Preparation process of rucotinib phosphate

Abstract

The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation process of rucotinib phosphate. The preparation process comprises the following steps: carrying out Suzuki coupling reaction on 1-(1-ethoxyethyl)-4-pyrazol boronic acid pinacol ester and (4-chloro-7H-pyrrolo [2, 3-D] pyrimidine-7-yl) methyl pivalate, carrying out acidification treatment, carrying out addition reaction, carrying out chiral resolution treatment, carrying out deprotection treatment, carrying out salt forming reaction and carrying out corresponding post-treatment. According to the preparation process disclosed by the invention, the rucotinib phosphate with high yield and high purity can be prepared.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry technology, and specifically relates to a preparation process of ruxolitinib phosphate. Background Technology

[0002] Ruxolitinib phosphate refers to the compound ruxolitinib in phosphate form. Its excellent water solubility and bioavailability have made it a major dosage form for clinical administration. With the continued growth in market demand for ruxolitinib phosphate, developing efficient, environmentally friendly, and industrially suitable synthetic processes for ruxolitinib phosphate has become a research hotspot.

[0003] Traditional synthetic routes typically employ linear strategies, involving multiple functional group transformations and protection / deprotection operations, resulting in low overall yields, difficulty in chiral control, and high risks of heavy metal residues. Crucially, ruxolitinib contains a chiral center, and its pharmacological activity is highly dependent on the (R)-configuration; achieving efficient chiral purification is one of the core challenges in process development. CN114044777A provides a method for preparing ruxolitinib phosphate, using 4-chloro-7H-pyrrolo[2,3-d]pyrimidine as a starting material. Through a series of reactions including SEM protection, Grignard reagent reaction, Suzuki coupling, Michael addition, and chiral acid resolution, ruxolitinib phosphate is finally obtained. However, SEM protection requires expensive sodium hydride as a base and must be performed under strictly low-temperature and anhydrous conditions. Furthermore, the quenching reaction generates a large amount of flammable hydrogen gas, posing a safety hazard. Moreover, the final purity cannot reach above 99.9%.

[0004] Therefore, there is an urgent need to develop an economical, efficient, and large-scale production process for synthesizing high-purity ruxolitinib phosphate. Summary of the Invention

[0005] The purpose of this invention is to provide a preparation process for ruxolitinib phosphate. This preparation process can produce ruxolitinib phosphate with high purity and high yield. To achieve the above objectives, the present invention provides the following technical solution: This invention provides a process for preparing ruxolitinib phosphate, comprising the following steps: S1. In the presence of a first catalyst, a first alkaline reagent aqueous solution, and a first solvent, 1-(1-ethoxyethyl)-4-pyrazoloborate pinacol ester is subjected to a Suzuki coupling reaction with (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentanoate to obtain a first material containing a first intermediate, followed by a first post-treatment including acidification to obtain a second intermediate; S2. In the presence of the second catalyst and the second solvent, the second intermediate undergoes an addition reaction with 3-cyclopentylacrylonitrile, followed by a second post-treatment to obtain the third intermediate. S3. In the presence of a third solvent and a resolving agent, the third intermediate is subjected to chiral resection, followed by a third post-processing to obtain the fourth intermediate. S4. In the presence of the fourth solvent, the fourth intermediate is deprotected under alkaline conditions, followed by a fourth post-treatment to obtain the fifth intermediate. S5. In the presence of the fifth solvent, the fifth intermediate undergoes a salt-forming reaction with phosphoric acid, followed by the fifth post-treatment to obtain ruxolitinib phosphate.

[0006] Step S1 In step S1, the Suzuki coupling reaction mainly occurs as follows, generating a first material containing the first intermediate.

[0007] Preferably, the first catalyst is selected from trifluoromethanesulfonic acid or tetra(triphenylphosphine)palladium (Pd(PPh3)4), and more preferably tetra(triphenylphosphine)palladium.

[0008] The first alkaline reagent aqueous solution refers to the solution obtained by mixing the first alkaline reagent with water. Preferably, the first alkaline reagent in the first alkaline reagent aqueous solution is selected from at least one of lithium carbonate, potassium carbonate, sodium carbonate and potassium phosphate, preferably potassium carbonate.

[0009] Preferably, the first solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether, and more preferably 1,4-dioxane.

[0010] The amount of 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester has a significant impact on the Suzuki reaction. Preferably, based on the molar amount of (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentanoate, the amount of 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester is 0.9-1.3 equivalents, preferably 1 equivalent.

[0011] Preferably, based on the molar amount of (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentanoate, the amount of the first alkaline reagent in the first alkaline reagent aqueous solution is 2-5 equivalents, preferably 2 equivalents.

[0012] Preferably, the volume of water in the first alkaline reagent aqueous solution is the same as the volume of the first solvent.

[0013] The amount of the first catalyst has a significant impact on the reaction rate and impurity profile. Preferably, the mass of the first catalyst is 1% to 7% based on the mass of (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentanoate, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, preferably 5%.

[0014] Preferably, the volume of the first solvent used for 1 g of (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentanoate is 3.5 to 5.5 mL, more preferably 4.5 mL.

[0015] Preferably, in step S1, the conditions for the Suzuki coupling reaction include: being carried out in an atmosphere at a temperature of 80-90°C for 2-3 hours.

[0016] In this invention, it was found that the conversion rate of (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentanoate was higher with the extension of reaction time, but the purity of the first intermediate product decreased slightly, while the overall product remained stable. Therefore, the preferred reaction time is 2 to 3 hours.

[0017] As an example, 1,4-dioxane, (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentovale ester, 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester and potassium carbonate aqueous solution were added sequentially to the reaction flask. The mixture was stirred until dissolved, and the reaction was purged with nitrogen 5 times. Then Pd(PPh3)4 was added, and the reaction was purged with nitrogen 5 times. The temperature was raised to 80-90℃, and the reaction was carried out for 2 hours. The sample was then taken and controlled by HPLC to the reaction endpoint ((4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentovale ester ≤0.5wt%).

[0018] Preferably, the first post-processing steps include: first extraction and separation, acidification treatment, neutralization treatment, first pulping A, first drying A, first pulping B, first washing, and first drying B.

[0019] Preferably, the first extraction and separation method includes: cooling the first material to about 40±5℃, separating the liquid, taking the upper organic phase, adding 5wt% sodium chloride aqueous solution to the organic phase, stirring for 5-10 min, separating the liquid, and taking the upper organic phase; adding activated carbon and silica gel (preferably the mass of activated carbon is 3%-6% of the mass of (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentovalerate, preferably the mass of silica gel is 8%-12% of the mass of (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentovalerate), controlling the temperature at 40±5℃ and stirring for 20-40 min (preferably 30 min), filtering out the activated carbon and silica gel to obtain the filtrate.

[0020] Preferably, the first acidification treatment method includes: adding a first solvent (preferably 1,4-dioxane, preferably 10% to 15% of the volume of the first solvent in step S1) to the filtrate obtained from the first extraction and separation, cooling to 25±5℃, and acidifying with an aqueous hydrochloric acid solution. Preferably, the concentration of the aqueous hydrochloric acid solution is 1M-3M, more preferably 2M, and preferably 1g of (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentanoate is treated with 3-mL of aqueous hydrochloric acid solution. Specifically, a portion of the aqueous hydrochloric acid solution can be added first to adjust the pH to 4-5, and the HPLC control should ensure that the mass content of the first intermediate is not higher than 2.0% (if not, samples should be taken every 1 hour thereafter) to obtain the acidified solution.

[0021] Preferably, the neutralization treatment method includes: adjusting the pH value to 7-8 with a saturated sodium bicarbonate aqueous solution, stirring for 0.5-2 hours (preferably 1 hour), filtering, and obtaining a filter cake.

[0022] Preferably, the first pulping method A includes: adding water (preferably purified water, preferably the volume of water here is 1-1.5 times the volume of water in the first alkaline reagent aqueous solution) to the filter cake obtained by neutralization treatment, controlling the temperature at 25±5℃, pulping for 0.5-2h (preferably 1h), and filtering.

[0023] Preferably, the method for the first drying A includes: vacuum drying the filter cake obtained from the first pulping at 45±5℃ to constant weight, and collecting the material.

[0024] Preferably, the first pulping method B includes: adding anhydrous ethanol to the solid material obtained from the first drying A (preferably using 5-10 mL of anhydrous ethanol per 1 g of dried filter cake), controlling the temperature at 65±5℃, pulping for 15 min, cooling to 15±5℃, stirring for 1-3 h (preferably 2 h), and then filtering.

[0025] In this invention, it was found that using ethanol for pulping can better reduce the impurity content.

[0026] Preferably, the first washing method includes rinsing the filter cake obtained from the first pulping B with anhydrous ethanol (preferably 0.5 to 5 mL of ethanol per 1 g of filter cake).

[0027] Preferably, the method for drying the first filter cake includes vacuum drying the first washed filter cake at 45±5℃ until the moisture content is ≤0.5wt%, collecting the material, and obtaining the second intermediate.

[0028] As an example, the acidification treatment described above in this invention mainly involves the following reactions:

[0029] The filtration method mentioned above in this invention can be achieved by first filtering with filter paper, and then filtering the filtrate through a 0.45μm organic membrane.

[0030] Step S2 The second intermediate reacts with 3-cyclopentylacrylonitrile primarily as follows:

[0031] Preferably, the second catalyst is selected from 1,8-diazabicycloundec-7-ene and / or potassium carbonate, preferably potassium carbonate.

[0032] In this invention, it was found that using potassium carbonate as a second catalyst resulted in fewer impurities in the reaction. To ensure a more complete reaction, the potassium carbonate can be ground before use.

[0033] Preferably, the second solvent comprises dimethyl sulfoxide (DMSO).

[0034] In addition reactions, the amount of reactants has a significant impact on the reaction. Preferably, in step S2, based on the molar amount of the second intermediate, the amount of 3-cyclopentylacrylonitrile is 1.8-3 equivalents, for example, 1.8 equivalents, 2 equivalents, 2.5 equivalents, or 3 equivalents, preferably 2 equivalents.

[0035] Preferably, in step S2, based on the molar amount of the second intermediate, the amount of the second catalyst is 0.05-1 equivalent, for example, 0.05 equivalent, 0.2 equivalent, 0.5 equivalent, or 1 equivalent, preferably 0.2 equivalent.

[0036] In this invention, when the amount of the second catalyst is too low, the reaction cannot be complete; when the amount of the second catalyst is too high, the impurities in the final product will increase. In this invention, controlling the amount of the second catalyst to 0.2 equivalents is more effective.

[0037] The amount of the second solvent used will affect the concentration of the reactants, and thus affect the reaction rate and the amount of impurities. Preferably, in step S2, the amount of the second solvent used for 1g of the second intermediate is 3.5 to 10 mL, for example, 3.5 mL, 6.3 mL, or 10 mL, preferably 6.3 mL.

[0038] Preferably, in step S2, the conditions for the addition reaction include: a temperature of 10-40℃, preferably 20-30℃, and a reaction time of 3-14h, for example 3h, 5h, 7h, 9h, 11h, 13h, or 14h, preferably 11-14h.

[0039] Reaction temperature has a significant impact on reaction rate and product quality. DMSO has a freezing point of 19℃. At 15±5℃, the reaction remains in a semi-solid, turbid state, with some solids being insoluble and others adhering to the reaction walls, making stirring difficult and resulting in a higher residue of the second intermediate. At 25±5℃ and 35±5℃, the residue of the second intermediate is lower, while the product content is comparable. Considering all factors, the optimal reaction temperature is 25±5℃.

[0040] The method of adding the second catalyst in this invention is not particularly limited. It can be added directly to the addition reaction system or added stepwise to the addition reaction system. This invention does not have any special restrictions on this.

[0041] As an example, in step S2, dimethyl sulfoxide, the second intermediate, and 3-cyclopentylacrylonitrile were added to the reaction flask in sequence. After stirring evenly, potassium carbonate (powder, pre-ground) was added. The temperature was controlled at 25±5℃, and the reaction was carried out for 12 hours before sampling. The reaction was controlled to the endpoint (second intermediate ≤2.0wt%) using HPLC. Preferably, the second post-processing method includes: second extraction and separation, second concentration, second crystallization, second washing A, second drying A, second pulping, second washing B, and second drying C.

[0042] Preferably, the second extraction and separation method includes: adding ethyl acetate and 5wt% sodium chloride aqueous solution sequentially to the reaction solution obtained from the addition reaction, stirring for 10-15 min, allowing to stand and separate the liquids, extracting the aqueous phase twice with ethyl acetate, and combining the organic phases; there is no special limitation on the amount of ethyl acetate and 5wt% sodium chloride aqueous solution used each time, generally 8-30 mL of ethyl acetate and 8-30 mL of 5wt% sodium chloride aqueous solution can be used for 1 g of the second intermediate.

