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Synthesis method of JAK kinase inhibitor intermediate

A technology of intermediates and compounds, applied in the field of medicinal chemistry, can solve the problems that N-iodosuccinimide is expensive, not easy to separate and purify, and not suitable for industrial production, and achieve simplified post-processing methods, stable yields, The effect of increasing the yield

Inactive Publication Date: 2018-01-19
CENTRAL SOUTH UNIVERSITY OF FORESTRY AND TECHNOLOGY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The world patent WO2009 / 062258A1 discloses a class of JAK inhibitors with a thieno[3,2-D]pyrimidine structure, which has a good therapeutic effect on tumors, but the synthesis of such compounds involves the key intermediate 2-chloro-7- Iodothieno[3,2-D]pyrimidine, the patent uses periodic acid and ICl for iodination reaction, the reaction effect is poor, and it is not easy to separate and purify, and the yield is only 37%
Chinese patent CN2012104339097 discloses a synthetic method using N-iodosuccinimide as the iodine reagent, although the yield of the reaction is improved to a certain extent, but directly using N-iodosuccinimide as the Substitute reagent, its yield is extremely unstable, ranging from 37.5%-75%, and N-iodosuccinimide is very expensive, still not suitable for industrial production

Method used

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  • Synthesis method of JAK kinase inhibitor intermediate
  • Synthesis method of JAK kinase inhibitor intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0032] 1) Synthesis of formula IV compound:

[0033] Add 500g of the compound of formula V and 800g of urea into a dry three-necked flask, stir, heat to 190°C, and stir for 4 hours. After the reaction is completed, add it to 1600ml of ice-saturated aqueous sodium hydroxide solution while hot, stir overnight, and filter , the filtrate was adjusted to pH 2 with hydrochloric acid, filtered, the filter cake was washed once with water, and dried to obtain 481g of the compound of formula IV, HPLC: 97%.

[0034] 2) Synthesis of formula III compound:

[0035] Add 400g of the compound of formula IV to 1500ml of thionyl chloride, add 10ml of DMF, and heat to reflux for 10h. The pH of the solution was adjusted to neutral, extracted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, backwashed with saturated brine, dried, and distilled under reduced pressure to obtain 450 g of intermediate III, HPLC: 95%.

[0036] 3) synthesis of formula II compound:

[00...

Embodiment 2

[0041] Add 80g of N-chlorosuccinimide to 600ml of dimethylacetamide, control the temperature at 25°C, then add 90g of KI, stir for 2.5 hours after the addition, then add 50g of intermediate II in batches, add After completion, the temperature was raised to 100° C., the reaction was completed and cooled to room temperature, water was added, a large amount of solids were precipitated, filtered by suction, and dried to obtain 82 g of product I with a yield of 95%, HPLC: 99%.

Embodiment 3

[0043] Add 150g of N-chlorosuccinimide to 800ml DMSO, control the temperature at 30°C, then add 180gNaI, stir for 4 hours after the addition, then add 100g of intermediate II in batches, after the addition is complete, heat up to 90 ℃. After the reaction was completed, cooled to room temperature, added water, a large amount of solids were precipitated, filtered with suction, and dried to obtain 161g of product I with a yield of 92%, HPLC: 98%.

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Abstract

The invention relates to a preparation method of 2-chlorine-7-iodothieno[3,2-D]pyrimidine. The 2-chlorine-7-iodothieno[3,2-D]pyrimidine is prepared from 3-amino-2-methyl thiophenecarboxylate serving as a starting material through urea cyclization, chlorination, reduction and iodination. The preparation method is simple and convenient in operation and mild in reaction condition, in particular, N-iodosuccinimide is generated by in-situ reaction to perform iodination, so that environmental friendliness is achieved and the yield of the iodination reaction is greatly increased; meanwhile, the production cost is reduced, and the preparation method is obviously improved compared with the prior art and is suitable for industrialized large-scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for synthesizing a JAK kinase inhibitor intermediate 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. The world patent WO2009 / 062258A1 discloses a class of JAK inhibitors with a thieno[3,2-D]pyrimidine structure, which has a good therapeutic effect on tumors, but the synthesis of such compounds involves the key intermediate 2-chloro-7- Iodothieno[3,2-D]pyrimidine, the patent uses periodic acid and ICl for iodination reaction, the reaction effect is poor, and it is not easy to separate and purify, and the yield...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 马强胡云楚谢练武王文磊文瑞芝陈选
Owner CENTRAL SOUTH UNIVERSITY OF FORESTRY AND TECHNOLOGY
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