Preparation method of tofacitinib perhydrogenated impurity

Abstract

The invention relates to a preparation method of a tofacitinib perhydrogenated impurity. The preparation method comprises the following step: under an alkaline condition, carrying out substitution reaction on a compound shown in a formula II and a compound shown in a formula III to prepare a compound shown in a formula IV. And debenzylating the compound in the formula IV to prepare the tofacitinib perhydrogenated impurity (a compound in a formula V). The preparation method provided by the invention is simple to operate, convenient to purify, high in yield and good in experimental repeatability, and provides a basis for quality research of tofacitinib.

Description

Technical Field

[0001] This invention relates to a method for preparing a tofacitinib perhydrogenated impurity. Background Technology

[0002] Rheumatoid arthritis (RA) is a chronic, systemic disease primarily characterized by inflammatory synovitis, with its etiology currently unknown. It manifests as polyarticular, symmetrical, and invasive joint inflammation of the small joints of the hands and feet, often accompanied by extra-articular organ involvement and a positive serum rheumatoid factor, leading to joint deformities and loss of function. RA is quite harmful, causing skin diseases, eye diseases, respiratory diseases, heart diseases, and neurological disorders. Current research suggests it is an autoimmune disease with an unclear cause, although some studies suggest it may be related to endocrine, nutritional, geographical, occupational, psychological, environmental, smoking, infectious, and genetic factors.

[0003] Anti-rheumatoid arthritis drugs mainly include nonsteroidal anti-inflammatory drugs (NSAIDs), DMARDs, cyclophosphamides, glucocorticoids, biologics, and herbal medicines. While these drugs are effective to some extent, they also have limitations. Many patients still suffer from the pain and discomfort caused by the disease. With deeper research into rheumatoid arthritis, treatment methods have greatly improved, and various drugs have developed rapidly. Among them, tofacitinib citrate, a new drug developed by Pfizer and launched in November 2012, is being widely researched and used clinically as a new type of anti-rheumatoid arthritis drug. This drug is a non-receptor tyrosine protein kinase (JAK) inhibitor, also known as a Janus kinase inhibitor. It selectively inhibits JKA kinase, blocking cytokine-stimulated signal transduction pathways. It is mainly used for patients with moderate to severe active rheumatoid arthritis who have not responded adequately to methotrexate treatment.

[0004] Impurity research is a key research area in drug development and commercial production, and it is conducted throughout the entire drug lifecycle. The presence of impurities directly affects the safety, efficacy, and quality control of drugs.

[0005] This invention relates to a method for preparing a tofacitinib hydrogenated impurity (compound V), which can be used for quality control during the production of tofacitinib active pharmaceutical ingredient or formulation.

[0006] Currently, there are very few publications reporting methods for preparing the hydrogenated impurities of tofacitinib, with only one patent, CN104926816A, reporting the preparation method as follows:

[0007] The method described in this patent has low yield and is difficult to purify, requiring the use of a high-efficiency preparative liquid chromatograph.

[0008] To address the shortcomings of existing technologies, this invention provides a novel method for preparing tofacitinib perhydrogenated impurities (compound V). The preparation method involved in this invention is simple to operate, easy to purify, has a high yield, and good experimental reproducibility. Summary of the Invention

[0009] The purpose of this invention is to provide a method for preparing tofacitinib perhydrogenated impurities.

[0010] This invention provides a tofacitinib perhydrogenated impurity (compound of formula V), the structural formula of which is as follows:

[0011] This invention also provides a method for preparing a tofacitinib perhydrogenated impurity (compound of formula V), comprising the following steps: (1) In at least one organic solvent, under alkaline conditions, compound II and compound III undergo a substitution reaction to prepare compound IV; (2) In at least one organic solvent, the compound of formula IV is debenzylated to prepare the tofacitinib perhydrogenated impurity (compound of formula V).

[0012] In step (1), the organic solvent is selected from a mixture of dioxane and water, and the volume of the organic solvent is 5-50 times (mL / g) the mass of the compound of formula II, preferably 10 times.

