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The synthetic method of the key intermediate of tofacitinib

A synthetic method, the technology of tofacitinib, applied in the direction of organic chemistry, organic chemistry, etc., can solve the problems of difficult refining of impurities, poor product purity, high cost of raw materials, etc., and achieve the effect of shortening the reaction steps, less impurities and improving quality

Active Publication Date: 2021-11-23
ZHEJIANG HUAYI PHARMA CO LTD OF HANGZHOU HUADONG PHARMA GRP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In actual production, the cost of raw materials is relatively high. Although this reaction step is short, there are many side reactions, the product has poor purity and impurities are difficult to refine.

Method used

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  • The synthetic method of the key intermediate of tofacitinib
  • The synthetic method of the key intermediate of tofacitinib
  • The synthetic method of the key intermediate of tofacitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: benzyl protection reaction prepares reaction product I

[0044] Starting material: 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, 70g (about 0.46mol);

[0045] Organic solvent: the present embodiment is selected from acetone 350ml;

[0046] Acid binding agent I: the present embodiment is selected from sodium hydroxide 22g (about 0.55mol);

[0047] Benzyl protection reagent: this embodiment is selected from 82g (about 0.48mol) of benzyl bromide;

[0048] Benzyl protection reaction process: Add 70.0g of the initial raw material 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, 350ml of acetone, 22.0g of sodium hydroxide into the reaction flask, cool down to 0-5°C, and keep warm for 0.5 h, drop 82.0g benzyl bromide into the above reaction system at 5°C, after dropping, raise the temperature to 20-23°C, and keep it warm for 3-4h; since sodium hydroxide is used as the acid-binding agent I, it can also be neutralized to form The acid promotes the reaction thoroughly, after the re...

Embodiment 2

[0049] Embodiment 2: condensation reaction prepares reaction product II

[0050] Raw material 1: the reaction product I 105g (about 0.43mol) that embodiment 1 obtains;

[0051]Raw material 2: N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methylamine dihydrochloride: 113g (about 0.39mol);

[0052] Reaction solvent: water 820ml;

[0053] Acid binding agent II: the present embodiment is selected from potassium carbonate: 391g (about 2.83mol);

[0054] Condensation reaction process: add reaction solvent 820ml water, 391g potassium carbonate to the reaction flask, stir, slowly add 113g N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl Add 105g of reaction product I to amine dihydrochloride, heat to 80-110°C and reflux for 12-13h, cool down to 20-30°C and let stand for 8h, filter with suction, wash with 500ml of water, dry to obtain reaction product II, use react in the next step.

Embodiment 3

[0055] Example 3: Preparation of the product of the present invention (N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d ]Pyrimidin-4-amine (key intermediate of tofacitinib)

[0056] Raw material: the reaction product II 147g that embodiment 2 obtains;

[0057] Organic solvent: the present embodiment is selected from ethanol 1470ml;

[0058] Catalyst: the present embodiment is selected from palladium carbon 14.7g;

[0059] Reaction process for de-dibenzyl protection: add 1470ml ethanol and 147g reaction product II to the reaction bottle, after nitrogen replacement, add 14.7g palladium carbon, pass in hydrogen, raise the temperature to 60-70°C, keep the reaction for 4-5h, detect by HPLC, After the reaction is completed, cool down to 0-5°C, filter with suction, and spin to remove ethanol at 50-60°C. After spinning, stir and crystallize with acetone, filter with suction, and dry to obtain 80g of the product of the present invention; the product has a purity of 98.6%,...

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Abstract

The present invention relates to a method for preparing high-purity (N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4- Amine (the key intermediate of Tofacitinib), using 4-chloro-7H-pyrrolo[2,3-d]pyrimidine as the initial raw material, through benzyl protection, condensation reaction and de-dibenzyl protection reaction, and then Purified to obtain the product of the present invention. The product of the present invention (N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine- The purity of the 4-amine is more than 98%, and the total yield of the synthesis method is more than 80%, which is suitable for industrial production.

Description

(1) Technical field: [0001] The invention belongs to the technical field of drug synthesis and relates to a key intermediate of tofacitinib (N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[ Process for the preparation of 2,3-d]pyrimidin-4-amine. (two) background technology: [0002] Tofacitinib is a new oral JAK pathway inhibitor developed by Pfizer. Unlike most other RA therapeutic drugs that mainly act on extracellular targets, tofacitinib targets intracellular signal transduction pathways and acts on the core part of the cytokine network. The inhibitory effect of tofacitinib on JAK3 is 5-100 times that of JAK1 and JAK2. Tofacitinib is the first drug developed for the treatment of rheumatoid arthritis. The FDA approved JAK inhibitors on November 6, 2012 for the treatment of adults with moderate to severe disease that is active and does not respond well to methotrexate. patients with rheumatoid arthritis. The product of the present invention is one of the key int...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07B2200/07C07D487/04
Inventor 方秋王笑黄依依杜子为王坚强
Owner ZHEJIANG HUAYI PHARMA CO LTD OF HANGZHOU HUADONG PHARMA GRP
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