[0043] Preferably, the concentration method includes: washing the organic phase obtained from the second extraction and separation three times with a 20wt% sodium chloride aqueous solution, separating the liquid, taking the organic phase (stirring for 10-15 min each time during washing), adding anhydrous sodium sulfate and silica gel to the organic phase, stirring and drying for 30 min, filtering, and concentrating the filtrate under reduced pressure at a controlled temperature of 40±5℃ until no liquid droplets flow out, to obtain a yellow oily substance; there are no special restrictions on the mass of anhydrous sodium sulfate and silica gel, for example, the mass of anhydrous sodium sulfate is 20%-30% of the mass of the second intermediate, and the mass of silica gel is 8%-15% of the mass of the second intermediate.

[0044] Preferably, the second crystallization method includes: adding ethyl acetate to the yellow oily substance obtained from the second concentration, controlling the temperature at 65±5℃, stirring to dissolve, adding n-heptane at 65±5℃, then cooling to 20~25℃, stirring at 20~25℃ for 5 hours, then further cooling to 10±5℃ and maintaining the temperature for crystallization for 3 hours; preferably, 1~5 mL of ethyl acetate is used for 1 g of the second intermediate, preferably the volume ratio of n-heptane to ethyl acetate is 1:(1.8~2.5), more preferably 1:(2.1-2.3).

[0045] In this invention, it was discovered that during the crystallization process, when the content of n-heptane is too low, the yield of the third intermediate will be low, and when the content of n-heptane is too high, the purity of the third intermediate will be low.

[0046] Furthermore, this invention has found that when the crystallization temperature is high, the yield of the third intermediate is low, but the purity is not significantly affected; when the crystallization time is long, the yield is high, but the purity is low.

[0047] Furthermore, the second washing method A includes rinsing the filter cake obtained from crystallization with n-heptane.

[0048] Further, the second drying method A includes: drying the solid material obtained by washing A under vacuum at 50±5°C to constant weight.

[0049] Further, the second pulping method includes: adding anhydrous ethanol to the material obtained from drying A (i.e., the crude third intermediate), controlling the temperature at 60~65℃, stirring for 10~15min, slowly reducing the temperature to 20±5℃, and stirring for 2h; preferably, 2~4mL, more preferably 3mL, of anhydrous ethanol is used for 1g of crude third intermediate.

[0050] Preferably, the washing method B includes: rinsing the solid material obtained by pulping with an ethanol-water mixed solvent, wherein the volume ratio of ethanol to water in the ethanol-water mixed solvent is preferably 1:4.

[0051] Preferably, the method for drying C includes: vacuum drying the solid material obtained by washing B at 50±5℃ to constant weight.

[0052] Step S3 In step S3, the chiral separation process mainly involves the following reaction to generate a material containing a fourth intermediate.

[0053]

[0054] Preferably, in step S3, the resolving reagent is selected from D-(+)-DBTA and / or D-(+)-DBTA·H2O.

[0055] Preferably, the third solvent is selected from alkyl alcohol solvents, including but not limited to ethanol, which is generally present in the form of anhydrous ethanol.

[0056] Preferably, the amount of the resolving reagent is 0.9-1.2 equivalents, more preferably 1.1-1.2 equivalents, based on the molar amount of the third intermediate.

[0057] Preferably, the amount of the third solvent is: 6 to 12 mL of the third solvent is used for 1 g of the third intermediate, preferably 10 mL of the third solvent.

[0058] Preferably, in step S3, the conditions for the chiral resolution treatment include: dissolving by stirring at a controlled temperature of 75±5℃, cooling to 40-45℃, maintaining the temperature and stirring for 1-3 hours, then cooling to 15±5℃ and stirring for at least 8 hours, preferably 10-15 hours. In this invention, research has found that stirring for more than 8 hours results in a lower content of isomers of the target product in the final fourth intermediate.

[0059] The aforementioned cooling can be rapid cooling, natural cooling, or gradient cooling, with natural cooling being preferred. That is, in step S3, the conditions for the chiral separation treatment include: dissolving by stirring at a controlled temperature of 75±5℃, slowly and naturally cooling to 40-45℃ at room temperature, stirring while maintaining the temperature for 1-3 hours, and then naturally cooling to 15±5℃ at room temperature and stirring for 10-15 hours.

[0060] Natural cooling refers to naturally cooling to 15±5℃ from room temperature.

[0061] The rapid cooling method can be any method in the field. For example, after setting the external temperature below the target temperature using a low-temperature cooling reactor, the reaction flask is transferred to the low-temperature cooling reactor, and the internal temperature drops rapidly. When the internal temperature approaches the target temperature, the external temperature is raised to the target temperature range. The cooling process is controlled to take about 0.5 hours.

[0062] The gradient cooling method can be any method in the field. For example, a low-temperature cooling reactor can be used. The external temperature is set about 10°C lower than the current internal temperature. The reaction flask is transferred to the low-temperature cooling reactor. After the internal temperature drops to the set temperature, it is kept at that temperature for a period of time before being set to cool down again, thus entering the next cooling gradient. By controlling the holding and cooling times, the total cooling time can be controlled to about 2 hours.

[0063] As an example, in step S3, the chiral separation process includes: adding anhydrous ethanol, the third intermediate and D-(+)-DBTA sequentially to the reaction flask, stirring to dissolve at 75±5℃, slowly cooling to precipitate a white solid (about 40~45℃), keeping warm and stirring for 2 hours, cooling to 15±5℃, and stirring for 12 hours.

[0064] Preferably, in step S3, the third post-processing step includes third filtration, third washing, third drying, and third crystallization.

[0065] The third filtering method is not specifically limited and is a conventional method in this field.

[0066] Preferably, the third washing method includes washing the filter cake obtained from the third filtration with anhydrous ethanol at 15±5°C.

[0067] Preferably, the conditions for the third drying process include: vacuum drying at 40-50°C to constant weight.

[0068] Preferably, the method for the third crystallization treatment includes: First crystallization: Add the solid obtained from the third drying to ethanol (preferably use 5-6 mL of anhydrous ethanol for 1 g of dried solid), stir and dissolve at 75±5℃, then slowly cool until a white solid precipitates (about 40-45℃), keep warm and stir for 1.5-2.5 h (preferably 2 h), cool to 15±5℃, stir for 8-20 h (preferably 12 h), filter, wash the filter cake with anhydrous ethanol at 15±5℃ (preferably use 1-2 mL of anhydrous ethanol for 1 g of filter cake), and vacuum dry at 40-50℃ to constant weight to obtain a white solid; Second recrystallization: The white solid obtained from the first crystallization is added to ethanol (preferably 5-6 mL of anhydrous ethanol for 1 g of dried solid), heated to 75±5℃ and refluxed to dissolve, then slowly cooled until the white solid precipitates (about 50-55℃), kept warm and stirred for 1.5-2.5 h (preferably 2 h), cooled to 15±5℃ and stirred for 8-20 h (preferably 12 h), filtered, the filter cake is washed with anhydrous ethanol at 15±5℃ (preferably 1-2 mL of anhydrous ethanol for 1 g of filter cake), and dried under vacuum at 40-50℃ to constant weight to obtain a white solid, which is the fourth intermediate.

[0069] Step S4 Preferably, the fourth solvent includes at least one of ethyl acetate, water, methanol, and tetrahydrofuran.

[0070] Preferably, the method for deprotection treatment includes: (1) Add ethyl acetate, water and the fourth intermediate to the reaction flask in sequence, then add alkaline solution to adjust the pH to 8-9, extract, separate, wash and separate, concentrate to obtain solid; (2) The solid was dissolved in a mixture of methanol and tetrahydrofuran, and then an alkaline solution was added for deprotection treatment.

[0071] Preferably, in step (1), the volume ratio of ethyl acetate to water is (1-3):1, more preferably 2:1.

[0072] Preferably, in step (1), the amount of ethyl acetate used is: 10-20 mL of ethyl acetate for 1 g of the fourth intermediate.

[0073] Preferably, the alkaline solution is selected from at least one of sodium hydroxide aqueous solution, potassium carbonate aqueous solution, and potassium hydroxide aqueous solution, and is preferably potassium carbonate aqueous solution.

[0074] Preferably, the concentration of the alkaline solution is 1M-3M.

[0075] Preferably, in step (1), the extraction and separation method includes: allowing the liquid to stand and separating the liquid, extracting the aqueous phase twice with ethyl acetate, and combining the organic phases.

[0076] Preferably, in step (1), the washing and separation method includes: washing and separating the organic phase twice with a 20% sodium chloride aqueous solution. Preferably, in step (1), the concentration method includes: concentrating the organic phase under reduced pressure at a controlled temperature of 35~45°C until no droplets flow out.

[0077] Preferably, in step (2), the volume ratio of methanol to tetrahydrofuran is 1:(0.5-1.5), and more preferably 1:1.

[0078] Preferably, the amount of methanol used is 4-6 mL of methanol for every 1 g of the fourth intermediate.

[0079] Preferably, the molar amount of alkali in the alkaline solution is 1.2-1.55 of the molar amount of the fourth intermediate.

[0080] Preferably, in step (2), an alkaline solution is added at 25±5℃.

[0081] In step (2) of this invention, the deprotection process can be monitored by TLC until the reaction endpoint (petroleum ether: ethyl acetate = 1:1, 254nm color development, showing no residue of the fourth intermediate free product).

[0082] Preferably, the fourth post-treatment step includes: adding a 20% sodium chloride aqueous solution to the deprotected reaction solution, adjusting the pH to 7-8 with a 1M hydrochloric acid aqueous solution, extracting twice with ethyl acetate, combining the organic layers, washing the organic phase twice with a 20% sodium chloride solution, concentrating the obtained organic phase under reduced pressure at 35-50℃ until no obvious droplets flow out; then adding methanol to the concentrate, stirring to dissolve, adding ammonia dropwise to adjust the pH to 9-10, stirring at 25±5℃ for 10-20 hours, and monitoring the reaction to the endpoint by HPLC (RRT 0.96 ≤ 1.5%); then adding a 20% sodium chloride solution to the reaction solution, extracting three times with ethyl acetate, and combining the organic phases. The organic phase is washed once with a 5% sodium chloride solution and then once with purified water. Separating the liquid, adding anhydrous sodium sulfate to the obtained organic phase, stirring for 20 minutes, filtering, and concentrating the filtrate under reduced pressure at 45±5℃ to obtain a white, foamy solid, which is the fifth intermediate.

[0083] Step S5 In step S5, the salt formation reaction mainly occurs as follows to obtain the final ruxolitinib phosphate.

[0084]

[0085] Preferably, the fifth solvent is selected from alcohol solvents, including but not limited to isopropanol.

[0086] Preferably, in step S5, the amount of the fifth solvent used is: 10-20 mL of the fifth solvent is used for 1 g of the fifth intermediate.

[0087] Preferably, in step S5, the conditions for the salt formation reaction include: reacting at 70±5℃ for 0.5 to 1.5 h, then cooling to 25±5℃ and stirring for 1.5 to 2.5 h.

[0088] Preferably, in step S5, the fifth post-processing steps include: fifth filtration, fifth washing A, fifth drying A, fifth pulping, fifth washing B, fifth drying B, fifth decolorization, fifth membrane filtration, fifth crystallization, fifth washing C, and fifth drying C.

[0089] Preferably, the fifth washing A can be performed using a fifth solvent. There is no special limitation on the amount of the fifth solvent used during washing, as long as the purpose of washing can be achieved.

[0090] Preferably, the fifth drying step A can be performed by vacuum drying at 55~65°C to constant weight.

[0091] Preferably, the fifth pulping method includes: adding methanol to the solid obtained from the fifth drying A, pulping at a controlled temperature of 50~55℃ for 0.5~1.5h, cooling to 5±5℃, and stirring for 1.5~2.5h.

[0092] Preferably, the fifth washing method B includes: rinsing the solid obtained from the fifth pulping with methanol; wherein, there is no special limitation on the amount of methanol used, as long as the washing purpose can be achieved.

[0093] Preferably, the fifth drying step B can be performed under vacuum at 50-60°C to constant weight. That is, the fifth drying step yields crude ruxolitinib phosphate, which can be further processed through a fifth decolorization step, a fifth membrane filtration step, a fifth crystallization step, and a fifth washing step C to obtain ruxolitinib phosphate.

[0094] Preferably, the fifth decolorization method includes: adding crude ruxolitinib phosphate and methanol to a reaction flask, controlling the temperature at 55±5℃, stirring for 10-30 min, and then adding activated carbon and stirring for 10-15 min; preferably, the amount of methanol used is 10-15 mL of methanol for 1 g of crude ruxolitinib phosphate; preferably, the mass of the activated carbon is 3-6 wt% of the mass of the crude ruxolitinib phosphate.

[0095] Preferably, the fifth membrane filtration method includes: filtering with filter paper and a 0.45 μm organic membrane.