[0013] In step (1), the alkali is selected from potassium carbonate, potassium tert-butoxide, and sodium tert-butoxide, and the molar ratio of the alkali to the compound of formula II is 2 to 20:1, preferably 5:1.

[0014] The reaction temperature in step (1) is 80 degrees to 120 degrees, preferably 100 degrees.

[0015] In step (1), the molar ratio of compound III to compound II is 1 to 4:1, preferably 1.5:1.

[0016] The reaction time for step (1) is 2-48 hours, preferably 18 hours.

[0017] In step (2), the organic solvent is selected from methanol and tetrahydrofuran, preferably methanol, and the volume of the organic solvent is 5-50 times (mL / g) the mass of the compound of formula II, preferably 10 times.

[0018] In step (2), the catalyst is selected from palladium / carbon and palladium hydroxide / carbon, and the mass ratio of the catalyst to the compound of formula IV is 0.05 to 0.5:1, preferably 0.2:1.

[0019] In step (2), the reaction temperature is 10 degrees to 65 degrees, preferably 25 degrees.

[0020] The reaction time for step (2) is 5-48 hours, preferably 18 hours.

[0021] Due to the application of the above technical solutions, this invention has the following advantages: simple operation, convenient purification, high yield, and good experimental reproducibility. The tofacitinib perhydrogenated impurity (compound of formula V) prepared by this invention can be used as a reference standard for tofacitinib-related substances, providing a basis for the quality study of tofacitinib. Attached Figure Description

[0022] Figure 1 This is the high performance liquid chromatogram of the tofacitinib perhydrogenated impurity (compound V) in step (2) of Example 1.

[0023] Figure 2 This is the mass spectrometry of the tofacitinib perhydrogenated impurity (compound V) in step (2) of Example 1.

[0024] Figure 3 The 1H NMR spectrum of the hydrogenated impurity (compound V) of tofacitinib in step (2) of Example 1 is shown. Detailed Implementation

[0025] It should be understood that those skilled in the art can make various modifications and improvements to the invention without departing from the spirit and scope of the invention, based on the content disclosed herein. All such modifications and improvements should fall within the patent protection scope defined by the claims of this application. Furthermore, it is understood that the embodiments provided herein are for illustrative purposes only and should not be construed as limiting the invention.

[0026] The present invention will be further described in detail below with reference to specific embodiments.

[0027] Example 1: (1) Preparation of compound IV. 3g of compound II was dissolved in 15ml of dioxane and 15ml of water. 13.32g of potassium carbonate and 8.42g of compound III were added, and the mixture was heated to 100°C and reacted overnight. TLC showed that the reaction proceeds were complete. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was evaporated to dryness and purified by column chromatography with silica gel to obtain 4.5g of compound IV as a yellow solid. (2) Preparation of the hydrogenated impurity of tofacitinib (compound V): 4.5 g of compound IV, 45 ml of methanol, and 900 mg of palladium on carbon were added to a three-necked flask. Under hydrogen protection, the mixture was reacted overnight at room temperature. After TLC showed the reaction was complete, the reaction solution was filtered, the filtrate was concentrated and evaporated to dryness, and purified by column chromatography with silica gel to obtain 3.05 g of the free form of compound V. This free form was dissolved in methanol, the pH was adjusted to 1-2 with dilute hydrochloric acid, and evaporated to dryness to obtain 3.5 g of compound V. It was a white solid. Characterization data are as follows: Figure 1 High performance liquid chromatography purity: 99.67%, chromatogram 2 (mass spectrometry [M+H]) + =248.1860, Figure 3 1H NMR spectrum (400MHz, DMSO-d6).

