Preparation method of rusotinib
By constructing the chiral intermediate RXTN-3 and adopting specific reaction steps, the problem of high cost of chiral construction steps in existing rusotinib synthesis is solved, and efficient and low-cost synthesis of rusotinib is achieved.
Patent Information
- Application Number
- CN202411960672.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-30
- Publication Date
- 2025-05-13
AI Technical Summary
In the existing Rusotinib synthesis method, the construction step of (R)⁃3-cyclopentyl propionitrile has the problems of low resolution yield and high chiral catalyst price, resulting in high production costs.
Rusotinib was obtained by constructing the intermediate 3-pyrazolyl-3-cyclopentyl-propinitrile (RXTN-3) that meets chiral requirements, using specific reaction steps and conditions, including reaction with the compound of formula I as a raw material under the action of a reducing agent, followed by reaction with the pyridine derivative and 7H-pyrrolo[2,3-d]pyrimidine.
It achieves high efficiency and low cost synthesis of rusotinib, improving productivity and economicality.
Smart Images
Figure CN119977970A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing ruxolitinib. Background Art
[0002] Ruxolitinib is a JAK1 and JAK2 inhibitor developed by Incyte Corp. It was granted the title of "orphan drug" by the U.S. Food and Drug Administration (FDA) and was approved for marketing through the FDA priority review channel in November 2011. The drug is the first FDA-approved drug for the treatment of myelofibrosis and is used to treat intermediate-risk or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.
[0003] The molecule of Ruxolitinib is composed of three modules: (R)-3-cyclopentylpropionitrile, 7H-pyrrolo[2,3-d]pyrimidine, and 1H-pyrazole. The synthesis of Ruxolitinib is generally prepared from commercially available 7H-pyrrolo[2,3-d]pyrimidine through different coupling sequences with 1H-pyrazole and (R)-3-cyclopentylpropionitrile. According to the different starting materials and module construction sequences, there are currently 7 reported synthetic routes. Among all the routes, as the only chiral source of Ruxolitinib, the construction of (R)-3-cyclopentylpropionitrile is the most critical step in the synthesis. The 7 routes use two methods, chiral resolution and asymmetric catalysis, which have disadvantages such as low resolution yield and expensive chiral catalysts, which increase production costs. Summary of the invention
[0004] In view of the above problems of the prior art, the present invention provides a method for preparing ruxolitinib, which achieves high-efficiency and low-cost synthesis of ruxolitinib by constructing an intermediate 3-pyrazolyl-3-cyclopentyl-propionitrile (RXTN-3) that meets the chiral requirements.
[0005] To achieve the above object, the present invention adopts the following technical solution:
[0006] A method for preparing ruxolitinib comprises the following steps:
[0007] (1) using the compound of formula I as a raw material, reacting under the action of a reducing agent to obtain a racemic compound of formula II;
[0008] (2) reacting the racemic compound of formula II with a pyridine derivative to obtain a compound of formula III;
[0009] (3) reacting the compound of formula III with 7H-pyrrolo[2,3-d]pyrimidine to obtain ruxolitinib;
[0010] The structural formula of the compound of formula I is , the structural formula of the compound of formula II is , the structural formula of the compound of formula III is , wherein X is halogen or nitro.
[0011] Preferably, the compound of formula I is prepared by the following method:
[0012] (0) Methyl cyclopentylcarboxylate and acetonitrile are reacted at 105° C. under the action of NaH to obtain a compound of formula I.
[0013] Preferably, the solvent for the reaction in step (0) is 1,4-dioxane.
[0014] Preferably, the reducing agent in step (1) is sodium borohydride.
[0015] Preferably, the solvent for the reaction in step (1) is methanol.
[0016] Preferably, the pyridine derivative in step (2) is 4-bromopyrazole or 4-nitropyrazole.
[0017] Preferably, the reaction in step (2) is carried out under the action of n-butyl phosphoric anhydride or n-butyl phosphoric anhydride and phosphorus pentoxide.
[0018] Preferably, the reaction temperature in step (2) is 100°C.
[0019] Preferably, the reaction in step (2) is carried out in chloroform solvent.
[0020] Step (3) is prior art.
[0021] The beneficial effects of the present invention are:
[0022] The preparation method of ruxolitinib provided by the present invention has high yield and low cost, and is conducive to expanding production. BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Figure 1 is the mass spectrum of the prepared compound of formula I.
