A method of preparing a compound of formula (I) or a salt thereof

Abstract

This invention relates to a novel method for preparing ruxolitinib phosphate. Methyl 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-D]pyrimidin-7-yl)terpentanoate (compound X) is deprotected under alkaline conditions, then directly resolved without separation, alkalized to release the free ruxolitinib, and salted to obtain the ruxolitinib phosphate. The obtained ruxolitinib phosphate has an HPLC purity >99.90%, and the ruxolitinib phosphate isomer has a purity >99.50%. The preparation method of this invention has the advantages of simple operation, controllable impurities, low cost, and suitability for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a method for preparing ruxolitinib phosphate or its salt. Background Technology

[0002] Ruxolitinib phosphate, chemical name: (3R)-3-cyclopentyl-3-4-[(7H-pyrrolo[2,3-D]pyrimidin-4-yl)-1H-pyrazolyl]propionitrile phosphate. Its chemical structure is shown in Formula I:

[0003]

[0004] Ruxolitinib phosphate tablets were approved for marketing in the United States in 2011 for the treatment of intermediate- or high-risk primary myelofibrosis, myelofibrosis secondary to polycythemia vera, or myelofibrosis secondary to essential thrombocythemia.

[0005] The ruxolitinib phosphate structure contains a chiral center, making its construction challenging. The currently reported synthetic methods for ruxolitinib phosphate are as follows:

[0006] WO2007070514A1 reports a route for the synthesis of ruxolitinib using cyclopentylformaldehyde and diethyl cyanomethyl phosphate as starting materials.

[0007]

[0008] This route is not suitable for industrial production because the key intermediate 6 needs to be prepared by chiral column. In addition, compound E is easily generated during the de-SEM protecting group removal process. Compound E is not easy to remove in the entire subsequent process, thus affecting the quality of ruxolitinib phosphate.

[0009]

[0010] CN113292569A reports a method for preparing ruxolitinib phosphate. This route involves the breaking of chemical bonds in the protecting group, requiring precise control of the reaction raw materials, making the operation relatively cumbersome. Furthermore, the use of NaOH during the salt separation process can easily cause hydrolysis of the ester group in the salt, making it difficult to control the impurities of compound E in ruxolitinib phosphate.

[0011]

[0012] Therefore, developing a method that is simple to operate, has controllable impurities, is low in cost, and is suitable for industrial production is an urgent problem to be solved. Summary of the Invention

[0013] To address the shortcomings of existing technologies, a method for preparing ruxolitinib or its salts that is simple to operate, allows for controllable impurities, and is suitable for industrial production is provided.

[0014] In one aspect, the present invention provides a method for preparing intermediate B of ruxolitinib or its salt, comprising the following steps:

[0015] (a) Methyl 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-D]pyrimidin-7-yl)terpentanoate (compound X) and sodium hydroxide solution undergo a deprotection reaction in an organic solvent, optionally followed by alkali treatment and concentration to give intermediate A concentrate without separation;

[0016] (b) The product obtained in step (a) is subjected to a resolution reaction with D-(+)-di-p-methoxybenzoyl tartaric acid in mixed solvent II to give intermediate B, optionally including a purification step.

[0017]

[0018] In some embodiments, in step (a), the amount of sodium hydroxide used is 0.05-0.15 eq of compound X, preferably 0.05-0.10 eq, more preferably 0.10 eq;

[0019] In some embodiments, in step (a), the sodium hydroxide solution is a 0.5-2N sodium hydroxide solution, preferably a 1N sodium hydroxide solution;

[0020] In some embodiments, in step (a), the temperature of the deprotection reaction is 0-30°C, preferably 10-25°C;

[0021] In some implementations, in step (a), the temperature control of the deprotection reaction can be controlled in one step or in a gradient. Gradient control is, for example, maintaining the temperature at 20-25°C while stirring, then cooling the temperature to 10-20°C and continuing to stir the reaction.

[0022] In some implementations, in step (a), the deprotection reaction takes 4-8 hours; preferably 4-6 hours. ；

[0023] In some embodiments, in step (a), the organic solvent is selected from alcohol solvents, preferably C. 1-6 Alcohols, such as methanol, ethanol, or isopropanol;

[0024] In some of these implementations, in step (a), the alkali is ammonia.