[0096] Preferably, the fifth crystallization method includes: adding isopropanol and n-heptane dropwise to the filtrate obtained by fifth membrane filtration at 55±5℃, then cooling to 25±5℃ and stirring for 4-6 hours. Preferably, the amount of isopropanol used is 15-20 mL of isopropanol for 1 g of crude ruxolitinib phosphate, and the mass ratio of isopropanol to n-heptane is (1.5-1.7):1. Preferably, the dropwise addition time of isopropanol and n-heptane is 15-25 min. Preferably, the cooling from 55±5℃ to 25±5℃ takes about 2-3 hours.

[0097] Preferably, the fifth washing method C includes: rinsing the solid obtained from the fifth crystallization with isopropanol; wherein, there is no special limitation on the amount of isopropanol used, as long as the washing purpose can be achieved.

[0098] Preferably, the fifth drying method C includes: vacuum drying the solid obtained from the fifth washing C at 50-60°C until the moisture content is ≤1.0%. The moisture content can be tested using a Karl Fischer thermometer.

[0099] Compared with the prior art, the present invention has at least the following beneficial effects: 1. High yield and high purity: This invention achieves a balance between high conversion rate and low impurity content in the Suzuki coupling reaction stage, providing a favorable intermediate for the subsequent preparation of high-purity and high-yield ruxolitinib phosphate. Furthermore, studies in the addition reaction have shown that using potassium carbonate instead of traditional organic bases effectively inhibits racemization, thereby improving the yield of the third intermediate. The post-processing of chiral resolution using a double recrystallization process significantly improves chiral control efficiency. Therefore, the preparation process of this invention can guarantee the yield and purity of each intermediate, ultimately obtaining high-purity and high-yield ruxolitinib phosphate.

[0100] 2. Economic and environmentally friendly overall preparation: Most of the solvents used in this invention are low-toxicity solvents such as alcohols and esters, replacing high-risk solvents such as DMF and dichloromethane. This reduces the need for solvent post-processing. All post-processing steps in this invention are based on conventional chemical unit operations, making the preparation method of this invention suitable for industrial production. Detailed Implementation

[0101] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0102] In the following examples, the preparation route of ruxolitinib phosphate is as follows:

[0103] Example 1A Preparation of the second intermediate: Suzuki coupling reaction: 2250 mL of 1,4-dioxane, 500 g of SM2, 546.77 g of SM1 (1.1 equivalents), and potassium carbonate solution (prepared by mixing 516.27 g of potassium carbonate (2 equivalents) with 2250 mL of purified water) were added sequentially to the reaction flask. The mixture was stirred until dissolved, and the mixture was purged with nitrogen 5 times. Then, 25.88 g of Pd(PPh3)4 (approximately 5% of the mass of SM2) was added, and the mixture was purged with nitrogen 5 times. The temperature was raised to 85 °C, and the reaction was controlled by HPLC until the reaction endpoint (SM2 ≤ 0.5%) was reached, yielding the first material containing the first intermediate (Int1).

[0104] First post-treatment: After cooling the first material to 40℃, separate the liquids and take the upper organic phase. Add 2000mL of 5wt% sodium chloride aqueous solution to the organic phase, stir for 10min, separate the liquids again, take the upper organic phase, add 25g of activated carbon and 50g of silica gel, maintain the temperature at 40℃ and stir for 30min, filter out the activated carbon and silica gel, transfer the filtrate to a reaction flask, add 250mL of 1,4-dioxane, cool to 25℃, and acidify with 2500mL of 2M hydrochloric acid aqueous solution. Specifically, adjust the pH to 4.5 with 2M hydrochloric acid aqueous solution, and add the remaining 2M hydrochloric acid aqueous solution dropwise (there is an exothermic phenomenon, maintain the temperature below 30℃, specific...). The temperature was controlled at 25℃, and the mixture was stirred for 3 hours before sampling. The HPLC control was performed (Int1 ≤ 2.0%). After the acidification reaction was completed, the pH value was adjusted to 7.5 with saturated sodium bicarbonate aqueous solution. The mixture was stirred for another 1 hour and then filtered. 2500 mL of purified water was added to the filter cake, and the temperature was controlled at 25℃. The mixture was then stirred for 1 hour and filtered again. The filter cake was vacuum dried at 45℃ to constant weight. The dried filter cake was then collected. 3900 mL of anhydrous ethanol was added to the dried filter cake, and the temperature was controlled at 65℃. The mixture was stirred for 15 minutes and then cooled to 15℃. After stirring for 2 hours, the mixture was filtered again. The filter cake was washed with 500 mL of anhydrous ethanol and vacuum dried at 45℃ until the moisture content was ≤ 0.5%. The second intermediate (Int2) was then collected.

[0105] Example 2A The method is the same as in Example 1, except that in the Suzuki coupling reaction, the mass of Pd(PPh3)4 is 7% of the mass of SM2, that is, 35g.

[0106] Example 3A The method is the same as in Example 1, except that in the Suzuki coupling reaction: The amount of 1,4-dioxane used was 1750 mL.

[0107] Example 4A The method is the same as in Example 1, except that in the Suzuki coupling reaction: The dosage of 1,4-dioxane is 2750 mL.

[0108] Example 5A The method of Example 1 differs in that, in the first post-processing, the first material is cooled to 30°C before subsequent processing.

[0109] Example 6A The method of Example 1 differs in that the first material is cooled to 50°C before subsequent processing in the first post-processing.

[0110] Example 7A The method of Example 1 differs in that, in the first post-treatment, 5000 mL of 1M hydrochloric acid aqueous solution is used for acidification.

[0111] Example 8A The method of Example 1 differs in that, in the first post-treatment, acidification is performed using 3000 mL of 2M hydrochloric acid aqueous solution.

[0112] Example 9A The method is the same as in Example 1, except that in the first post-treatment, 400 mL of 1,4-dioxane is added.

[0113] Example 10A The method of Example 1 differs in that, in the first post-treatment, the acidification temperature is 15°C.

[0114] Example 11A The method of Example 1 differs in that the acidification temperature in the first post-treatment is 35°C.

[0115] Example 12A The method of Example 1 is different in that, in the first post-treatment: anhydrous ethanol is added, the temperature is controlled at 75°C, and the mixture is stirred for 15 minutes.

[0116] Example 13A The method is the same as in Example 1, except that in the first post-treatment: anhydrous ethanol is added, the temperature is controlled at 55°C, and the mixture is stirred for 15 minutes.

[0117] Example 14A The method of Example 1 differs in that, in the first post-treatment: after adding anhydrous ethanol and slurrying, the temperature is lowered to 5°C.

[0118] Comparative Example 1A The method is the same as in Example 1A, except that in the Suzuki coupling reaction, the amount of SM1 added is 0.9 equivalents, which is 447.43 g.

[0119] Comparative Example 2A The method is the same as in Example 1A, except that in the Suzuki coupling reaction, the amount of SM1 added is 1 equivalent, which is 497.15 g.

[0120] Comparative Example 3A The method is the same as in Example 1A, except that in the Suzuki coupling reaction, the amount of 5SM1 added is 1.2 equivalents, which is 596.58g.

[0121] Comparative Example 4A The method is the same as in Example 1A, except that in the Suzuki coupling reaction, the amount of SM1 added is 1.3 equivalents, which is 646.29 g.

[0122] Comparative Example 5A The method is the same as in Example 1, except that in the Suzuki coupling reaction, the potassium carbonate solution is prepared by mixing 774.53 g of potassium carbonate (3 equivalents) with 2250 mL of purified water.

[0123] Comparative Example 6A The method is the same as in Example 1, except that in the Suzuki coupling reaction, the potassium carbonate solution is prepared by mixing 1032.71 g of potassium carbonate (4 equivalents) with 2250 mL of purified water.

[0124] Comparative Example 7A The method is the same as in Example 1, except that in the Suzuki coupling reaction, the potassium carbonate solution is prepared by mixing 1290.88 g of potassium carbonate (5 equivalents) with 2250 mL of purified water.

[0125] Comparative Example 8A The method is the same as in Example 1, except that in the Suzuki coupling reaction, the mass of Pd(PPh3)4 is 1% of the mass of SM2, that is, 5g.

[0126] Comparative Example 9A The method is the same as in Example 1, except that in the Suzuki coupling reaction, the mass of Pd(PPh3)4 is 3% of the mass of SM2, that is, 15g.

[0127] Comparative Example 10A The method is the same as in Example 1, except that in the Suzuki coupling reaction, the temperature is raised to 70°C and the reaction is carried out.

[0128] Comparative Example 11A The method is the same as in Example 1, except that in the Suzuki coupling reaction, the temperature is raised to 95°C to carry out the reaction.

[0129] Comparative Example 12A The method is the same as in Example 1, except that in the first post-treatment, 250 mL of 1,4-dioxane is replaced with 250 mL of tetrahydrofuran (THF).

[0130] Comparative Example 13A The method is the same as in Example 1, except that in the first post-treatment, acidification is performed using 1700 mL of 3M hydrochloric acid aqueous solution.

[0131] Comparative Example 14A The method is the same as in Example 1, except that in the first post-treatment, acidification is performed using 1500 mL of 2M hydrochloric acid aqueous solution.

[0132] Comparative Example 15A The method is the same as in Example 1, except that in the first post-treatment, acidification is performed using 2000 mL of 2M hydrochloric acid aqueous solution.

[0133] Comparative Example 16A The method is the same as in Example 1, except that in the first post-treatment, 150 mL of 1,4-dioxane is added.

[0134] Comparative Example 17A The method of Example 1 differs in that, in the first post-treatment, the pH value is adjusted to 6.5 using a saturated sodium bicarbonate aqueous solution.

[0135] Comparative Example 18A The method of Example 1 differs in that, in the first post-treatment, the pH value is adjusted to 8.5 using a saturated sodium bicarbonate aqueous solution.

[0136] Comparative Example 19A The method of Example 1 differs in that, in the first post-treatment, the pH value is adjusted to 9.5 using a saturated sodium bicarbonate aqueous solution.

[0137] Comparative Example 20A The method of Example 1 differs in that, in the first post-treatment: 2790 mL of anhydrous ethanol is added to the dried filter cake, the temperature is controlled at 65°C, and the mixture is stirred for 15 min.

[0138] Comparative Example 21A The method of Example 1 differs in that, in the first post-treatment: 5570 mL of anhydrous ethanol is added to the dried filter cake, the temperature is controlled at 65°C, and the mixture is stirred for 15 min.

[0139] Comparative Example 22A The method of Example 1 differs in that, in the first post-treatment: after adding anhydrous ethanol and slurrying, the temperature is lowered to 25°C.

[0140] Comparative Example 23A The method of Example 1 differs in that, in the first post-treatment: after adding anhydrous ethanol and slurrying, the temperature is lowered to 35°C.

[0141] Table 1 shows the relevant substances and their contents of the first material containing the first intermediate (Int1) in Examples 1A and Comparative Examples 1A-4A. Table 2 shows the reaction control data of the Suzuki coupling reaction in Examples 1A and Comparative Examples 5A-7A. Table 3 shows the reaction control data of the Suzuki coupling reaction in Examples 1A-2A and Comparative Examples 8A-9A. Table 4 shows the reaction control data of the Suzuki coupling reaction in Examples 1A and Examples 3A-4A. Table 5 shows the reaction control data of the Suzuki coupling reaction in Examples 1A and Comparative Examples 10A-11A.

[0142] Table 1

[0143] Table 2

[0144] Table 3

[0145] Table 4

[0146] Table 5

[0147] The test results in Table 1 show that when the amount of SM1 is 0.9 equivalents and 1.0 equivalents, after 3 hours of reaction, a large amount of SM2 remains. The highest purity is achieved with 1.1 equivalents of SM1, making 1.1 equivalents the preferred amount. The test results in Table 2 show that when the amount of potassium carbonate is 2.0 equivalents, after 3 hours of reaction, the remaining SM2 is within the limit. Considering both the remaining SM2 and the product content, 2.0 equivalents of potassium carbonate is the preferred amount. The test results in Table 3 show that with 1% and 3% Pd(PPh3)4, a significant amount of SM2 remains, indicating incomplete reaction; with 5% and 7% Pd(PPh3)4, the reaction is complete, and the product content is high. Considering both cost and reaction conditions, 5% Pd(PPh3)4 is the preferred amount. The test results in Table 4 show that the volume of the reaction solvent has a relatively small impact on the reaction; the reaction can be adjusted based on the stirring effect and the requirements of the production scale-up equipment. As shown in Table 5, the reaction time is longer and more SM2 remains when the reaction temperature is around 75℃. The reaction temperatures around 85℃ and 95℃ are comparable, but at 95℃, the product purity gradually decreases with increasing reaction time. Therefore, the preferred reaction temperature is around 85℃. In summary, this invention allows for obtaining a higher content of the first intermediate, which is more advantageous for achieving high yields and high purity of ruxolitinib phosphate.

