product through three-step reaction, and aftertreatment is loaded down with trivial details, and cost is higher, is unfavorable for suitability for industrialized production.

Summary of the invention

In order to overcome the defect existing in technique scheme, the invention discloses one and treat different things alike legal system for 6,9-difluoro benzisoquinoline-5, the technique of 10-diketone, reaction scheme is as follows:

Concrete operation step is: 3,4-pyridine dicarboxylic acid joins in oleum, in 45-55 ℃ of stirring 2-3 h, slowly drip difluorobenzene, dropwise rear rising temperature to 80-90 ℃ of reaction 2-4 h, continue to increase the temperature to 135-145 ℃ of reaction 2-4 h and stop heating, be cooled to room temperature, reaction solution is slowly poured in frozen water, in process, temperature control is lower than 25 ℃, regulate pH to 1-2, filter and obtain target product.

The feed ratio (mass ratio) of its Raw is 3,4-pyridine dicarboxylic acid: to difluorobenzene: oleum=1:6.5 ~ 7.0:3.5 ~ 4.2.

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embodiment:

Following instance is used for illustrating the present invention, is not limited to the present invention, all any modifications of doing within principle of the present invention and spirit, is equal to and replaces and improvement etc., within being all just included in protection scope of the present invention.

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Example one:

In the reaction vessel of 250 mL, add 20% oleum 40 mL, add 3,4-pyridine dicarboxylic acid 20 g, at 50 ℃, heated and stirred is reacted 2 h, temperature is elevated to 90 ℃, stir and lower slowly drip difluorobenzene 123 mL, heated and stirred is reacted 2.5 h, and normal pressure steams unnecessary to difluorobenzene, increase the temperature to about 140 ℃ reaction 3 h, reaction mixture is cooled to room temperature, slowly pours in 500 mL frozen water, with 40%NaOH adjusting pH to 1, suction filtration, filter cake frozen water drip washing, in THF, recrystallization obtains yellow solid 18.2 g, and yield is 62%.

Mp.：197.0-199.0?℃。

¹H?NMR(CDCl ₃)：9.54(s,1H),9.12(d,1H),8.03(d,1H),7.57(m,2H)

Example two:

In there-necked flask, add 20% oleum 176 mL, add 3,4-pyridine dicarboxylic acid 100 g, at 48 ℃, heated and stirred is reacted 2.5 h, temperature is elevated to 89 ℃, stir and lower slowly drip difluorobenzene 586 mL, heated and stirred is reacted 3 h, and normal pressure steams unnecessary to difluorobenzene, increase the temperature to about 140 ℃ reaction 3.5 h, reaction mixture is cooled to room temperature, slowly pours in 2.5 L frozen water, with 40%NaOH adjusting pH to 2, suction filtration, filter cake frozen water drip washing, in THF, recrystallization obtains yellow solid 82.2g, and yield is 56%.

Mp：197.5-199.9?℃。

Example three:

In the reaction vessel of 3 L, add 20% oleum 633 mL, add 3,4-pyridine dicarboxylic acid 300 g, at 52 ℃, heated and stirred is reacted 2 h, temperature is elevated to 91 ℃, stir and lower slowly drip difluorobenzene 1.9 L, heated and stirred is reacted 3 h, and normal pressure steams unnecessary to difluorobenzene, increase the temperature to about 140 ℃ reaction 4 h, the cooling reaction mixture room temperature that is cooled to, slowly pour in 7.5 L frozen water, with 40%NaOH adjusting pH to 2, suction filtration, filter cake frozen water drip washing, in THF, recrystallization obtains yellow solid 135.5 g, and yield is 52%.

Mp：196.5-198.1?℃。

Claims (2)

1. the legal system for the treatment of different things alike is for 6,9-difluoro benzisoquinoline-5, the technique of 10-diketone (I), it is characterized in that: by 3,4-pyridine dicarboxylic acid joins in oleum, stir 2-3 h in 45-55 ℃, slowly drip difluorobenzene, dropwise rear rising temperature to 80-90 ℃ of reaction 2-4 h, continue to increase the temperature to 135-145 ℃ of reaction 2-4 h and stop heating, reaction solution is cooled to room temperature, slowly pour in frozen water, in process, temperature control, lower than 25 ℃, regulates pH to 1-2, filters and obtains target product

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2. method according to claim 2, the feed ratio (mass ratio) of raw material is 3,4-pyridine dicarboxylic acid: to difluorobenzene: oleum=1: 6.5 ~ 7.0: 3.5 ~ 4.2.