[0025] In some embodiments, in step (b), the molar ratio of compound X to D-(+)-di-p-methoxybenzoyl tartaric acid is 1:0.4 to 1:1, preferably 1:0.5 to 1:0.7;

[0026] In some implementations, in step (b), the temperature of the splitting reaction is 25-60°C, preferably 40-55°C;

[0027] In some embodiments, in step (b), the mixed solvent is selected from alcohol-containing solvents (preferably C). 1-6 Alcohols, such as methanol, ethanol, and isopropanol), wherein the mixed solvent is preferably methanol and acetone (preferably, the volume ratio of methanol to acetone is 9:2 to 9:8, more preferably 9:3.5);

[0028] In some embodiments, the refining step is as follows: intermediate B is added to a mixed solvent (preferably methanol and water, more preferably methanol and water volume ratio of 80:1 to 80:5), heated (e.g., 50 to 80°C, preferably 60 to 70°C) to dissolve, and then cooled to crystallize or seed crystals are added and cooled to crystallize; preferably, the volume of the mixed solvent is more than 30 times the volume of intermediate B, such as 30 to 60 times, preferably 30 to 40 times; and / or, preferably, the cooling rate is 13 ± 5°C / h;

[0029] In some of these embodiments, the salt is a phosphate.

[0030] In another aspect, the present invention provides a method for preparing ruxolitinib or a salt thereof, comprising the following steps:

[0031] Intermediate B undergoes an alkalization reaction to yield ruxolitinib. Optionally, it can be reacted with an acid to form a salt, producing ruxolitinib salt.

[0032]

[0033] In some embodiments, the alkali used in the alkali-free reaction is an alkali metal or alkaline earth metal alkane oxide, hydroxide, carbonate or bicarbonate, preferably a carbonate (such as sodium carbonate, potassium carbonate) or a bicarbonate (such as sodium bicarbonate, potassium bicarbonate), more preferably sodium carbonate or sodium bicarbonate.

[0034] In some embodiments, the amount of alkali used in the alkalization and free reaction is 1.0-3.0 eq, preferably 1.5-2.5 eq;

[0035] In some embodiments, the acid is phosphoric acid or a phosphoric acid-alcohol solution; preferably, the alcohol solvent is C. 1-6 Alcohols, such as methanol, ethanol, and isopropanol, with isopropanol being preferred;

[0036] In some embodiments, the salt is a phosphate;

[0037] In some implementations, the intermediate B is prepared by any of the methods described above.

[0038] In another aspect, the present invention provides a method for preparing ruxolitinib or a salt thereof, comprising the following steps:

[0039] (a) Methyl 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-D]pyrimidin-7-yl)terpentanoate (compound X) and sodium hydroxide solution undergo a deprotection reaction in an organic solvent, optionally followed by alkali treatment and concentration to give intermediate A concentrate without separation;

[0040] (b) The product obtained in step (a) is subjected to a resolution reaction with D-(+)-di-p-methoxybenzoyl tartaric acid in mixed solvent II to give intermediate B, optionally including a purification step;

[0041] (c) Intermediate B undergoes an alkalization reaction to yield ruxolitinib. Optionally, it may undergo a salt formation reaction with an acid to generate ruxolitinib salt.

[0042]

[0043] In some embodiments, in step (a), the amount of sodium hydroxide used is 0.05-0.15 eq of compound X, preferably 0.05-0.10 eq, more preferably 0.10 eq;

[0044] In some embodiments, in step (a), the sodium hydroxide solution is a 0.5-2N sodium hydroxide solution, preferably a 1N sodium hydroxide solution;

[0045] In some embodiments, in step (a), the temperature of the deprotection reaction is 0-30°C, preferably 10-25°C;

[0046] In some implementations, in step (a), the temperature control of the deprotection reaction can be controlled in one step or in a gradient. Gradient control is, for example, maintaining the temperature at 20-25°C while stirring, then cooling the temperature to 10-20°C and continuing to stir the reaction.