[0148] The yield of Int2 and the residual Pd content in Int2 in Examples 1A and 5A-6A are shown in Table 6. The reaction phenomena of adding 1,4-dioxane in Example 1A, the reaction phenomena of adding tetrahydrofuran in Comparative Example 12A, and the related substances in the second intermediate (Int2) in Examples 1A and Comparative Example 12A are shown in Table 7. The reaction control data of the acidification reaction in Examples 1A, 7A, and Comparative Example 13A are shown in Table 8. The reaction control data of the acidification reaction in Examples 1A, 8A, and Comparative Examples 14A-15A are shown in Table 9. The reaction control data of the acidification reaction in Examples 1A, 9A, and Comparative Example 16A are shown in Table 10. The reaction control data of the acidification reaction in Examples 1A and 10A-11A are shown in Table 11. The reaction control data of adjusting the pH value using saturated sodium bicarbonate aqueous solution in Examples 1A and Comparative Examples 17A-19A are shown in Table 12. Table 13 shows the mid-scale reaction data for pulping with anhydrous ethanol in Examples 1A and Comparative Examples 20A-21A before pulping in Example 1A. Table 14 shows the mid-scale reaction data for pulping with anhydrous ethanol in Examples 1A and 12A-13A before pulping in Example 1A. Table 15 shows the mid-scale reaction data for pulping with anhydrous ethanol in Examples 1A, 14A, and Comparative Examples 22A-23A before pulping in Example 1A.

[0149] Table 6

[0150] Table 7

[0151] Table 8

[0152] Table 9

[0153] Table 10

[0154] Table 11

[0155] Table 12

[0156] Table 13

[0157] Table 14

[0158] Table 15

[0159] The test results in Table 6 show that different filtration temperatures have no significant impact on Pd residue and product yield. Considering all factors, an extraction and separation temperature of around 40℃ is preferred. The test results in Table 7 show that the reaction phenomena of 1,4-dioxane and tetrahydrofuran are different, and the post-treatment methods also differ. The 1,4-dioxane reaction system can directly crystallize to obtain a solid with a purity of 97.8%. Using tetrahydrofuran results in cumbersome post-treatment operations. Therefore, 1,4-dioxane is preferred as the reaction solvent. The test results in Table 8 show that there is no significant difference between the results of Example 1A and Example 7A. In Example 7A, the hydrochloric acid aqueous solution has the largest volume, while in Comparative Example 13A, the volume of the hydrochloric acid aqueous solution is smaller, but stirring is difficult. Therefore, the concentration of the hydrochloric acid aqueous solution in Example 7A is preferred. The test results in Table 9 show that when the amount of hydrochloric acid is small, there is a larger amount of Int1 residue in the reaction. The test results in Table 10 show that when the amount of 1,4-dioxane added is too small, stirring becomes difficult due to insufficient solvent usage. Adding excessive amounts of 1,4-dioxane does not affect the mixed yield of Int2. The test results in Table 11 show that the acidification temperature has little effect on the reaction. The test results in Table 12 show that the higher the pH of the saturated sodium bicarbonate aqueous solution, the higher the yield, the higher the impurity content, and the lower the purity of Int2. Considering both quality and yield, the optimal pH for adjusting the alkali is 7-8. The test results in Table 13 show that using anhydrous ethanol for pulping increases product purity and reduces the number of impurities. Controlling the amount of anhydrous ethanol within a suitable range further enhances product purity. The test results in Table 14 show that when the ethanol pulping temperature is raised to reflux, the temperature has little effect on the final result. The test results in Table 15 show that the yield is lower when the crystallization temperature after anhydrous ethanol pulping is around 25℃ and around 35℃. At temperatures around 5°C and 15°C, the yields are comparable, with higher purity at around 15°C. Considering all factors, a pulping and crystallization temperature of around 15°C is preferred. That is, by controlling the purity and yield of the second intermediate within a high range, this invention is more conducive to obtaining ruxolitinib phosphate with high yield and high purity.

[0160] Example 1B Preparation of the third intermediate (Int3): Addition reaction: 3024 mL of dimethyl sulfoxide, 480 g of Int2 (obtained in Example 1A) and 388.75 g (2 equivalents) of SM3 were added sequentially to the reaction flask. After stirring evenly, 44.36 g (0.2 equivalents) of potassium carbonate (powder, pre-ground) was added. The temperature was controlled at 25°C. Samples were taken during the reaction, and the reaction was controlled by HPLC until the reaction endpoint (Int2 ≤ 2%). Second post-treatment: 4800 mL of ethyl acetate and 5 wt% sodium chloride aqueous solution were added sequentially to the reaction solution, stirred for 15 min, allowed to stand, and separated. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed three times with 20 wt% sodium chloride aqueous solution (4800 mL each time), separated, and the organic phase was collected (stirred for 15 min each time during washing). 120 g of anhydrous sodium sulfate and 48 g of silica gel were added to the organic phase, stirred and dried for 30 min, filtered, and the filtrate was concentrated under reduced pressure at 40℃ until no more droplets flowed out, yielding a yellow oily substance. 1440 mL of ethyl acetate was added to the oily substance, and the mixture was stirred and dissolved at 65℃. 3120 mL of n-heptane was added while maintaining the temperature at 65℃, then the temperature was lowered to 23℃ and stirred for 5 h. The temperature was then further lowered to 10℃ and maintained for crystallization for 3 h. The mixture was filtered, and the filter cake was treated with 960 mL of n-heptane. The filter cake was washed with alkane; the resulting filter cake was dried under vacuum at 50°C to constant weight, yielding a white solid powder, which was the crude Int3 product; 1557 mL of anhydrous ethanol was added to the crude Int3 product and stirred, the temperature was controlled at 65°C, stirred for 10 min, slowly reduced to 20°C, stirred for 2 h, filtered, and the filter cake was washed with 240 mL of ethanol-water mixed solvent (ethanol to water volume ratio 1:4). The resulting filter cake was dried under vacuum at 50°C to constant weight, yielding the third intermediate (Int3).

[0161] Example 2B The method is the same as in Example 1B, except that in the addition reaction, the amount of SM3 added is 349.87 g (1.8 equivalents).

[0162] Example 3B The method is the same as in Example 1B, except that in the addition reaction, the amount of SM3 added is 485.93 g (2.5 equivalents).

[0163] Example 4B The method is the same as in Example 1B, except that in the addition reaction, the amount of SM3 added is 583.12 g (3 equivalents).

[0164] Example 5B The method is the same as in Example 1B, except that in the addition reaction, the amount of dimethyl sulfoxide used is 52800 mL.

[0165] Example 6B The method is the same as in Example 1B, except that the temperature is controlled at 35°C during the addition reaction.

[0166] Example 7B The method of Example 1B differs in that, in the second post-processing, the filtrate is concentrated under reduced pressure at a controlled temperature of 30°C until no more droplets flow out.

[0167] Example 8B The method of Example 1B differs in that, in the second post-processing, the filtrate is concentrated under reduced pressure at a controlled temperature of 50°C until no more droplets flow out.

[0168] Example 9B The method is the same as in Example 1B, except that in the second post-treatment: 1290 mL of ethyl acetate is added to the oil, the temperature is controlled at 65°C, the mixture is stirred and dissolved, and 2790 mL of n-heptane is added at 65°C for further treatment.

[0169] Example 10B The method is the same as in Example 1B, except that in the second post-treatment: 1590 mL of ethyl acetate is added to the oil, the temperature is controlled at 65°C, the mixture is stirred and dissolved, and 3450 mL of n-heptane is added at 65°C for further treatment.

[0170] Example 11B The method is the same as in Example 1B, except that in the second post-treatment: 1440 mL of ethyl acetate is added to the oil, the temperature is controlled at 65°C, and the mixture is stirred to dissolve. 3120 mL of n-heptane is added while maintaining the temperature at 65°C. The temperature is then lowered to 23°C, and the mixture is stirred while maintaining the temperature at 23°C for 5 hours. The temperature is then lowered to 5°C and maintained for 3 hours to allow crystals to precipitate.

[0171] Example 12B The method is the same as in Example 1B, except that in the second post-processing: 1038 mL of anhydrous ethanol is added to the crude Int3 and the mixture is stirred.

[0172] Example 13B The method is the same as in Example 1B, except that in the second post-processing: 1557 mL of anhydrous ethanol is added to the crude Int3 product and stirred, the temperature is controlled at 65°C, stirred for 10 min, slowly reduced to 10°C, and stirred for 2 h.

[0173] Example 14B The method is the same as in Example 1B, except that in the second post-processing: 1557 mL of anhydrous ethanol is added to the crude Int3 product and stirred, the temperature is controlled at 65°C, stirred for 10 min, slowly reduced to 20°C, and stirred for 3 h.

[0174] Comparative Example 1B The method is the same as in Example 1B, except that in the addition reaction, potassium carbonate is replaced with dicycloamidine (DBU).

[0175] Comparative Example 2B The method is the same as in Example 1B, except that in the addition reaction, the amount of potassium carbonate used is 11.08 g (0.05 equivalents).

[0176] Comparative Example 3B The method is the same as in Example 1B, except that in the addition reaction, the amount of potassium carbonate used is 110.84 g (0.5 equivalents).

[0177] Comparative Example 4B The method is the same as in Example 1B, except that in the addition reaction, the amount of potassium carbonate used is 221.69 g (1 equivalent).

[0178] Comparative Example 5B The method is the same as in Example 1B, except that in the addition reaction, the amount of dimethyl sulfoxide used is 1680 mL.

[0179] Comparative Example 6B The method is the same as in Example 1B, except that the temperature is controlled at 15°C during the addition reaction.

[0180] Comparative Example 7B The method is the same as in Example 1B, except that in the second post-treatment: 1630 mL of ethyl acetate is added to the oil, the temperature is controlled at 65°C, the mixture is stirred and dissolved, and 2930 mL of n-heptane is added at 65°C for further treatment.

[0181] Comparative Example 8B The method is the same as in Example 1B, except that in the second post-treatment: 1300 mL of ethyl acetate (oil) is dissolved by stirring at 65°C, and 3260 mL of n-heptane is added at 65°C for further treatment.

[0182] Comparative Example 9 The method is the same as in Example 1B, except that in the second post-treatment: 1440 mL of ethyl acetate is added to the oil, the temperature is controlled at 65°C, and the mixture is stirred to dissolve. 3120 mL of n-heptane is added while maintaining the temperature at 65°C. The temperature is then lowered to 23°C and stirred while maintaining the temperature at 23°C for 5 hours. The temperature is then further lowered to 20°C and kept at this temperature for 3 hours to allow crystals to precipitate.

[0183] Comparative Example 10B The method is the same as in Example 1B, except that in the second post-processing: 2076 mL of anhydrous ethanol is added to the crude Int3 and the mixture is stirred.

[0184] Comparative Example 11B The method is the same as in Example 1B, except that in the second post-processing: 1557 mL of anhydrous ethanol is added to the crude Int3 product and stirred, the temperature is controlled at 65°C, stirred for 10 min, slowly reduced to 30°C, and stirred for 2 h.

[0185] Comparative Example 12B The method is the same as in Example 1B, except that in the second post-processing: 1557 mL of anhydrous ethanol is added to the crude Int3 product and stirred, the temperature is controlled at 65°C, stirred for 10 min, slowly reduced to 20°C, and stirred for 1 h.

[0186] The intermediate control data for the addition reactions in Examples 1B-4B are shown in Table 16. The intermediate control data for the addition reactions in Example 1B and Comparative Example 1B are shown in Table 17. The intermediate control data for the addition reactions in Examples 1B and Comparative Examples 2B-4B are shown in Table 18. The intermediate control data for the addition reactions in Examples 1B, 5B, and Comparative Example 5B are shown in Table 19. The intermediate control data for the addition reactions in Examples 1B, 6B, and Comparative Example 6B are shown in Table 20.

[0187] Table 16

[0188] Table 17

[0189] Table 18

[0190] Table 19

[0191] Table 20

[0192] The test results in Table 16 show that when the SM3 equivalents are 1.8, 2, 2.5, and 3, the residual Int2 in the reaction solution detected by HPLC is less than 1.0%. Considering all factors, 2.00 equivalents of SM3 is preferred. The test results in Table 17 show that using DBU results in a higher amount of racemic Int5 impurities during the reaction, while using potassium carbonate results in lower amounts of racemic Int5 impurities; therefore, potassium carbonate is preferred. The test results in Table 18 show that 0.05 equivalents of potassium carbonate did not react completely after 11 hours, 0.2 equivalents of potassium carbonate reacted completely after 11 hours, and 0.5 and 1 equivalents of potassium carbonate reacted completely after 3 hours. With increasing potassium carbonate equivalents, the impurities tend to increase after 17 minutes; therefore, 0.2 equivalents of potassium carbonate is preferred. The test results in Table 19 show that when the amount of dimethyl sulfoxide (DMSO) is too low, material stirring and sampling are difficult. When the amount of DMSO is appropriate, further increasing the amount of DMSO does not significantly affect the reaction. As shown in Table 20, the freezing point of dimethyl sulfoxide is 19℃. During the reaction near 15℃, it remains in a semi-solid, turbid state, with some solids being insoluble and others adhering to the reaction walls, making stirring difficult and resulting in a relatively high amount of Int2 residue. At temperatures near 25℃ and 35℃, the Int2 residue is lower, and the product content is comparable. Considering all factors, the optimal reaction temperature is around 25℃. In other words, by controlling the conditions of the addition reaction, this invention can obtain a reaction solution with higher Int3 content and fewer impurities, reducing the difficulty of the second post-processing and ultimately obtaining a high-purity, high-yield third intermediate, which is more conducive to obtaining high-yield and high-purity ruxolitinib phosphate.

