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Preparation method of 2, 4-dichloro-7H-pyrrolo [2, 3-D] pyrimidine

A 3-D, pyrrole technology, applied in the field of pharmaceutical synthesis, can solve the problems of good production economy, difficult to prepare high-quality, etc., achieve good production economy, inhibit the formation of colloids and color impurities, and simplify post-processing and the effect of the operation of the refining process

Pending Publication Date: 2022-03-25
四川新迪生物制药有限公司
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  • Description
  • Claims
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Problems solved by technology

[0008] The purpose of the embodiment of this application is to provide a preparation method of 2,4-dichloro-7H-pyrrolo[2,3-D]pyrimidine, aiming to solve the problem of existing 2,4-dichloro-7H-pyrrolo The preparation method of [2,3-D]pyrimidine is difficult to prepare 2,4-dichloro-7H-pyrrolo[2,3-D]pyrimidine with high quality and good production economy

Method used

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  • Preparation method of 2, 4-dichloro-7H-pyrrolo [2, 3-D] pyrimidine
  • Preparation method of 2, 4-dichloro-7H-pyrrolo [2, 3-D] pyrimidine
  • Preparation method of 2, 4-dichloro-7H-pyrrolo [2, 3-D] pyrimidine

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preparation example Construction

[0035] The embodiment of the present application provides a preparation method of 2,4-dichloro-7H-pyrrolo[2,3-D]pyrimidine comprising the following steps:

[0036] Step S1, using 6-aminouracil (formula IV) as a starting material, reacting with chloroacetaldehyde (formula III) under alkaline conditions, and controlling the reaction temperature at 45-65°C to obtain an intermediate (formula II);

[0037] Step S2, reacting the intermediate (formula II) with a chlorination reagent under the catalysis of an organic nitrogen base, controlling the reaction temperature to 75-90°C, and undergoing crystallization, dissolution extraction, and decolorization and crystallization treatment to obtain the target product (Formula I); the molar ratio of the intermediate (Formula II) to phosphorus oxychloride is 1:9.0 to 13.0; the weight ratio of the intermediate to N,N-diisopropylethylamine is 1:1.20 ~1.80.

[0038] One of the synthetic routes is as follows:

[0039]

[0040] In a preferred...

Embodiment 1

[0067] Preparation of Example 1 product 2,4-dichloro-7H-pyrrolo[2,3-D]pyrimidine (formula I)

[0068] Sodium bicarbonate is the acid-binding agent, the chlorinating agent is phosphorus oxychloride, and the organic base catalytic agent is DIPEA.

[0069]

[0070] (1) Preparation of chloroacetaldehyde solution: add 20 mL of drinking water and 4.0 g of 40% chloroacetaldehyde solution to the dropping funnel, mix well and set aside.

[0071] (2) Preparation of intermediate (Formula II): Add 30ml of drinking water, 2.0g of compound IV, and 1.98g of sodium bicarbonate to the reaction flask, stir, heat to 40-50°C, and add dropwise the prepared chloroacetaldehyde solution. After the dropwise addition, control the temperature at 60-65°C, continue to stir for 1 hour, cool down to room temperature, adjust the pH to 3-4 with dilute hydrochloric acid, filter, and obtain the filter cake, which is washed with drinking water and dried to obtain about 1.8 g of intermediate (Formula II) . ...

Embodiment 2

[0114] Example 2 Product 2,4-dichloro-7H-pyrrolo[2,3-D]pyrimidine (Formula I) small-scale process verification (preparation in ten grams)

[0115]

[0116] (1) Preparation of chloroacetaldehyde solution: add 200 mL of drinking water and 37 g of 40% chloroacetaldehyde solution to the dropping funnel, mix well and set aside.

[0117] (2) Preparation of intermediate (Formula II): Add 300ml of drinking water, 20.0g of compound IV, and 19.8g of sodium bicarbonate to the reaction flask, stir, heat to 50-60°C, and add the above-prepared chloroacetaldehyde dropwise solution. After the dropwise addition, control the temperature at 50-60°C, continue to stir and react for 1 hour, lower to room temperature, adjust the pH to 2-3 with dilute hydrochloric acid, and filter to obtain a filter cake, which is washed with drinking water and dried to obtain about 20 g of the intermediate (Formula II). Sampling and HPLC detection showed that the purity of the intermediate (Formula II) was 91.25...

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Abstract

The invention is suitable for the technical field of drug synthesis, and provides a preparation method of 2, 4-dichloro-7H-pyrrolo [2, 3-D] pyrimidine, which comprises the following steps: taking 6-aminouracil as an initial raw material, reacting with chloroacetaldehyde under the action of sodium bicarbonate, and controlling the reaction temperature at 45-65 DEG C to obtain an intermediate; and reacting the intermediate with phosphorus oxychloride under the catalytic action of N, N-diisopropylethylamine, controlling the reaction temperature to be 75-90 DEG C, crystallizing, dissolving and extracting, and decolorizing and crystallizing to obtain the compound. According to the invention, the generation of jelly and color impurities can be inhibited, the operation of post-treatment and refining procedures is remarkably simplified, the production efficiency is improved, the production economy is relatively good, the total yield of 30-kilogram-level production and preparation is greater than 50%, the product purity reaches 100%, the appearance is white, and the use quality requirements of downstream products are completely met.

Description

technical field [0001] The application belongs to the technical field of drug synthesis, and in particular relates to a preparation method of 2,4-dichloro-7H-pyrrolo[2,3-D]pyrimidine. Background technique [0002] 2,4-Dichloro-7H-pyrrolo[2,3-D]pyrimidine is a key intermediate in the synthesis of tofacitinib citrate. Tofacitinib Citrate Tablets is the first JAK pathway inhibitor with a mechanism of action and a new type of oral protein tyrosine kinase inhibitor. Indicated for adult patients with moderately to severely active rheumatoid arthritis (RA) who are insufficiently cured or intolerant of methotrexate, in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs) use. The product was first approved for marketing in the United States on November 6, 2012, and has been approved for marketing in more than 50 countries and regions around the world, including the United States, Japan, Russia, Australia, and Canada. Therefore, it is o...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 杨仨东文景徐帮健卢林波马东李友强吴小愚崔德修陈海权
Owner 四川新迪生物制药有限公司
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