[0047] In some implementations, in step (a), the deprotection reaction takes 4-8 hours; preferably 4-6 hours. ；

[0048] In some embodiments, in step (a), the organic solvent is selected from alcohol solvents, preferably C. 1-6 Alcohols, such as methanol, ethanol, or isopropanol;

[0049] In some of these implementations, in step (a), the alkali is ammonia.

[0050] In some embodiments, in step (b), the molar ratio of compound X to D-(+)-di-p-methoxybenzoyl tartaric acid is 1:0.4 to 1:1, preferably 1:0.5 to 1:0.7;

[0051] In some implementations, in step (b), the temperature of the splitting reaction is 25-60°C, preferably 40-55°C;

[0052] In some embodiments, in step (b), the mixed solvent is selected from alcohol-containing solvents (preferably C). 1-6 Alcohols, such as methanol, ethanol, and isopropanol), wherein the mixed solvent is preferably methanol and acetone (preferably, the volume ratio of methanol to acetone is 9:2 to 9:8, more preferably 9:3.5);

[0053] In some embodiments, the refining step is as follows: intermediate B is added to a mixed solvent (preferably methanol and water, more preferably methanol and water volume ratio of 80:1 to 80:5), heated (e.g., 50-80°C, preferably 60-70°C), stirred to dissolve, cooled to crystallize, or seed crystals are added and cooled to crystallize; preferably, the volume of the mixed solvent is more than 30 times the volume of intermediate B, such as 30-60 times, preferably 30-40 times; and / or, preferably, the cooling rate is 13±5°C / h;

[0054] In some of the embodiments, in step (c), the alkalization free reaction uses an alkali metal or alkaline earth metal alkane oxide, hydroxide, carbonate or bicarbonate, preferably a carbonate (such as sodium carbonate, potassium carbonate) or a bicarbonate (such as sodium bicarbonate, potassium bicarbonate), more preferably sodium carbonate or sodium bicarbonate.

[0055] In some embodiments, in step (c), the amount of base used in the alkalization and ionization reaction is 1.0-3.0 eq of compound B, preferably 1.5-2.5 eq;

[0056] In some embodiments, in step (c), the salt-forming step employs an alcohol solvent for dissolution, preferably C. 1-6 Alcohols, such as methanol, ethanol, and isopropanol, with isopropanol being preferred;

[0057] In some embodiments, the salt-forming step involves adding a phosphoric acid or phosphoric acid-alcohol solution;

[0058] In some embodiments, the salt is a phosphate;

[0059] In some embodiments, step (a) is as follows: methyl 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-D]pyrimidin-7-yl)terpentanoate (compound X) is taken, added to an alcohol solvent, and 0.05-0.15 eq sodium hydroxide is added at 10-25°C. The mixture is stirred and reacted, optionally further treated with an alkali (such as ammonia) and concentrated to obtain a concentrate without separation;

[0060] In some embodiments, step (b) is: adding the product obtained in step (a) to a mixed solvent of methanol and acetone, stirring and heating, adding D-(+)-di-p-methoxybenzoyl tartaric acid, stirring the reaction, cooling and crystallizing to generate intermediate B;

[0061] Some of these implementations also include a purification step for intermediate B: adding intermediate B to a mixed solvent of methanol and water in a volume of 30-60 times, heating to 50-80°C to dissolve, and then cooling to crystallize or adding seed crystals and cooling to crystallize.

[0062] In some embodiments, step (c) is: intermediate B undergoes an alkalization and release reaction with sodium carbonate or sodium bicarbonate to obtain ruxolitinib; optionally, isopropanol is added for dissolution, and phosphate-isopropanol solution is added to form a salt.