[0193] The relevant data for the yellow oily substance obtained in Examples 1B, 7B, and 8B are shown in Table 21. The relevant data for the crude Int3 obtained in Examples 1B, 7B, and 8B are shown in Table 22. The relevant data for the crude Int3 obtained in Examples 1B, 9B, and 10B are shown in Table 23. The relevant data for the crude Int3 obtained in Examples 1B, 11B, and 9B are shown in Table 24. The relevant data for the third intermediate (Int3) obtained in Examples 1B, 12B, and 10B are shown in Table 25. The relevant data for the third intermediate (Int3) obtained in Examples 1B, 13B, and 11B are shown in Table 26. The relevant data for the third intermediate (Int3) obtained in Examples 1B, 14B, and 12B are shown in Table 27.

[0194] Table 21

[0195] Table 22

[0196] Table 23

[0197] Table 24

[0198] Table 25

[0199] Table 26

[0200] Table 27

[0201] The test results in Table 21 show that the concentration temperature of the filtrate has little impact on the final result. The test results in Table 22 show that in the second post-treatment, a low amount of n-heptane results in a low yield, while a high amount of n-heptane results in a low purity. The test results in Table 23 show that increasing the volume of the ethyl acetate / n-heptane mixture has little impact on the experiment. The test results in Table 24 show that a high crystallization temperature results in a lower yield, but no significant impact on purity; considering energy consumption and yield, a temperature around 10℃ is chosen. The test results in Table 25 show that when the ethanol content is too high, the final product yield is low; however, when the ethanol content is too low, stirring becomes difficult in actual operation. As shown in Table 26, the crystallization yield is low when the ethanol slurry crystallization temperature is around 30℃. There is no significant difference in yield and purity at temperatures around 10℃ and 20℃. Considering energy conservation and environmental protection, a temperature around 20℃ is preferred. Table 27 shows that the ethanol crystallization yield is low after 1 hour, while there is no significant difference in purity and yield after 2 and 3 hours of crystallization. Considering energy conservation and environmental protection, 2 hours of crystallization is preferred. In other words, the controlled embodiments of this invention can obtain a high-yield and high-purity third intermediate, thereby ultimately obtaining a high-yield and high-purity ruxolitinib phosphate.

[0202] Example 1C Chiral resolution: 3768 mL of anhydrous ethanol, 471 g of the third intermediate Int3 (obtained from Example 1B) and 441.44 g of D-(+)-DBTA were added sequentially to the reaction flask. The mixture was stirred and dissolved at 75°C. The mixture was then allowed to cool slowly and naturally at room temperature for about 1 hour until a white solid precipitated (about 40~45°C). The mixture was kept at this temperature and stirred for 2 hours. The mixture was then allowed to cool naturally at room temperature for about 1 hour to 15°C while stirring under control.

[0203] Third post-processing: Filtration, the filter cake was washed with 471 mL of anhydrous ethanol at 15°C, and dried under vacuum at 45°C to constant weight to obtain white solid A; First recrystallization: The above white solid A was added to 2826 mL of anhydrous ethanol, and dissolved by stirring at 75°C. Then, the temperature was slowly lowered until the white solid precipitated (about 40~45°C), and the mixture was kept at this temperature and stirred for 2 hours; then, the temperature was lowered to 15°C, and the mixture was stirred for 12 hours. Filtration was performed, and the filter cake was washed with 471 mL of anhydrous ethanol at 15°C, and dried under vacuum at 45°C to constant weight to obtain white solid B; Second recrystallization: The above white solid B was added to 2826 mL of anhydrous ethanol, and dissolved by reflux at 75°C. Then, the temperature was slowly lowered until the white solid precipitated (about 50~55°C), and the mixture was kept at this temperature and stirred for 2 hours. Then, the temperature was lowered to 15°C, and the mixture was stirred for 12 hours. Filtration was performed, and the filter cake was washed with 471 mL of anhydrous ethanol at 15°C, and dried under vacuum at 45°C to constant weight to obtain white solid C, which is the fourth intermediate Int4.

[0204] Example 1C-a The method is the same as in Example 1C, except that in the chiral separation process: after cooling to 15°C, the mixture is stirred for 8 hours.

[0205] Example 1C-b The method is the same as in Example 1C, except that in the chiral separation process: after cooling to 15°C, the mixture is stirred for 12 hours.

[0206] Example 1C-c The method is the same as in Example 1C, except that in the chiral separation process: after cooling to 15°C, the mixture is stirred for 16 hours.

[0207] Example 1C-d The method is the same as in Example 1C, except that in the third post-processing: filtration, the filter cake is washed with 471 mL of anhydrous ethanol at 20°C, and dried under vacuum at 45°C to constant weight to obtain white solid A; first recrystallization: the above white solid A is added to 2826 mL of anhydrous ethanol, stirred and dissolved at 75°C, then slowly cooled until the white solid precipitates (about 40~45°C), and kept at this temperature and stirred for 2 hours; then cooled to 20°C, stirred for 8 hours, filtered, and the filter cake is washed with 471 mL of anhydrous ethanol at 20°C. L was washed with anhydrous ethanol and dried under vacuum at 45°C to constant weight to obtain white solid B. For the second recrystallization: the white solid B was added to 2826 mL of anhydrous ethanol, heated to 75°C and refluxed to dissolve. The temperature was then slowly lowered until a white solid precipitated (approximately 50-55°C), and stirred for 2 hours. The temperature was then lowered to 20°C and stirred for 8 hours. The mixture was filtered, and the filter cake was washed with 471 mL of anhydrous ethanol at 20°C and dried under vacuum at 45°C to constant weight to obtain white solid C, which is the fourth intermediate Int4.

[0208] Example 1 C-e The method is the same as in Example 1C, except that in the third post-processing: filtration, the filter cake is washed with 471 mL of anhydrous ethanol at 20°C, and dried under vacuum at 45°C to constant weight to obtain white solid A; first recrystallization: the above white solid A is added to 2826 mL of anhydrous ethanol, stirred and dissolved at 75°C, then slowly cooled until the white solid precipitates (about 40~45°C), and stirred for 2 hours; then cooled to 20°C, stirred for 16 hours, filtered, and the filter cake is washed with 471 mL of anhydrous ethanol at 20°C. L was washed with anhydrous ethanol and dried under vacuum at 45°C to constant weight to obtain white solid B. For the second recrystallization: the white solid B was added to 2826 mL of anhydrous ethanol, heated to 75°C and refluxed to dissolve. The temperature was then slowly lowered until a white solid precipitated (approximately 50-55°C), and the mixture was stirred at this temperature for 2 hours. The temperature was then lowered to 20°C and stirred for 16 hours. The mixture was filtered, and the filter cake was washed with 471 mL of anhydrous ethanol at 20°C and dried under vacuum at 45°C to constant weight to obtain white solid C, which is the fourth intermediate Int4.

[0209] Example 1C-f The method is the same as in Example 1C, except that in the third post-processing: filtration, the filter cake is washed with 471 mL of anhydrous ethanol at 20°C, and dried under vacuum at 45°C to constant weight to obtain white solid A; first recrystallization: the above white solid A is added to 2826 mL of anhydrous ethanol, stirred and dissolved at 75°C, then slowly cooled until the white solid precipitates (about 40~45°C), and kept at this temperature and stirred for 2 hours; then cooled to 20°C, stirred for 20 hours, filtered, and the filter cake is washed with 471 mL of anhydrous ethanol at 20°C. L was washed with anhydrous ethanol and dried under vacuum at 45°C to constant weight to obtain white solid B. For the second recrystallization: the white solid B was added to 2826 mL of anhydrous ethanol, heated to 75°C and refluxed to dissolve. The temperature was then slowly lowered until a white solid precipitated (approximately 50-55°C), and the mixture was stirred at this temperature for 2 hours. The temperature was then lowered to 20°C and stirred for 20 hours. The mixture was filtered, and the filter cake was washed with 471 mL of anhydrous ethanol at 20°C and dried under vacuum at 45°C to constant weight to obtain white solid C, which is the fourth intermediate Int4.

[0210] Example 1 C-g The method is the same as in Example 1C, except that in the third post-processing: filtration, the filter cake is washed with 471 mL of anhydrous ethanol at 20°C, and dried under vacuum at 45°C to constant weight to obtain white solid A; first recrystallization: the above white solid A is added to 2826 mL of anhydrous ethanol, stirred and dissolved at 75°C, then slowly cooled until the white solid precipitates (about 40~45°C), and stirred for 2 hours; then cooled to 20°C, stirred for 24 hours, filtered, and the filter cake is washed with 471 mL of anhydrous ethanol at 20°C. L was washed with anhydrous ethanol and dried under vacuum at 45°C to constant weight to obtain white solid B. For the second recrystallization: the white solid B was added to 2826 mL of anhydrous ethanol, heated to 75°C and refluxed to dissolve. The temperature was then slowly lowered until a white solid precipitated (approximately 50-55°C), and the mixture was stirred at this temperature for 2 hours. The temperature was then lowered to 20°C and stirred for 24 hours. The mixture was filtered, and the filter cake was washed with 471 mL of anhydrous ethanol at 20°C and dried under vacuum at 45°C to constant weight to obtain white solid C, which is the fourth intermediate Int4.

[0211] Example 2C The method according to Example 1C differs in that, in the chiral separation process, D-(+)-DBTA is replaced with D-(+)-DBTA·H2O.

[0212] Example 3C The method according to Example 1C differs in that, in the chiral separation process, the amount of the third intermediate Int3 is 481.56g.

[0213] Comparative Example 1C The method according to Example 1C differs in that, in the chiral separation process, D-(+)-DBTA is replaced with D-(+)-DTTA.

[0214] Comparative Example 2C The method according to Example 1C differs in that, in the chiral separation process, the amount of the third intermediate Int3 is 316.17g.

[0215] Comparative Example 3C The method according to Example 1C differs in that, in the chiral separation process, the amount of the third intermediate Int3 is 401.3g.

[0216] Comparative Example 4C The method is the same as in Example 1C, except that in the chiral separation process, the amount of anhydrous ethanol added is 2826 mL.

[0217] Comparative Example 5C The method is the same as in Example 1C, except that in the chiral separation process, the amount of anhydrous ethanol added is 4710 mL.

[0218] Comparative Example 6C The method is the same as in Example 1C, except that in the chiral separation process, the amount of anhydrous ethanol added is 5652 mL.

[0219] Comparative Example 7C The method of Example 1C differs in that, in the chiral separation process, the final step is to allow the temperature to naturally cool to 5°C at room temperature.

[0220] Comparative Example 8C The method according to Example 1C differs in that, in the chiral separation process, the natural cooling at room temperature involved in the chiral separation process is replaced with gradient cooling for about 2 hours. Specifically, a low-temperature cooling reactor is used, and the external temperature is set about 10°C lower than the current internal temperature. The reaction flask is transferred to the low-temperature cooling reactor, and after the internal temperature drops to the set temperature, it is kept at that temperature for a period of time before being set to cool down again, thus entering the next cooling gradient. By controlling the holding and cooling times, the total time of the cooling process is controlled to be about 2 hours.

[0221] Comparative Example 9C The method according to Example 1C differs in that, in the chiral separation process, the natural cooling at room temperature involved in the chiral separation process is replaced with rapid cooling for about 0.5 hours. Specifically, after setting the external temperature below the target temperature using a low-temperature cooling reactor, the reaction flask is transferred to the low-temperature cooling reactor, and the internal temperature is rapidly reduced. When the internal temperature approaches the target temperature, the external temperature is raised to the target temperature range. This cooling process is controlled to take about 0.5 hours.

[0222] Comparative Example 10C The method is the same as in Example 1C, except that in the chiral separation process: after cooling to 15°C, the mixture is stirred for 3 hours.

[0223] Comparative Example 11C The method of Example 1C differs in that, in the chiral separation process, the temperature is lowered to 15°C and then stirred for 5 hours.

