Preparation process of 7-bromo-4-chlorothieno [3, 2-d] pyrimidine

A preparation process, 2-d technology, applied in organic chemistry and other directions, can solve the problems of high temperature and many by-products, and achieve the effects of simple quenching, high reaction yield, and high utilization rate of chlorine atoms.

Inactive Publication Date: 2022-05-24
郑州猫眼农业科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the prior art, Preparation of bicyclic heteroaryls, especially thienopyrimidines, asectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) modulators (Pinkerton, Anthony et al, From PCT Int.Appl., 2021133915, 01Jul 2021) discloses the use of 7-bromo-3H- Thieno[3,2-d]pyrimidin-4-one reacts with phosphorus oxychloride to obtain 7-bromo-4-chlorothieno[3,2-d]pyrimidine, the reaction temperature is relatively high, and there are many by-products

Method used

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  • Preparation process of 7-bromo-4-chlorothieno [3, 2-d] pyrimidine
  • Preparation process of 7-bromo-4-chlorothieno [3, 2-d] pyrimidine
  • Preparation process of 7-bromo-4-chlorothieno [3, 2-d] pyrimidine

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Embodiment 1

[0023] The preparation process of 7-bromo-4-chlorothieno[3,2-d]pyrimidine of the present embodiment includes the following steps:

[0024] 1) Synthesis of 3H-thiophene[3,2-d]pyrimidin-4-one: take a 500mL three-necked flask, put a magnet, add 15.72g of methyl 3-amino-2-thiophenecarboxylate at 25°C, and then Add 100 mL of absolute ethanol to dissolve, add 15.61 g of formamidine acetate at 25 °C and stir to dissolve, the temperature rises to 100 °C and react for 2 hours, cool to 25 °C, filter, wash the filtrate with petroleum ether three times, and dry it in a vacuum dryer to obtain a white Solid product 9.81 g, yield 64.5%. figure 1 is the hydrogen NMR spectrum of 3H-thiophene[3,2-d]pyrimidin-4-one, 1 H NMR (400MHz, CDCl 3 ): δ(ppm) 12.52(s, 1H), 8.20(d, J=2.6Hz, 1H), 8.17(s, 1H), 7.41(d, J=2.4Hz 1H).

[0025] 2) Synthesis of 7-bromo-3H-thiophene[3,2-d]pyrimidin-4-one: take a 500mL round bottom flask, add 6.30g of 3H-thiophene[3,2-d] prepared in step 1) Pyrimidine-4-one was ...

Embodiment 2

[0030] The preparation process of 7-bromo-4-chlorothieno[3,2-d]pyrimidine of the present embodiment includes the following steps:

[0031] 1) Take a 500mL three-necked flask, put it into a magnet, add 15.72g of methyl 3-amino-2-thiophenecarboxylate at 25°C, then add 100mL of absolute ethanol to dissolve, and add 16.91g of formamidine acetate at 25°C for stirring Dissolved, the temperature was raised to 100°C and reacted for 2h, cooled to 25°C, filtered, the filtrate was washed three times with petroleum ether, and dried in a vacuum dryer to obtain 8.95 g of a white solid product with a yield of 58.8%.

[0032] 2) Synthesis of 7-bromo-3H-thiophene[3,2-d]lopyrimidine-4-one: take a 500mL round bottom flask, add 6.30g of the prepared 3H-thiophene[3,2-d]lopyrimidine-4 - Ketone, dissolve with 50mL butyric acid, add 23.1g of N-bromosuccinimide (NBS) in four equal amounts at a rate of 15min each time, after adding, the temperature is raised to 120°C, and the reaction is performed for ...

Embodiment 3

[0035] 1) Take a 500mL three-necked flask, put it in a magnet, add 15.72g of methyl 3-amino-2-thiophenecarboxylate at 25°C, then add 100mL of absolute ethanol to dissolve, add 18.21g of formamidine acetate at 25°C and stir Dissolved, the temperature was raised to 100°C and reacted for 2h, cooled to 25°C, filtered, the filtrate was washed three times with petroleum ether, and dried in a vacuum dryer to obtain 8.83 g of a white solid product with a yield of 58.1%.

[0036] 2) Synthesis of 7-bromo-3H-thiophene[3,2-d]lopyrimidine-4-one: take a 500mL round bottom flask, add 6.30g of the prepared 3H-thiophene[3,2-d]lopyrimidine-4 - Ketone, dissolved in 50 mL of acetic acid, 23.1 g of N-bromosuccinimide (NBS) was added in four equal amounts at a rate of 15 min each time, and the temperature was raised to 100 °C after the addition, and the reaction was performed for 18 h. After the reaction was completed, the mother liquor was cooled to 60° C., then most of the acetic acid was removed b...

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Abstract

The invention relates to a preparation process of 7-bromo-4-chlorothieno [3, 2-d] pyrimidine, which comprises the following steps: dissolving 7-bromo-3H-thieno [3, 2-d] pyrimidine-4-ketone in a solvent A, adding an acetic acid solution of HBr, reacting, adding phosphorus oxychloride and triethylamine, heating to 80-90 DEG C, reacting for 1.5-4.5 hours, and purifying to obtain the 7-bromo-4-chlorothieno [3, 2-d] pyrimidine. According to the preparation process of the 7-bromo-4-chlorothieno [3, 2-d] pyrimidine, an HBr / phosphorus oxychloride / triethylamine system is adopted for preparation, the dosage of phosphorus oxychloride is small, and the utilization rate of chlorine atoms is high; by-products harmful to the environment are not easily generated, the quenching is simple, the purification is easy, and the reaction yield is higher.

Description

technical field [0001] The invention belongs to the technical field of compound synthesis, in particular to a preparation process of 7-bromo-4-chlorothieno[3,2-d]pyrimidine. Background technique [0002] 7-Bromo-4-chlorothieno[3,2-d]pyrimidine is a pharmaceutical intermediate, which can be synthesized in many ways. In the prior art, Preparation of bicyclic heteroaryls, especially thienopyrimidines, asectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) modulators (Pinkerton, Anthony et al, From PCT Int.Appl., 2021133915, 01Jul 2021) disclosed the use of 7-bromo-3H- Thieno[3,2-d]lopyrimidine-4-one reacts with phosphorus oxychloride to give 7-bromo-4-chlorothieno[3,2-d]pyrimidine. The reaction temperature is high and there are many by-products. . SUMMARY OF THE INVENTION [0003] The purpose of the present invention is to provide a preparation process of 7-bromo-4-chlorothieno[3,2-d]pyrimidine, the preparation process has lower reaction temperature, less by-products ...

Claims

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Application Information

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IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor不公告发明人
Owner郑州猫眼农业科技有限公司