[0063] In some embodiments, the salt is a phosphate;

[0064] In some embodiments, when the salt is a phosphate, the method for preparing ruxolitinib phosphate includes the following steps:

[0065] Step (a): Take methyl 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-D]pyrimidin-7-yl)terpentanoate (compound X), add an alcohol solvent, add 0.05-0.10 eq sodium hydroxide (preferably 0.5-2N sodium hydroxide solution) at 10-25°C, stir the reaction, further treat with ammonia water and concentrate to obtain a concentrate without separation;

[0066] Step (b): Add the concentrate obtained in step (a) to a mixed solvent of methanol and acetone, stir and heat to 25-60°C, add D-(+)-di-p-methoxybenzoyl tartaric acid, stir to react, cool and crystallize to generate intermediate B;

[0067] Refining of intermediate B: Add intermediate B to a mixed solvent of methanol and water in a volume of 30-40 times, heat to 50-80℃ to dissolve, cool down to crystallize, or add seed crystals and cool down to crystallize.

[0068] Step (c): Intermediate B undergoes an alkalization and release reaction with 1.0-3.0 eq of sodium carbonate or sodium bicarbonate to obtain ruxolitinib;

[0069] It also includes a salt-forming reaction: isopropanol is added to the ruxolitinib obtained in step (c) to dissolve it, and then a phosphate-isopropanol solution is added to form a salt.

[0070]

[0071] In another aspect, the present invention provides an intermediate B, namely, ruxolitinib or a salt thereof.

[0072]

[0073] In another aspect, the present invention provides a composition comprising intermediate B of ruxolitinib or a salt thereof and compound E.

[0074]

[0075] In some embodiments, the purity of compound E is no more than 0.5%, preferably no more than 0.4%, and more preferably no more than 0.2%.

[0076] In another aspect of the present invention, the use of the above-described intermediate B or intermediate B obtained by any of the above-described preparation methods or the above-described composition in the preparation of ruxolitinib or its salts is provided.

[0077] In some embodiments, the salt is a phosphate.

[0078] The beneficial effects of this invention are as follows:

[0079] (1) In the preparation of compound B, methyl tervastatin (1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-D]pyrimidin-7-yl)tervastatin (compound X) and sodium hydroxide (e.g., 0.05-0.15 eq, preferably 0.05-0.10 eq) undergo a deprotection reaction in an alcoholic organic solvent (e.g., methanol) at an appropriate temperature (e.g., 10-25 °C). The reaction is directly resolved without separation, which is simple to operate and can effectively control the formation of compound E in the entire synthesis process. The purity of compound E can not exceed 0.5%, thereby ensuring the purity of ruxolitinib or its salt (e.g., phosphate) in the subsequent formation. That is, the purity of impurity compound E in the active pharmaceutical ingredient does not exceed 0.1%.

[0080] (2) In the purification of intermediate B in this invention, when the volume of the mixed solvent (preferably methanol and water, especially methanol and water volume ratio of 80:1 to 80:5, such as 80:3) reaches 30 times or more the volume of intermediate B (such as 30V-40V), the chiral purity of intermediate B obtained is higher than 99.50%, and the ee value is >99.00%. It can be directly used to synthesize ruxolitinib or its salt (such as phosphate). The operation is simple, the reaction conditions are mild, and the solvent is green and environmentally friendly, making it suitable for industrial production.

[0081] (3) In this invention, intermediate B undergoes an alkaline release reaction under sodium carbonate or sodium bicarbonate conditions (e.g., in amounts of 1.0-3.0 eq), followed by reaction with an acid (e.g., phosphoric acid or phosphoric acid-isopropanol solution) to obtain ruxolitinib salt (e.g., ruxolitinib phosphate). This method does not involve the breaking of chemical bonds and can be directly removed by washing with water. It has fewer sources of impurities and is easier to control impurities (e.g., compound E). The ruxolitinib salt (e.g., ruxolitinib phosphate) obtained by this method has an HPLC purity of over 99.90%, and the purity of the isomers is greater than 99.50%. The yields of the two steps of release and salt formation are greater than 90%, and the purity of impurity compound E is less than 0.1%.

[0082] (4) The method for preparing ruxolitinib phosphate of the present invention uses a phosphate-isopropanol solution to form salt, which does not easily precipitate a large amount of solid. By slowly cooling and crystallizing, the particle size D (0.9) of ruxolitinib phosphate raw material obtained by this method is >25 μm, which can be better met by pulverizing to meet the needs of the formulation for raw materials with different particle sizes.