[0224] The central control data for chiral splitting processing in Examples 1C, 2C, and Comparative Example 1C are shown in Table 28. The central control data for chiral splitting processing in Examples 1C, 3C, and Comparative Examples 2C-3C are shown in Table 29. The central control data for chiral splitting processing in Examples 1C and Comparative Examples 4C-6C are shown in Table 30. The central control data for chiral splitting processing in Examples 1C and Comparative Example 7C are shown in Table 31. The central control data for chiral splitting processing in Examples 1C and Comparative Examples 8C-9C are shown in Table 32. The data for chiral splitting processing in Examples 1C-a to 1C-c and Comparative Examples 10C-11C are shown in Table 33.

[0225] Table 28

[0226] Table 29

[0227] Table 30

[0228] Table 31

[0229] Table 32

[0230] Table 33

[0231] The test results in Table 28 show that D-(+)-DBTA and D-(+)-DBTA·H2O have essentially no difference in yield and isomerization. Considering cost, D-(+)-DBTA is cheaper. Therefore, D-(+)-DBTA is selected as the resolving agent. The test results in Table 29 show that increasing the resolving agent dosage increases the yield, but when too much resolving agent is used, crystallization and stirring become significantly difficult. The test results in Table 30 show that when insufficient anhydrous ethanol is used for resolving, stirring after crystallization becomes difficult, and the crystals cannot be stirred. However, when excessive anhydrous ethanol is used for resolving, the resolving yield is lower. The test results in Table 31 show that a lower final crystallization temperature for chiral resolving is not necessarily better; a lower temperature results in larger isomers. A crystallization temperature of 15±5℃ is more suitable. The test results in Table 32 show that rapid cooling results in higher impurities in the isomers, and natural cooling is the most effective method. As shown in Table 33, the chiral resolution process resulted in more thorough stirring for over 8 hours during crystallization, leading to smaller isomers. In other words, by controlling the purity and yield of the fourth intermediate within a high range, this invention is more conducive to obtaining high-yield and high-purity ruxolitinib phosphate.

[0232] Comparative Example 12C The method is the same as in Example 1C-b, except that in the third post-treatment, all anhydrous ethanol is replaced with an equal amount of a mixture of acetonitrile / tetrahydrofuran (volume ratio 1:1).

[0233] Comparative Example 13C The method is the same as in Example 1C-b, except that in the third post-treatment, all anhydrous ethanol is replaced with an equal amount of acetonitrile.

[0234] Comparative Example 14C The method is the same as in Example 1C-b, except that in the third post-treatment: filtration, the filter cake is washed with 471 mL of anhydrous ethanol at 15°C, and dried under vacuum at 45°C to constant weight to obtain white solid A; first recrystallization: the above white solid A is added to 1884 mL of anhydrous ethanol, stirred and dissolved at 75°C, then slowly cooled until the white solid precipitates (about 40~45°C), and kept at this temperature with stirring for 2 hours; then cooled to 15°C, stirred for 12 hours, filtered, and the filter cake is washed with 471 mL of anhydrous ethanol at 15°C. Wash with 1884 mL of anhydrous ethanol, dry under vacuum at 45 °C to constant weight to obtain white solid B; Second recrystallization: Add the above white solid B to 1884 mL of anhydrous ethanol, heat to 75 °C and reflux to dissolve, then slowly cool until white solid precipitates (about 50~55 °C), keep warm and stir for 2 h, then cool to 15 °C and stir for 12 h, filter, wash the filter cake with 471 mL of anhydrous ethanol at 15 °C, dry under vacuum at 45 °C to constant weight to obtain white solid C, which is the fourth intermediate Int4.

[0235] Comparative Example 15C The method is the same as in Example 1C-b, except that in the third post-treatment: filtration, the filter cake is washed with 471 mL of anhydrous ethanol at 15°C, and dried under vacuum at 45°C to constant weight to obtain white solid A; first recrystallization: the above white solid A is added to 3768 mL of anhydrous ethanol, stirred and dissolved at 75°C, then slowly cooled until the white solid precipitates (about 40~45°C), and stirred for 2 hours; then cooled to 15°C, stirred for 12 hours, filtered, and the filter cake is washed with 471 mL of anhydrous ethanol at 15°C. Wash with 3768 mL of anhydrous ethanol, dry under vacuum at 45 °C to constant weight to obtain white solid B; Second recrystallization: Add the above white solid B to 3768 mL of anhydrous ethanol, heat to 75 °C and reflux to dissolve, then slowly cool until white solid precipitates (about 50~55 °C), keep warm and stir for 2 h, then cool to 15 °C and stir for 12 h, filter, wash the filter cake with 471 mL of anhydrous ethanol at 15 °C, dry under vacuum at 45 °C to constant weight to obtain white solid C, which is the fourth intermediate Int4.

[0236] Comparative Example 16-C The method is the same as in Example 1C-b, except that in the third post-treatment: filtration, the filter cake is washed with 471 mL of anhydrous ethanol at 5°C, and dried under vacuum at 45°C to constant weight to obtain white solid A; first recrystallization: the above white solid A is added to 2826 mL of anhydrous ethanol, stirred and dissolved at 75°C, then slowly cooled until the white solid precipitates (about 40~45°C), and kept at this temperature and stirred for 2 hours; then cooled to 5°C, stirred for 12 hours, filtered, and the filter cake is washed with 471 mL of anhydrous ethanol at 5°C. L was washed with anhydrous ethanol and dried under vacuum at 45°C to constant weight to obtain white solid B. For the second recrystallization: the white solid B was added to 2826 mL of anhydrous ethanol, heated to 75°C and refluxed to dissolve. The temperature was then slowly lowered until a white solid precipitated (approximately 50-55°C), and the mixture was stirred at this temperature for 2 hours. The temperature was then lowered to 5°C and stirred for 12 hours. The mixture was filtered, and the filter cake was washed with 471 mL of anhydrous ethanol at 5°C and dried under vacuum at 45°C to constant weight to obtain white solid C, which is the fourth intermediate Int4.

[0237] Comparative Example 17-C The method is the same as in Example 1C-b, except that in the third post-treatment: filtration, the filter cake is washed with 471 mL of anhydrous ethanol at 20°C, and dried under vacuum at 45°C to constant weight to obtain white solid A; first recrystallization: the above white solid A is added to 2826 mL of anhydrous ethanol, stirred and dissolved at 75°C, then slowly cooled until the white solid precipitates (about 40~45°C), and kept at this temperature with stirring for 2 hours; then cooled to 20°C, stirred for 12 hours, filtered, and the filter cake is washed with 471 mL of anhydrous ethanol at 20°C. Wash with 2826 mL of anhydrous ethanol, dry under vacuum at 45 °C to constant weight to obtain white solid B; Second recrystallization: Add the above white solid B to 2826 mL of anhydrous ethanol, heat to 75 °C and reflux to dissolve, then slowly cool until white solid precipitates (about 50~55 °C), keep warm and stir for 2 h, then cool to 20 °C and stir for 12 h, filter, wash the filter cake with 471 mL of anhydrous ethanol at 20 °C, dry under vacuum at 45 °C to constant weight to obtain white solid C, which is the fourth intermediate Int4.

[0238] Comparative Example 18-C The method is the same as in Example 1C-b, except that in the third post-treatment: the filter cake is washed with 471 mL of anhydrous ethanol at 15°C and dried under vacuum at 45°C to constant weight to obtain white solid A; for the first recrystallization: the above white solid A is added to 2826 mL of anhydrous ethanol, stirred and dissolved at 75°C, and then slowly cooled until the white solid precipitates (about 40~45°C), and stirred for 2 hours; then cooled to 15°C, stirred for 3 hours, filtered, and the filter cake is washed with 471 mL of anhydrous ethanol at 15°C. Wash with anhydrous ethanol and dry under vacuum at 45°C to constant weight to obtain white solid B; Second recrystallization: Add the above white solid B to 2826 mL of anhydrous ethanol, heat to 75°C and reflux to dissolve, then slowly cool until white solid precipitates (about 50~55°C), keep warm and stir for 2 h, then cool to 15°C and stir for 3 h, filter, wash the filter cake with 471 mL of anhydrous ethanol at 15°C, and dry under vacuum at 45°C to constant weight to obtain white solid C, which is the fourth intermediate Int4.

[0239] Comparative Example 19-C The method is the same as in Example 1C-b, except that in the third post-treatment: the filter cake is washed with 471 mL of anhydrous ethanol at 15°C and dried under vacuum at 45°C to constant weight to obtain white solid A; for the first recrystallization: the above white solid A is added to 2826 mL of anhydrous ethanol, stirred and dissolved at 75°C, and then slowly cooled until the white solid precipitates (about 40~45°C), and stirred for 2 hours; then cooled to 15°C, stirred for 5 hours, filtered, and the filter cake is washed with 471 mL of anhydrous ethanol at 15°C. Wash with anhydrous ethanol and dry under vacuum at 45°C to constant weight to obtain white solid B; Second recrystallization: Add the above white solid B to 2826 mL of anhydrous ethanol, heat to 75°C and reflux to dissolve, then slowly cool until white solid precipitates (about 50~55°C), keep warm and stir for 2 h, then cool to 15°C and stir for 5 h, filter, wash the filter cake with 471 mL of anhydrous ethanol at 15°C, and dry under vacuum at 45°C to constant weight to obtain white solid C, which is the fourth intermediate Int4.

[0240] Data related to white solid A in Examples 1C-b and Comparative Examples 12C-13C are shown in Table 34. Data related to white solid A in Examples 1C-b and Comparative Examples 14C-15C are shown in Table 35. Data related to white solid A in Examples 1C-b and Comparative Examples 16C-17C are shown in Table 36. Data related to white solid A in Examples 1C-b, 1C-d, 1C-e, 1C-f, 1C-g, Comparative Examples 18C and 19C are shown in Table 37. Following the method of Example 1C-b, the temperature and time for vacuum drying in the third post-processing were controlled according to Table 38, while data related to the fourth intermediate were recorded.

[0241] Table 34

[0242] Table 35

[0243] Table 36

[0244] Table 37

[0245] Table 38

[0246] The test results in Table 34 show that Int4 cannot be completely dissolved in acetonitrile around T=75℃. Ethanol, as the refining solvent, yields the product with the fewest isomers and a higher yield. The test results in Table 35 show that during crystallization, too much ethanol, while reducing the isomer content in the target product, decreases the yield; conversely, too little ethanol increases the isomer content. The test results in Table 36 show that a crystallization temperature around 15℃ in the third post-treatment yields the best product quality and yield. The test results in Table 37 show that the crystallization time in the third post-treatment significantly affects the isomer content; crystallization times of 8 hours or longer result in better product quality. The results in Table 38 show that the fourth intermediate remains stable in quality after drying at vacuum 45±5℃ and 55±5℃ for 27 hours, with no significant differences in related substances and isomers. Therefore, a drying temperature around 45℃ is preferred. That is, by controlling the purity and yield of the fourth intermediate in the present invention to be in a high range, it is more advantageous to obtain ruxolitinib phosphate with high yield and high purity.

[0247] Example 1D Deprotection treatment: (1) Add 4998 mL of ethyl acetate, 2499 mL of purified water and 357 g of the fourth intermediate Int4 (obtained from Example 1C-b) to the reaction flask in sequence. Control the temperature at 25°C, add 2M potassium carbonate aqueous solution dropwise, adjust the pH value to 8.6, stir for 15 min, let stand and separate the liquids. Extract the aqueous phase with ethyl acetate twice, using 3570 mL each time. Combine the organic phases and wash the organic phase twice with 20% sodium chloride solution, using 1785 mL each time. Separate the liquids and concentrate the organic phase under reduced pressure at 40°C until no liquid droplets flow out, to obtain a solid. (2) Add 1785 mL of methanol and 1785 mL of tetrahydrofuran to the obtained solid and stir to dissolve. Control the temperature at 25°C. Add 298 mL of 2M potassium carbonate aqueous solution dropwise and control the temperature at 25°C. Monitor the reaction endpoint by TLC (petroleum ether: ethyl acetate = 1:1, color development at 254 nm, the endpoint is when there is no residue of Int4 free product). Fourth post-processing: <1> Add 1928 mL of 20% sodium chloride aqueous solution to the above reaction solution, adjust the pH to 7.4 with 1M hydrochloric acid aqueous solution, extract twice with ethyl acetate, using 1928 mL each time, combine the organic layers, wash the organic phase twice with 20% sodium chloride aqueous solution, using 964 mL each time, and concentrate the obtained organic phase under reduced pressure at 40℃ until no obvious droplets flow out, to obtain the concentrate; add 1392 mL of methanol to the concentrate, stir to dissolve, adjust the pH to 9.5 by adding ammonia water dropwise, stir at 25℃, and monitor the reaction until the endpoint (RRT 0.96 ≤ 1.5%) using HPLC. <2> Then, 1678 mL of 20% sodium chloride solution was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, using 1392 mL each time. The organic phases were combined, washed once with 1785 mL of 5% sodium chloride solution, and then washed once with 1785 mL of purified water. The mixture was separated, and 114.24 g of anhydrous sodium sulfate was added to the obtained organic phase. The mixture was stirred for 20 min, filtered, and the filtrate was concentrated under reduced pressure at 45 °C to obtain a white foamy solid, which was the fifth intermediate Int5.