[0024] Figure 2 It is the HPLC chart of the compound of formula III. DETAILED DESCRIPTION
[0025] Example 1
[0026] (1) Preparation of the compound of formula I:
[0027] Place NaH (175 mg) in a branched reaction tube, add ultra-dry 1,4-dioxane (5 mL) in an ice-water bath, add a rotor and start stirring. Then add acetonitrile reagent (225 μL), stir at room temperature for 30 minutes, then add methyl cyclopentanecarboxylate (330 μL) under nitrogen, and continue stirring at room temperature for 30 minutes. Then heat the oil bath to 105°C for reaction, and monitor the reaction progress by thin layer chromatography during the reaction.
[0028] After the reaction is completed, the reaction solution is cooled to room temperature and a small volume of water is added. At this time, the solid in the reaction solution is completely dissolved and becomes a yellow clear liquid. After it is rotary evaporated to a small volume, it is diluted with water and extracted with dichloromethane. 1N HCl solution is added to the extracted water layer to adjust the pH to about 5-6. At this time, the reaction solution becomes a whitish turbid liquid. It is then extracted again with dichloromethane to obtain dark yellow oily droplets with a yield of 83%. The mass spectrometry results are as follows Figure 1 shown.
[0029] (2) Preparation of the compound of formula II:
[0030] Dissolve 0.5g of the compound of formula I in 2g of methanol, cool to 0-5°C, and add 0.15g of sodium borohydride in batches (control the temperature at 0-5°C when adding). Naturally warm to room temperature and react for 2h. Perform thin layer chromatography during the process (petroleum ether: ethyl acetate = 1:1). After the reaction is completed, add an appropriate amount of saturated ammonium chloride reagent to quench, then spin off part of the methanol, cool to 0-5°C, add 1M hydrochloric acid to adjust the pH to 6-7, add 3g of water, extract twice with dichloromethane, and concentrate to dryness to obtain an oily substance with a yield of 87%.
[0031] (3) Preparation of the compound of formula III:
[0032] Add n-butylphosphoric anhydride (50%wt, 1eq) and phosphorus pentoxide (2eq) to a flask, put in a magnetic bar, add chloroform reagent, and stir. Then add the compound of formula II (1.01eq) and 4-bromopyrazole (1eq), heat to 100°C and reflux for 2h. After the reaction is completed, quench with water and extract with dichloromethane. During the extraction process, add saturated brine and separate the layers. Take the organic phase and wash it with water + saturated brine twice. After drying with anhydrous sodium sulfate, rotary evaporate to obtain a yellow oily liquid. Use column chromatography (developing agent PE:EA=5:1) to separate and purify to obtain the compound of formula III. The HPLC chart is as follows Figure 2 shown.
Claims
1. A method for preparing ruxolitinib, characterized in that: The steps include: (1) using the compound of formula I as a raw material, reacting under the action of a reducing agent to obtain a racemic compound of formula II; (2) reacting the racemic compound of formula II with a pyridine derivative to obtain a compound of formula III; (3) reacting the compound of formula III with 7H-pyrrolo[2,3-d]pyrimidine to obtain ruxolitinib; The structural formula of the compound of formula I is , the structural formula of the compound of formula II is , the structural formula of the compound of formula III is , wherein X is halogen or nitro.
2. The preparation method according to claim 1, characterized in that: The compound of formula I is prepared by the following method: (0) Methyl cyclopentylcarboxylate and acetonitrile are reacted at 105° C. under the action of NaH to obtain a compound of formula I.
3. The preparation method according to claim 1, characterized in that: The solvent for the reaction in step (0) is 1,4-dioxane.
4. The preparation method according to claim 1, characterized in that: The reducing agent in step (1) is sodium borohydride.
5. The preparation method according to claim 1, characterized in that: The solvent for the reaction in step (1) is methanol.
6. The preparation method according to claim 1, characterized in that: The pyridine derivative in step (2) is 4-bromopyrazole or 4-nitropyrazole.
7. The preparation method according to claim 1, characterized in that: The reaction in step (2) is carried out under the action of n-butyl phosphoric anhydride or n-butyl phosphoric anhydride and phosphorus pentoxide.
8. The preparation method according to claim 1, characterized in that: The reaction temperature in step (2) is 100°C.
9. The preparation method according to claim 1, characterized in that: The reaction described in step (2) is carried out in chloroform solvent.