[0083] (5) The preparation method of ruxolitinib phosphate of the present invention is simple to operate and saves time and energy costs. Detailed Implementation

[0084] The present invention will be further described below with reference to specific embodiments. It should be noted that these specific embodiments are only used to illustrate the present invention and are not intended to limit the entire scope of the invention.

[0085] Example 1:

[0086] Take 100.00 g (1.00 eq) of methyl 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-D]pyrimidin-7-yl)terpentanoate, add methanol (7.50 mL / g), stir, and add in portions of 1NNaOH solution prepared from NaOH (0.10 eq) at 20-25°C. After the addition is complete, stir at 20-25°C for a total reaction time of 1 h. Sampling is then performed to detect the purity of impurity compound E, which is 0.18%.

[0087] Example 2

[0088] The preparation method was the same as in Example 1, except that the amount of sodium hydroxide used was 0.05 eq. Samples were taken and tested after a total reaction time of 1 hour, and the purity of impurity compound E was 0.06%.

[0089] Comparative Example 1

[0090] The preparation method was the same as in Example 1, except that the amount of sodium hydroxide used was 1.10 eq. Samples were taken and tested after a total reaction time of 1 hour, and the purity of impurity compound E was 1.16%.

[0091] Comparative Example 2

[0092] The preparation method was the same as in Example 1, except that the amount of sodium hydroxide used was 0.20 eq. Samples were taken and tested after a total reaction time of 1 hour, and the purity of impurity compound E was 0.76%.

[0093] Data from Examples 1 and 2 and Comparative Examples 1 and 2 show that when the amount of sodium hydroxide is 0.05-0.15 eq (e.g., 0.05-0.10 eq), and samples are taken after a total reaction time of 1 hour, the purity of impurity compound E is low, all less than 0.5% (and all less than 0.2%). However, when the amount of sodium hydroxide is 0.20 eq or higher, the detection rate of impurity compound E exceeds 0.7%. ， It is not easy to remove during the entire subsequent process, which is not conducive to the control of impurity compound E in the subsequent production of ruxolitinib or its salts (such as phosphate).

[0094] Example 3:

[0095] 100.00 g (1.00 eq) of methyl 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-D]pyrimidin-7-yl)terpentanoate (compound X) was placed in a reactor, and methanol (7.50 mL / g) was added. The mixture was stirred, and a 1N NaOH solution prepared with 0.10 eq of NaOH was added in portions while maintaining the temperature at 20–25 °C. After the addition was complete, the mixture was stirred at 20–25 °C for 1.5 h, then cooled to 10–20 °C and stirred again. Sampling was started after a total reaction time of 4 h. The purity of impurity compound E was 0.36%. The reaction was quenched after the raw materials had completely reacted, and the mixture was concentrated. THF was then added to dissolve the impurities, and ammonia was added dropwise while maintaining the temperature at 20–25 °C. The mixture was stirred for 1.5 h, concentrated, and then ethyl acetate and water were added. The mixture was stirred and separated, and the organic phase was concentrated to obtain a concentrate, which was not separated further.

[0096] Methanol (550 mL) and acetone (214 mL) were added to the reactor concentrate, stirred, and heated to 50–55 °C. D-(+)-di-p-methoxybenzoyl tartrate (54.72 g) was added at 50–55 °C. After a brief period of dissolution, a large amount of white solid precipitated out. The mixture was stirred at 50–55 °C for 3 h, then cooled to 0–10 °C at a rate of 10 °C / h and stirred for 1 h. The mixture was filtered, and the filter cake was washed with methanol to obtain 73.52 g of crude (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile-D-p-methoxybenzoyl tartrate (intermediate B). The chiral purity was 94.31% according to chiral HPLC analysis.