[0248] Example 1D-a The method according to Example 1D differs in that the deprotection process is performed: (1) Add 4998 mL of ethyl acetate, 2499 mL of purified water and 357 g of the fourth intermediate Int4 (obtained from Example 1C-b) to the reaction flask in sequence. Control the temperature at 25°C, add 2M potassium carbonate aqueous solution dropwise, adjust the pH value to 8.6, stir for 15 min, let stand and separate the liquids. Extract the aqueous phase with ethyl acetate twice, using 3570 mL each time. Combine the organic phases and wash the organic phase twice with 20% sodium chloride solution, using 1785 mL each time. Separate the liquids and concentrate the organic phase under reduced pressure at 40°C until no liquid droplets flow out, to obtain a solid. (2) Add 1785 mL of methanol and 1785 mL of tetrahydrofuran to the obtained solid and stir to dissolve. Control the temperature at 25°C. Add 298 mL of 2M potassium carbonate aqueous solution dropwise and control the temperature at 25°C. Monitor the reaction endpoint by TLC and react for 3 hours.

[0249] Example 1D-b The method according to Example 1D-a differs in that, in the fourth post-processing: step <1> Add ammonia dropwise to adjust the pH to 11.4.

[0250] Example 1D-c The method is the same as in Example 1D-a, except that in the fourth post-treatment: ammonia water is added dropwise to adjust the pH value to 9.5, and the temperature is controlled at 5°C while stirring.

[0251] Example 1D-d The method is the same as in Example 1D-a, except that the steps in Example 1D-a are taken as follows. <2> The filtrate was concentrated under reduced pressure at 20°C to obtain a white, foamy solid, which is the fifth intermediate, Int5.

[0252] Example 2D The method according to Example 1D differs in that, in the deprotection treatment: in step (2), 257 mL of 2M potassium carbonate aqueous solution is replaced with 229 mL of 2M potassium carbonate aqueous solution.

[0253] Example 3D The method according to Example 1D differs in that, in the deprotection treatment: in step (2), 257 mL of 2M potassium carbonate aqueous solution is replaced with 344 mL of 2M potassium carbonate aqueous solution.

[0254] Comparative Example 1D The method according to Example 1D differs in that, in the deprotection treatment: in step (2), 298 mL of 2M potassium carbonate aqueous solution is replaced with 298 mL of sodium hydroxide aqueous solution.

[0255] Comparative 2D The method according to Example 1D differs in that, in the deprotection treatment: in step (2), 257 mL of 2M potassium carbonate aqueous solution is replaced with 298 mL of sodium hydroxide aqueous solution.

[0256] Comparative 3D The method of Example 1D differs in that, in the deprotection process: in step (2), 3750 mL of methanol is added to the obtained solid and stirred to dissolve it.

[0257] Comparative 4D The method of Example 1D differs in that, in the deprotection process: in step (2), 3750 mL of tetrahydrofuran is added to the obtained solid and stirred to dissolve.

[0258] Comparative 5D The method of Example 1D differs in that, in the deprotection process: in step (2), 1983 mL of methanol and 1587 mL of tetrahydrofuran are added to the resulting solid and stirred to dissolve.

[0259] Comparative Example 6D The method of Example 1D differs in that, in the deprotection treatment: in step (2), 1587 mL of methanol and 1983 mL of tetrahydrofuran are added to the resulting solid and stirred to dissolve.

[0260] Comparative Example 7D The method of Example 1D differs in that, in the deprotection treatment: in step (2), 1071 mL of methanol and 1071 mL of tetrahydrofuran are added to the resulting solid and stirred to dissolve.

[0261] Comparative Example 8D The method of Example 1D differs in that, in the deprotection treatment: in step (2), 1428 mL of methanol and 1428 mL of tetrahydrofuran are added to the resulting solid and stirred to dissolve.

[0262] Comparative Example 9D The method according to Example 1D differs in that, in the deprotection treatment: in step (2), 2142 mL of methanol and 2142 mL of tetrahydrofuran are added to the resulting solid and stirred to dissolve.

[0263] Comparative Example 10D The method of Example 1D differs in that, in the deprotection treatment: in step (2), 1785 mL of methanol and 1785 mL of tetrahydrofuran are added to the obtained solid and stirred to dissolve. The temperature is controlled at 15°C. 298 mL of 2M potassium carbonate aqueous solution is added dropwise and the temperature is controlled at 15°C. The reaction is monitored by TLC until the endpoint (petroleum ether: ethyl acetate = 1:1, 254 nm color development, the endpoint is when there is no residue of Int4 free product).

[0264] Comparative Example 11D The method of Example 1D differs in that, in the deprotection treatment: in step (2), 1785 mL of methanol and 1785 mL of tetrahydrofuran are added to the obtained solid and stirred to dissolve. The temperature is controlled at 35°C. 298 mL of 2M potassium carbonate aqueous solution is added dropwise and the temperature is controlled at 35°C. The reaction is monitored by TLC until the endpoint (petroleum ether: ethyl acetate = 1:1, 254 nm color development, the endpoint is when there is no residue of Int4 free product).

[0265] Comparative Example 12D The method according to Example 1D-a differs in that, in the fourth post-processing: step <1> Add ammonia water dropwise to adjust the pH value to 7.6.

[0266] Comparative Example 13D The method is the same as in Example 1D-a, except that in the fourth post-treatment: ammonia water is added dropwise to adjust the pH value to 9.5, and the temperature is controlled at 45°C while stirring.

[0267] Comparative Example 14D The method is the same as in Example 1D-a, except that the steps in Example 1D-a are taken as follows. <2> The filtrate was concentrated under reduced pressure at 60°C to obtain a white, foamy solid, which is the fifth intermediate, Int5.

[0268] Table 39 shows the centrally controlled reaction data for the deprotection treatment in Example 1D and Comparative Examples 1D-2D, as well as the relevant data for the fifth intermediate. Table 40 shows the centrally controlled reaction data for the deprotection treatment in Example 1D-3D. Table 41 shows the reaction data for the deprotection treatment in Example 1D and Comparative Examples 3D-4D. Table 42 shows the reaction data for the deprotection treatment in Example 1D and Comparative Examples 5D-6D. Table 43 shows the centrally controlled reaction data for the deprotection treatment in Example 1D and Comparative Examples 7D-9D. Table 44 shows the centrally controlled reaction data for the deprotection treatment in Example 1D and Comparative Examples 10D-11D. According to Example 1D, the time from TLC monitoring to the reaction endpoint and the reaction results in the deprotection treatment step (2) are examined, as shown in Table 45. The fourth post-processing step in Example 1D-a, Example 1D-b, and Comparative Example 12D. <1> The relevant data after the reaction are shown in Table 46. The fourth post-processing step in Examples 1D-a, 1D-c, and Comparative Example 13D. <1> The relevant data after the reaction are shown in Table 47. The test steps were performed according to the method of Example 1D-a. <1> The effect of adding ammonia to adjust the pH to 9.5 and stirring at 25°C for different times on the reaction is shown in Table 48. Data on the penta-intermediate Int5 in Examples 1D-a, 1D-d, and Comparative Example 14D are shown in Table 49.

[0269] Table 39

[0270] Table 40

[0271] Table 41

[0272] Table 42

[0273] Table 43

[0274] Table 44

[0275] Table 45

[0276] Table 46

[0277] Table 47

[0278] Table 48

[0279] Table 49

[0280] The test results in Table 39 show that with sodium hydroxide, the impurities increased significantly at 19.5 min as the reaction time increased, and the final Int5 solid was difficult to remove. With potassium carbonate, even with a reaction time extended to 60 min, there were no significant changes in related substances and impurities, and the final solid purity was relatively high. Therefore, potassium carbonate is the preferred alkali for deprotection. The test results in Table 40 show that the impurities did not change significantly within 60 min with different amounts of potassium carbonate (2M). The test results in Table 41 show that pure methanol has a faster deprotection reaction, with Int4 reacting completely within 1 hour. After 1 hour, the impurities at 20 min were 1.55%. In the methanol and tetrahydrofuran system, with a reaction time extended to 20 hours, the impurities at 20 min were 1.06%, indicating greater controllability of the reaction system. The substance at 17 min was a hydroxymethyl structure, which could be removed by adjusting the pH with ammonia. The pure tetrahydrofuran system showed almost no reaction. Therefore, the methanol / tetrahydrofuran system is preferred as a solvent, allowing for control of the reaction rate. HPLC monitoring of the reaction solution further enhances the controllability of the reaction solution. Table 42 shows that after 6 hours of reaction, the impurity at 17 minutes can be removed by adjusting the alkali with ammonia. In the equal volume methanol and tetrahydrofuran system, the impurity is lowest at 20 minutes. Table 43 shows that both excessively high and low total additions of methanol and tetrahydrofuran increase the content of impurity components. Table 44 shows that at around 35℃, the deprotection treatment significantly increases the impurities at 13 minutes and 17 minutes. At around 15℃, a large amount of Int4 remains. The hydroxymethyl intermediate is an intermediate product that can be converted to Int5 later. Considering all factors, the optimal deprotection temperature is around 25℃. Table 45 shows that the reaction is complete after stirring for 3 hours at around 25℃. Table 46 shows that before adjusting the pH with ammonia, the impurity (hydroxymethyl impurity) at 17 minutes is relatively large. There is no significant difference in results at pH 9.5 and around pH 11.4; pH 9-10 is preferred. The test results in Table 47 show that adjusting the pH with ammonia and the reaction temperature have little effect on the 17-minute impurity (hydroxymethyl impurity), but higher temperatures will reduce the purity of the main peak. The test results in Table 48 show that after adjusting the pH to around 9.5 with ammonia and stirring for 30 hours, the mixture is relatively stable with little change in purity, and the 17-minute hydroxymethyl impurity was not detected. The test results in Table 49 show that the purity of Int5 decreases when the concentration temperature is too high. It is preferable to perform vacuum concentration at around 45°C. That is, by controlling the purity and yield of the fifth intermediate within a high range in this invention, it is more advantageous to obtain ruxolitinib phosphate with high yield and high purity.

[0281] Example 1E Salt formation reaction: 1964.5 mL of isopropanol and 140.32 g of Int5 (obtained from Example 1D-a) were added sequentially to the reaction flask, the temperature was raised to 65 °C, stirred and dissolved, 51.62 g of crystalline phosphoric acid and 393 mL of isopropanol were added dropwise, the temperature was controlled at 70 °C, and the reaction was carried out for 1 h. Then the temperature was lowered to 25 °C, stirred for 2 h, filtered, and the filter cake was washed with 421 mL of isopropanol. The obtained filter cake was dried under vacuum at 60 °C to constant weight to obtain an off-white solid powder. Fifth post-processing: (1) Add 720 mL of methanol to the above-mentioned off-white solid powder, control the temperature at 55℃ and slurry for 1 h, cool down to 5℃, stir for 2 h, filter, wash the filter cake with 360 mL of methanol pre-cooled to 5℃, and dry the obtained filter cake under vacuum at 60℃ to constant weight to obtain crude ruxolitinib phosphate. (2) Add 140g of crude ruxolitinib phosphate and 1820mL of methanol to the reaction flask, control the temperature at 55℃, stir for 15min, then add 7g of activated carbon and stir for 115min, keep the temperature at 55℃ and filter while hot (filter paper + 0.45μm organic membrane), heat the filtrate to 55℃, stir to dissolve, control the temperature at 55℃, add 2310mL of isopropanol and 1400mL of n-heptane dropwise (dropwise time about 20min), cool to 25℃ (cooling time about 2h), stir for 5h, filter, wash the filter cake with 280mL of isopropanol solvent, control the temperature of the obtained filter cake at 560℃, vacuum dry until the moisture content is ≤1.0% (Karl Fischer test), collect the material, and obtain a white solid powder, which is ruxolitinib phosphate.

[0282] Example 2E The method is the same as in Example 1E, except that in the salt formation reaction, cooling to 25°C is replaced with cooling to 15°C.

[0283] Example 3E The method is the same as in Example 1E, except that in the salt formation reaction, cooling to 25°C is replaced with cooling to 35°C.

[0284] Example 4E The method is the same as in Example 1E, except that in the salt formation reaction, the temperature is lowered to 25°C and then stirred for 1 hour.

[0285] Example 5E The method is the same as in Example 1E, except that in the salt formation reaction, the temperature is lowered to 25°C and then stirred for 3 hours.

[0286] Example 6E The method according to Example 1E differs in that, in the fifth post-processing step (1), 720 mL of methanol is added to the above-mentioned off-white solid powder, the temperature is controlled at 55°C and the mixture is pulped for 1 hour, then cooled to -5°C and stirred for 2 hours. The mixture is filtered, and the filter cake is washed with 360 mL of methanol pre-cooled to -5°C. The resulting filter cake is vacuum dried at 60°C to constant weight to obtain crude ruxolitinib phosphate.