[0028] Example 2: (1) Preparation of compound IV. 3 g of compound II was dissolved in 15 ml of dioxane and 15 ml of water. 10.82 g of potassium tert-butoxide and 8.42 g of compound III were added, and the mixture was heated to 100°C and reacted overnight. TLC showed that the reaction proceeds were complete. The reaction solution was cooled to room temperature and extracted with dichloromethane. The organic layer was evaporated to dryness and purified by column chromatography with silica gel to obtain 4.2 g of compound IV as a yellow solid. (2) Preparation of the hydrogenated impurity of tofacitinib (compound V): 4.2 g of compound IV, 42 ml of methanol, and 840 mg of palladium hydroxide on carbon were added to a three-necked flask. Under hydrogen protection, the mixture was reacted overnight at room temperature. After TLC showed completion, the reaction solution was filtered, the filtrate was concentrated and evaporated to dryness, and purified by column chromatography with silica gel to obtain 2.7 g of the free form of compound V. This free form was dissolved in methanol, the pH was adjusted to 1-2 with dilute hydrochloric acid, and evaporated to dryness to obtain 3.1 g of compound V. It was a white solid with an HPLC purity of 97.90%.

[0029] Example 3: (1) Preparation of compound IV. 3g of compound II was dissolved in 30ml of dioxane and 30ml of water. 9.27g of sodium tert-butoxide and 8.42g of compound III were added, and the mixture was heated to 100°C and reacted overnight. TLC showed that the reaction proceeds were complete. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was evaporated to dryness and purified by column chromatography with silica gel to obtain 4.3g of compound IV as a yellow solid. (2) Preparation of the hydrogenated impurity of tofacitinib (compound V): 4.3 g of compound IV, 43 ml of tetrahydrofuran, and 1.29 g of palladium on carbon were added to a three-necked flask. Under hydrogen protection, the mixture was reacted overnight at room temperature. After TLC showed completion, the reaction solution was filtered, the filtrate was concentrated and evaporated to dryness, and purified by column chromatography with silica gel to obtain 2.9 g of free compound V. This free compound was dissolved in methanol, the pH was adjusted to 1-2 with dilute hydrochloric acid, and evaporated to dryness to obtain 3.33 g of compound V. It was a white solid with an HPLC purity of 96.04%.

Claims

1. The structural formula of a tofacitinib perhydrogenated impurity (compound V) is as follows:

2. A method for preparing a tofacitinib perhydrogenated impurity (compound of formula V), characterized in that: The method includes the following steps: (1) In at least one organic solvent, under alkaline conditions, compound II and compound III undergo a substitution reaction to prepare compound IV; (2) In at least one organic solvent, the compound of formula IV is debenzylated to prepare the tofacitinib perhydrogenated impurity (compound of formula V).

3. The method as described in claim 2, characterized in that: The organic solvent in step (1) is selected from a mixed solvent of dioxane and water, and the volume of the organic solvent is 5-50 times (mL / g) the mass of the compound of formula II, preferably 10 times.

4. The method as described in claim 2, characterized in that: The alkali in step (1) is selected from potassium carbonate, potassium tert-butoxide, and sodium tert-butoxide. The molar ratio of the alkali to the compound of formula II is 2 to 20:1, preferably 5:

1.

5. The method as described in claim 2, characterized in that: The reaction temperature in step (1) is 80 degrees to 120 degrees, preferably 100 degrees.

6. The method as described in claim 2, characterized in that: In step (1), the molar ratio of compound III to compound II is 1 to 4:1, preferably 1.5:

1.

7. The method as described in claim 2, characterized in that: The reaction time for step (1) is 2-48 hours, preferably 18 hours.

8. The method as described in claim 2, characterized in that: In step (2), the organic solvent is selected from methanol and tetrahydrofuran, preferably methanol, and the volume of the organic solvent is 5-50 times (mL / g) the mass of the compound of formula II, preferably 10 times.

9. The method as described in claim 2, characterized in that: In step (2), the catalyst is selected from palladium / carbon and palladium hydroxide / carbon, and the mass ratio of the catalyst to the compound of formula IV is 0.05 to 0.5:1, preferably 0.2:

1.

10. The method as described in claim 2, characterized in that: The reaction temperature in step (2) is 10 degrees to 65 degrees, preferably 25 degrees.

11. The method as described in claim 2, characterized in that: The reaction time for step (2) is 5-48 hours, preferably 18 hours.

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