[0097] Example 4: Refining Intermediate B

[0098] 5.00 g of the crude (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile-D-p-methoxydibenzoyltartrate (intermediate B) obtained in Example 3 was added to a 250 mL flask, along with methanol (144.6 mL) and water (5.4 mL). The mixture was stirred, heated to 60–65 °C and stirred until dissolved, then cooled to 0–10 °C at a rate of 10 °C / h. After stirring at ℃ for 1 hour, the mixture was filtered, the filter cake was washed with methanol, and then dried under vacuum at 45℃ to obtain (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile-D-p-methoxydibenzoyltartrate (B) 4.30 g. HPLC analysis showed that the purity of impurity compound E was 0.26%, and chiral HPLC analysis showed that the chiral purity was 99.60%.

[0099] Example 5

[0100] During the refining process, the effect of the added volume of mixed solvent 3 on the chiral purity of the refined intermediate B was studied. Mixed solvent 3 is composed of methanol and water in a volume ratio of 80:3.

[0101] Referring to the preparation method of Example 4, the volume of mixed solvent 3 was adjusted while other parameters remained unchanged. The chiral purity of the obtained product is shown in Table 1 below:

[0102] Table 1. Effect of the added volume of mixed solvent 3 on the chiral purity of intermediate B refined product.

[0103]

[0104] The data above shows that increasing the volume of mixed solvent 3 during the purification process is beneficial to the purification of ruxolitinib or its salts (such as phosphate) intermediate B. When the volume of mixed solvent 3 reaches more than 30 times the volume of intermediate B (e.g., 30V-40V), the chiral purity of the purified intermediate B is higher than 99.50%, and the ee value is >99.00%.

[0105] Example 6

[0106] Preparation of ruxolitinib phosphate

[0107]

[0108] In a reaction flask, intermediate B (4.00 g, 5.52 mmol, 1.00 eq) obtained in Example 4 and methyl tert-butyl ether (60 mL) were added and stirred. Sodium carbonate (1.23 g, 11.6 mmol, 2.10 eq) dissolved in water (40 mL) was added and stirred until dissolved. The mixture was separated, and the aqueous phase was extracted twice with methyl tert-butyl ether (13 mL). The combined organic phases were washed with water, and the product was concentrated and then added to isopropanol (34 mL). Dissolve the precipitate, heat to 70-75℃ and add dropwise isopropanol phosphate solution (0.70 g of phosphoric acid dissolved in 5 mL of isopropanol), the solid precipitates, keep warm and stir for 2 h, then cool to 20-30℃ and filter, dry under reduced pressure at 45℃ to obtain 2.05 g of white solid ruxolitinib phosphate (yield 91.75%), HPLC purity 99.97%, impurity compound E purity 0.03%, and isomer purity 99.74% as determined by chiral HPLC.

Claims

1. A method for preparing intermediate B of ruxolitinib or its salt, characterized in that, The preparation method includes the following steps: (a) Methyl 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-D]pyrimidin-7-yl)terpentanoate (compound X) and sodium hydroxide solution undergo a deprotection reaction in an organic solvent, optionally followed by alkali treatment and concentration to give intermediate A concentrate without separation; (b) The product obtained in step (a) is reacted with D-(+)-di-p-methoxybenzoyl tartaric acid in mixed solvent II to give intermediate B, optionally including a purification step.

2. The preparation method according to claim 1, characterized in that, In step (a), the amount of sodium hydroxide used is 0.05-0.15 eq of compound X, preferably 0.05-0.10 eq, and more preferably 0.10 eq; And / or, in step (a), the sodium hydroxide solution is a 0.5-2N sodium hydroxide solution, preferably a 1N sodium hydroxide solution; And / or, in step (a), the temperature of the deprotection reaction is 0-30°C, preferably 10-25°C; And / or, in step (a), the temperature control of the deprotection reaction can be controlled in one step or in a gradient. Gradient control is, for example, maintaining the temperature at 20-25°C while stirring, then cooling the temperature to 10-20°C and continuing to stir the reaction. And / or, in step (a), the deprotection reaction takes 4-8 hours; preferably 4-6 hours. ； And / or, in step (a), the organic solvent is selected from alcohol solvents, preferably C 1-6 Alcohols, such as methanol, ethanol, or isopropanol; And / or, in step (a), the alkali is ammonia; And / or, in step (b), the molar ratio of compound X to D-(+)-di-p-methoxybenzoyl tartaric acid is 1:0.4 to 1:1, preferably 1:0.5 to 1:0.7; And / or, in step (b), the temperature of the splitting reaction is 25-60°C, preferably 40-55°C; And / or, in step (b), the mixed solvent two is selected from alcohol-containing solvents (preferably C...). 1-6 Alcohols, such as methanol, ethanol, and isopropanol), wherein the mixed solvent is preferably methanol and acetone (preferably, the volume ratio of methanol to acetone is 9:2 to 9:8, more preferably 9:3.5); And / or, the refining step is as follows: adding intermediate B to a mixed solvent three (preferably methanol and water, more preferably methanol and water volume ratio of 80:1 to 80:5), heating (e.g., 50 to 80°C, preferably 60 to 70°C) to dissolve, cooling to crystallize, or adding seed crystals to cool to crystallize; preferably, the volume of the mixed solvent three is more than 30 times the volume of intermediate B, such as 30 to 60 times, preferably 30 to 40 times; and / or, preferably, the cooling rate is 13 ± 5°C / h.