[0287] Example 7E The method of Example 1E differs in that, in the fifth post-processing step (1), 720 mL of methanol is added to the above-mentioned off-white solid powder, the temperature is controlled at 55°C and the mixture is pulped for 1 hour, then cooled to 5°C and stirred for 3 hours. The mixture is then filtered, and the filter cake is washed with 360 mL of methanol pre-cooled to 5°C. The resulting filter cake is then vacuum dried at 60°C to constant weight to obtain crude ruxolitinib phosphate.

[0288] Example 8E The method is the same as in Example 1E, except that in the fifth post-treatment: 140 g of crude ruxolitinib phosphate and 1820 mL of methanol are added to the reaction flask, and the temperature is controlled at 65°C.

[0289] Example 9E The method is the same as in Example 1E, except that in the fifth post-treatment, 4.2 g of activated carbon is added.

[0290] Example 10E The method is the same as in Example 1E, except that in the fifth post-treatment: 2024 mL of isopropanol and 1686 mL of n-heptane are added dropwise.

[0291] Example 12E The method according to Example 1E differs in that, in the fifth post-processing step (2), the temperature is reduced to 15°C.

[0292] Example 13E The method according to Example 1E differs in that, in the fifth post-processing step (2), the temperature is lowered to 25°C and then stirred for 8 hours.

[0293] Comparative Example 1E The method according to Example 1E differs in that, in the fifth post-processing step (1), 720 mL of methanol is added to the above-mentioned off-white solid powder, the temperature is controlled at 55°C and the mixture is pulped for 1 hour, then cooled to 15°C and stirred for 2 hours. The mixture is filtered, and the filter cake is washed with 360 mL of methanol pre-cooled to 15°C. The resulting filter cake is vacuum dried at 60°C to constant weight to obtain crude ruxolitinib phosphate.

[0294] Comparative Example 2E The method according to Example 1E differs in that, in the fifth post-processing step (1), 720 mL of methanol is added to the above-mentioned off-white solid powder, the temperature is controlled at 55°C and the mixture is pulped for 1 hour, then cooled to 5°C and stirred for 1 hour. The mixture is filtered, and the filter cake is washed with 360 mL of methanol pre-cooled to 5°C. The resulting filter cake is vacuum dried at 60°C to constant weight to obtain crude ruxolitinib phosphate.

[0295] Comparative Example 3E The method is the same as in Example 1E, except that in the fifth post-treatment: 140 g of crude ruxolitinib phosphate and 1400 mL of methanol are added to the reaction flask.

[0296] Comparative Example 4E The method is the same as in Example 1E, except that in the fifth post-treatment: 140 g of crude ruxolitinib phosphate and 2100 mL of methanol are added to the reaction flask.

[0297] Comparative Example 5E The method is the same as in Example 1E, except that in the fifth post-treatment: 140 g of crude ruxolitinib phosphate and 1820 mL of methanol are added to the reaction flask, and the temperature is controlled at 45°C.

[0298] Comparative Example 6E The method is the same as in Example 1E, except that in the fifth post-treatment, 9.8 g of activated carbon is added.

[0299] Comparative Example 7E The method is the same as in Example 1E, except that in the fifth post-treatment: 2586 mL of isopropanol and 1124 mL of n-heptane are added dropwise.

[0300] Comparative Example 8E The method is the same as in Example 1E, except that in the fifth post-treatment: 1743 mL of isopropanol and 1057 mL of n-heptane are added dropwise.

[0301] Comparative Example 9E The method according to Example 1E differs in that, in the fifth post-processing step (2), the temperature is reduced to 35°C.

[0302] Comparative Example 10E The method according to Example 1E differs in that, in the fifth post-processing step (2), the temperature is lowered to 25°C and then stirred for 3 hours.

[0303] Data on the off-white solid powders in Examples 1E-5E are shown in Table 50. Data on crude ruxolitinib phosphate in Examples 1E, 6E-7E, and Comparative Examples 1E-2E are shown in Table 51. Data on ruxolitinib phosphate in Examples 1E, 8E-13E, and Comparative Examples 3E-10E are shown in Table 52.

[0304] Table 50

[0305] Table 51

[0306] Table 52

[0307] The test results in Table 50 show that there are no significant differences in the related substances and yield of the crude product obtained from crystallization at different temperatures and crystallization times during the salt formation reaction. The test results in Table 51 show that in the fifth post-treatment, excessively high crystallization temperature reduces the yield, while crystallization time has little effect on related substances but does affect the yield. The test results in Table 52 show that hot filtration is required during the purification of ruxolitinib phosphate. Low methanol content and high concentration lead to solid precipitation and losses during hot filtration. When using activated carbon for decolorization, excessively low temperatures result in more insoluble solids, leading to a lower yield. Increasing the amount of activated carbon used for decolorization also reduces the yield. When using isopropanol and n-heptane, a lower proportion of n-heptane results in a lower yield for the same volume. Lower yields are also observed when the amounts of isopropanol and n-heptane are low, and lower yields are also observed when the crystallization temperature is too high and the time is too short.

[0308] The above experimental results further demonstrate the importance of the technical solution defined in this invention to its technical effect.

[0309] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A preparation process for ruxolitinib phosphate, characterized in that, Includes the following steps: S1. In the presence of a first catalyst, a first alkaline reagent aqueous solution, and a first solvent, 1-(1-ethoxyethyl)-4-pyrazoloborate pinacol ester is subjected to a Suzuki coupling reaction with (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentanoate to obtain a first material containing a first intermediate, followed by a first post-treatment including acidification to obtain a second intermediate; S2. In the presence of the second catalyst and the second solvent, the second intermediate undergoes an addition reaction with 3-cyclopentylacrylonitrile, followed by a second post-treatment to obtain the third intermediate. S3. In the presence of a third solvent and a resolving agent, the third intermediate is subjected to chiral resection, followed by a third post-processing to obtain the fourth intermediate. S4. In the presence of the fourth solvent, the fourth intermediate is deprotected under alkaline conditions, followed by a fourth post-treatment to obtain the fifth intermediate. S5. In the presence of the fifth solvent, the fifth intermediate undergoes a salt-forming reaction with phosphoric acid, followed by the fifth post-treatment to obtain ruxolitinib phosphate.

2. The preparation process of ruxolitinib phosphate according to claim 1, characterized in that, The first catalyst is selected from trifluoromethanesulfonic acid or tetra(triphenylphosphine)palladium; And / or, the first alkaline reagent in the first alkaline reagent aqueous solution is selected from at least one of lithium carbonate, potassium carbonate, sodium carbonate and potassium phosphate; And / or, the first solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; And / or, based on the molar amount of (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentanoate, the amount of the first alkaline reagent in the first alkaline reagent aqueous solution is 2-5 equivalents; And / or, based on the mass of (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentanoate, the mass of the first catalyst is 1% to 7%; And / or, the volume of the first solvent used for 1 g of (4-chloro-7H-pyrrolo[2,3-D]pyrimidin-7-yl)methylpentanoate is 3.5 to 5.5 mL.

3. The preparation process of ruxolitinib phosphate according to claim 1, characterized in that, In step S1, the conditions for the Suzuki coupling reaction include: being carried out in an atmosphere, at a temperature of 80-90°C, for a time of 2-3 hours; And / or, the first post-processing steps include: first extraction and separation, acidification treatment, neutralization treatment, first pulping A, first drying A, first pulping B, first washing, and first drying B; the first acidification treatment method includes: adding a first solvent to the filtrate obtained from the first extraction and separation, cooling to 25±5℃, and acidifying with hydrochloric acid aqueous solution.

4. The preparation process of ruxolitinib phosphate according to claim 1, characterized in that, The second catalyst is selected from 1,8-diazabicycloundec-7-ene and / or potassium carbonate; And / or, the second solvent includes dimethyl sulfoxide; And / or, in step S2, based on the molar amount of the second intermediate obtained, the amount of 3-cyclopentylacrylonitrile used is 1.8-3 equivalents; And / or, in step S2, based on the molar amount of the second intermediate obtained, the amount of the second catalyst is 0.05-1 equivalent; And / or, in step S2, based on the molar amount of the second intermediate obtained, the amount of the second catalyst is 0.05-1 equivalent; And / or, in step S2, the amount of the second solvent used for 1g of the second intermediate is 3.5 to 10 mL; And / or, in step S2, the conditions for the addition reaction include: a temperature of 10-40°C and a reaction time of 3-14 h; And / or, the second post-processing method includes: second extraction and separation, second concentration, second crystallization, second washing A, second drying A, second pulping, second washing B, and second drying C.

5. The preparation process of ruxolitinib phosphate according to claim 1, characterized in that, In step S3, the resolving reagent is selected from D-(+)-DBTA and / or D-(+)-DBTA·H2O; And / or, the third solvent is selected from alkyl alcohol solvents; And / or, based on the molar amount of the third intermediate, the amount of the resolving agent is 0.9-1.2 equivalents. And / or, the amount of the third solvent used is: 6 to 12 mL of the third solvent for every 1 g of the third intermediate; And / or, in step S3, the conditions for the chiral separation process include: stirring and dissolving at a temperature of 75±5℃, cooling down to 40-45℃, stirring and maintaining the temperature for 1-3 hours, then cooling down to 15±5℃ and stirring for at least 8 hours; And / or, in step S3, the third post-processing steps include third filtration, third washing, third drying, and third crystallization.

6. The preparation process of ruxolitinib phosphate according to claim 5, characterized in that, The method for the third crystallization process includes: First crystallization: The solid obtained from the third drying was added to ethanol and stirred at 75±5℃ to dissolve. Then the temperature was lowered until a white solid precipitated. The mixture was kept at this temperature and stirred for 1.5~2.5h. The temperature was then lowered to 15±5℃ and stirred for 8~20h. The mixture was filtered, and the filter cake was washed with anhydrous ethanol at 15±5℃. The mixture was then vacuum dried at 40~50℃ to constant weight to obtain a white solid. Second recrystallization: The white solid obtained from the first crystallization was added to ethanol, heated to 75±5℃ and refluxed to dissolve, then cooled until the white solid precipitated, kept warm and stirred for 1.5~2.5h, cooled to 15±5℃ and stirred for 8~20h, filtered, the filter cake was washed with anhydrous ethanol at 15±5℃, and dried under vacuum at 40~50℃ to constant weight to obtain a white solid, which is the fourth intermediate.

7. The preparation process of ruxolitinib phosphate according to claim 1, characterized in that, The fourth solvent includes at least one of ethyl acetate, water, methanol, and tetrahydrofuran; And / or, the method for deprotection processing includes: (1) Add ethyl acetate, water and the fourth intermediate to the reaction flask in sequence, then add alkaline solution to adjust the pH to 8-9, extract, separate, wash and separate, concentrate to obtain solid; (2) The solid was dissolved in a mixture of methanol and tetrahydrofuran, and then an alkaline solution was added for deprotection treatment.

8. The preparation process of ruxolitinib phosphate according to claim 7, characterized in that, In step (1), the volume ratio of ethyl acetate to water is (1-3):1; And / or, in step (1), the amount of ethyl acetate used is: 10-20 mL of ethyl acetate for 1 g of the fourth intermediate; And / or, the alkaline solution is selected from at least one of sodium hydroxide aqueous solution, potassium carbonate aqueous solution, and potassium hydroxide aqueous solution; And / or, the concentration of the alkaline solution is 1M-3M.

9. The preparation process of ruxolitinib phosphate according to claim 1, characterized in that, The fifth solvent is selected from alcohol solvents; And / or, in step S5, the amount of the fifth solvent used is: 10-20 mL of the fifth solvent is used for 1 g of the fifth intermediate; And / or, in step S5, the conditions for the salt formation reaction include: reacting at 70±5℃ for 0.5 to 1.5 h, then cooling to 25±5℃ and stirring for 1.5 to 2.5 h; And / or, in step S5, the fifth post-processing steps include: fifth filtration, fifth washing A, fifth drying A, fifth pulping, fifth washing B, fifth drying B, fifth decolorization, fifth membrane filtration, fifth crystallization, fifth washing C, and fifth drying C.

10. The preparation process of ruxolitinib phosphate according to claim 9, characterized in that, The fifth pulping method includes: adding methanol to the solid obtained from the fifth drying A, pulping at a controlled temperature of 50~55℃ for 0.5~1.5h, cooling to 5±5℃, and stirring for 1.5~2.5h; And / or, the fifth decolorization method includes: adding crude ruxolitinib phosphate and methanol to a reaction flask, controlling the temperature at 55±5℃, stirring for 10 to 30 minutes, then adding activated carbon and stirring for 10 to 15 minutes, wherein the mass of the activated carbon is 3-6 wt% of the crude ruxolitinib phosphate.

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