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Preparation method of 2-chlorine-7-iodothieno[3,2-D] pyrimidine

A technology of chlorothiophene and dichlorothiophene, which is applied in the field of medicinal chemistry, can solve problems such as poor economic benefits and environmental impact, long process steps, and complicated operations, so as to simplify the reaction process and post-treatment process, reduce production costs, optimize Effect of Reaction Conditions

Active Publication Date: 2013-02-13
上海毕得医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

2-Chloro-7-iodothieno[3,2-D]pyrimidine is an important intermediate of JAK. The yield of the original production and synthesis process is only 35%. The operation is complicated, the process steps are long, the reaction is difficult, and the yield Low economic benefit and poor environmental impact

Method used

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  • Preparation method of 2-chlorine-7-iodothieno[3,2-D] pyrimidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Synthesis of the first step 1,3-dihydrothiophene [3,2-D] pyrimidine-2,4-dione:

[0027] Add 75g of methyl 3-amino-2-thiophenecarboxylate (0.48mol) and 145g of urea (2.40mol) into a 500ml dry three-necked flask, stir mechanically, heat to 190°C, and stir for 3 hours. After the reaction is completed by TLC detection, Add it to 200ml of ice-saturated saturated sodium hydroxide aqueous solution while it is hot, then add 200ml of water, stir overnight, filter, control the temperature at room temperature, adjust the pH of the filtrate to 3-4 with hydrochloric acid, filter, and wash the filter cake with water once. After drying in air, 60 g of 1,3-dihydrothieno[3,2-D]pyrimidine-2,4-dione was obtained.

[0028] Synthesis of second step 2,4-dichlorothieno[3,2-D]pyrimidine:

[0029] Add 60g of 1,3-dihydrothiophene[3,2-D]pyrimidine-2,4-dione (0.36mol) into 600ml of phosphorus oxychloride (7.2mol), heat and reflux overnight, and TLC detects that the reaction is complete Finally, ...

Embodiment 2

[0035] Synthesis of the first step 1,3-dihydrothiophene [3,2-D] pyrimidine-2,4-dione:

[0036] Add 75g of methyl 3-amino-2-thiophenecarboxylate (0.48mol) and 29g of urea (0.48mol) into a 250ml dry three-necked flask, stir mechanically, heat to 190°C, and stir for 3 hours. After the reaction is completed by TLC detection, Add it to 40ml of ice-saturated saturated sodium hydroxide aqueous solution while it is hot, then add 40ml of water, stir overnight, filter, control the temperature at room temperature, adjust the pH of the filtrate to 3-4 with hydrochloric acid, filter, and wash the filter cake with water once. After drying in air, 30 g of 1,3-dihydrothieno[3,2-D]pyrimidine-2,4-dione was obtained.

[0037] Synthesis of second step 2,4-dichlorothieno[3,2-D]pyrimidine:

[0038] Add 60g of 1,3-dihydrothiophene[3,2-D]pyrimidine-2,4-dione (0.36mol) into 300ml of phosphorus oxychloride (3.6mol), heat and reflux overnight, and TLC detects that the reaction is complete Finally, mos...

Embodiment 3

[0044] Synthesis of the first step 1,3-dihydrothiophene [3,2-D] pyrimidine-2,4-dione:

[0045] Add 75g of methyl 3-amino-2-thiophenecarboxylate (0.48mol) and 72.5g of urea (1.2mol) into a 250ml dry three-neck flask, stir mechanically, heat to 190°C, stir for 3 hours, and TLC detects that the reaction is complete , add it to 100ml of ice-saturated saturated sodium hydroxide aqueous solution while it is hot, then add 100ml of water, stir overnight, filter, control the temperature at room temperature, adjust the pH of the filtrate to 3-4 with hydrochloric acid, filter, and wash the filter cake with water once , and dried to obtain 45g of 1,3-dihydrothiophene[3,2-D]pyrimidine-2,4-dione.

[0046] Synthesis of second step 2,4-dichlorothieno[3,2-D]pyrimidine:

[0047] Add 60g of 1,3-dihydrothiophene[3,2-D]pyrimidine-2,4-dione (0.36mol) into 450ml of phosphorus oxychloride (5.4mol), heat and reflux overnight, and TLC detects that the reaction is complete Finally, most of the phospho...

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Abstract

The invention discloses a preparation method of 2-chlorine-7-iodothieno[3,2-D] pyrimidine. 3-amino-2-thiophene methyl formate, urea, phosphorus oxychloride, N-iodosuccinimide (NIS) and the like serve as the raw materials, and under the action of 10wt% of a palladium-charcoal catalyst, a target product 2-chlorine-7-iodothieno[3,2-D] pyrimidine is obtained after four steps of reactions. The method is simple and convenient to operate, mild in reaction conditions, environmental-friendly and suitable for industrialization scale production; the total yield is higher than 75% and is greatly improved compared with the existing yield of 35%; and the production cost of the existing drugs is reduced remarkably.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of 2-chloro-7-iodothieno[3,2-D]pyrimidine. Background technique [0002] JAK (non-receptor type, intracellular kinase) plays an important role in the regulation of cell function, and has a great impact on the activity, location and function of proteins. JAK and gene mutations or regulation disorders are associated with a variety of diseases, such as: autoimmune diseases, tumors, leukemia and diabetes. 2-Chloro-7-iodothieno[3,2-D]pyrimidine is an important intermediate of JAK. The yield of the original production and synthesis process is only 35%. The operation is complicated, the process steps are long, the reaction is difficult, and the yield Low economic benefit and environmental impact are not good. Contents of the invention [0003] The technical problem to be solved by the present invention is to provide a preparation method of 2-chloro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 刘汉余国春黄冬瑞郦荣浩毛永浩
Owner 上海毕得医药科技股份有限公司
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