3. A method for preparing ruxolitinib or a salt thereof, comprising the following steps: Intermediate B undergoes an alkalization reaction to yield ruxolitinib (preferably, the alkali used in the alkalization reaction is an alkali metal or alkaline earth metal alkane oxide, hydroxide, carbonate, or bicarbonate, preferably a carbonate or bicarbonate, more preferably sodium carbonate or sodium bicarbonate). Optionally, it undergoes a salt-forming reaction with an acid (preferably phosphoric acid or a phosphoric acid-alcohol solution) to generate ruxolitinib salt (preferably ruxolitinib phosphate).

4. The preparation method according to claim 3, wherein the intermediate B is prepared by any one of the methods of claims 1-2.

5. A method for preparing ruxolitinib or its salt, characterized in that... Includes the following steps: (a) Methyl 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-D]pyrimidin-7-yl)terpentanoate (compound X) and sodium hydroxide solution undergo a deprotection reaction in an organic solvent, optionally followed by alkali treatment and concentration to give intermediate A concentrate without separation; (b) The product obtained in step (a) is subjected to a resolution reaction with D-(+)-di-p-methoxybenzoyl tartaric acid in mixed solvent II to give intermediate B, optionally including a purification step; (c) Intermediate B undergoes an alkalization reaction to yield ruxolitinib. Optionally, it may undergo a salt formation reaction with an acid to generate ruxolitinib salt.

6. The preparation method according to claim 5, characterized in that, In step (a), the amount of sodium hydroxide used is 0.05-0.15 eq of compound X, preferably 0.05-0.10 eq, and more preferably 0.10 eq; And / or, in step (a), the sodium hydroxide solution is a 0.5-2N sodium hydroxide solution, preferably a 1N sodium hydroxide solution; And / or, in step (a), the temperature of the deprotection reaction is 0-30°C, preferably 10-25°C; And / or, in step (a), the temperature control of the deprotection reaction can be controlled in one step or in a gradient. Gradient control is, for example, maintaining the temperature at 20-25°C while stirring, then cooling the temperature to 10-20°C and continuing to stir the reaction. And / or, in step (a), the deprotection reaction takes 4-8 hours; preferably 4-6 hours. ； And / or, in step (a), the organic solvent is selected from alcohol solvents, preferably C 1-6 Alcohols, such as methanol, ethanol, or isopropanol; And / or, in step (a), the alkali is ammonia; And / or, in step (b), the molar ratio of compound X to D-(+)-di-p-methoxybenzoyl tartaric acid is 1:0.4 to 1:1, preferably 1:0.5 to 1:0.7; And / or, in step (b), the temperature of the splitting reaction is 25-60°C, preferably 40-55°C; And / or, in step (b), the mixed solvent two is selected from alcohol-containing solvents (preferably C...). 1-6 Alcohols, such as methanol, ethanol, and isopropanol), wherein the mixed solvent is preferably methanol and acetone (preferably, the volume ratio of methanol to acetone is 9:2 to 9:8, more preferably 9:3.5); And / or, the refining step is as follows: adding intermediate B to a mixed solvent three (preferably methanol and water, more preferably methanol and water volume ratio of 80:1 to 80:5), heating (e.g., 50 to 80°C, preferably 60 to 70°C), stirring to dissolve, cooling to crystallize, or adding seed crystals to cool to crystallize; preferably, the volume of the mixed solvent three is more than 30 times the volume of intermediate B, such as 30 to 60 times, preferably 30 to 40 times; and / or, preferably, the cooling rate is 13 ± 5°C / h; And / or, in step (c), the alkali used in the alkaliification and ionization reaction is an alkali metal or alkaline earth metal alkane oxide, hydroxide, carbonate or bicarbonate, preferably a carbonate or bicarbonate, more preferably sodium carbonate or sodium bicarbonate. And / or, in step (c), the amount of base used in the alkalization and release reaction is 1.0-3.0 eq of compound B, preferably 1.5-2.5 eq; And / or, in step (c), the salt-forming step uses an alcohol solvent for dissolution, preferably C. 1-6 Alcohols, such as methanol, ethanol, and isopropanol, with isopropanol being preferred; And / or, in the salt-forming step, phosphoric acid or a phosphoric acid-alcohol solution is added; preferably, the alcohol solvent is C. 1-6 Alcohols, such as methanol, ethanol, and isopropanol, with isopropanol being preferred; And / or, in the salt-forming step, a phosphoric acid or phosphoric acid-alcohol solution is added; And / or, the salt is a phosphate. And / or, step (a) is as follows: take methyl 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-D]pyrimidin-7-yl)terpentanoate (compound X), add an alcohol solvent, add 0.05-0.15 eq sodium hydroxide at 10-25°C, stir to react, optionally further treat with an alkali (such as ammonia) and concentrate to obtain a concentrate without separation; And / or, step (b) is: adding the product obtained in step (a) to a mixed solvent of methanol and acetone, stirring and heating, adding D-(+)-di-p-methoxybenzoyl tartaric acid, stirring the reaction, cooling and crystallizing to generate intermediate B; And / or, the refining step is as follows: add intermediate B to a mixed solvent of methanol and water in a volume of 30-60 times, heat to 50-80°C, dissolve, cool down to crystallize, or add seed crystals and cool down to crystallize; And / or, step (c) is: intermediate B undergoes an alkalization and release reaction with sodium carbonate or sodium bicarbonate to obtain ruxolitinib; optionally, isopropanol is added for dissolution, and phosphate-isopropanol solution is added to form a salt.

7. A method for preparing ruxolitinib phosphate, characterized in that... Includes the following steps: Step (a): Take methyl 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-D]pyrimidin-7-yl)terpentanoate (compound X), add an alcohol solvent, add 0.05-0.10 eq sodium hydroxide (preferably 0.5-2N sodium hydroxide solution) at 10-25°C, stir the reaction, further treat with ammonia water and concentrate to obtain a concentrate without separation; Step (b): Add the concentrate obtained in step (a) to a mixed solvent of methanol and acetone, stir and heat to 25-60°C, add D-(+)-di-p-methoxybenzoyl tartaric acid, stir to react, cool and crystallize to generate intermediate B; Refining of intermediate B: Add intermediate B to a mixed solvent of methanol and water in a volume of 30-40 times, heat to 50-80℃ to dissolve, cool down to crystallize, or add seed crystals and cool down to crystallize. Step (c): Intermediate B undergoes an alkalization and release reaction with 1.0-3.0 eq of sodium carbonate or sodium bicarbonate to obtain ruxolitinib; It also includes a salt-forming reaction: isopropanol is added to the ruxolitinib obtained in step (c) to dissolve it, and then a phosphate-isopropanol solution is added to form a salt.

8. An intermediate B of ruxolitinib or a salt thereof, 9. A composition comprising an intermediate B of ruxolitinib or a salt thereof and compound E (preferably, compound E having a purity not exceeding 0.5%).

10. Use of intermediate B of claim 8, or intermediate B obtained by the preparation method of any one of claims 1-2, or the composition of claim 9, in the preparation of ruxolitinib or its salts.

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