Preparation method of rucotinib phosphate intermediate

Abstract

The invention discloses a preparation method of a rucotinib phosphate intermediate. The method comprises the step of preparing an intermediate compound shown as a formula II from a compound shown as a formula I under an acidic condition. The method has the advantages of low cost, simple post-treatment and simple operation, avoids the use of expensive coupling metal reagents, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry. Specifically, the present invention relates to a method for preparing an intermediate of ruxolitinib phosphate. Background Art

[0002] The chemical name of ruxolitinib phosphate is: ( R )-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile phosphate, and its English name is: ( R )-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile phosphate. Trade name: Jakavi. The structural formula is as follows:

[0003] Ruxolitinib phosphate, a highly selective inhibitor targeting protein tyrosine kinases JAK1 and JAK2, was jointly developed by Incyte Corporation in the United States and Novartis AG in Switzerland. It can be used for the treatment of patients with intermediate-risk or high-risk primary myelofibrosis, myelofibrosis secondary to polycythemia vera, and myelofibrosis secondary to essential thrombocythemia. It was approved for marketing by the US Food and Drug Administration (FDA) in 2011, by the European Medicines Agency (EMA) in 2012, by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan in 2014, and by the China National Medical Products Administration (NMPA) in 2017. It is currently the only drug approved for the treatment of myelofibrosis in China. At present, many patents have reported the preparation methods of ruxolitinib phosphate, but mainly two preparation methods are applied in industrialization, which are respectively disclosed in Patent CN102348693B and Patent CN108699063B.

[0004] The preparation method disclosed in Patent CN102348693 involves palladium-catalyzed coupling to prepare Compound 1. The catalyst dosage is extremely low, and the reaction conditions are harsh to control. At the same time, this preparation method uses a chiral column to separate the target chiral compound 2, and the protecting group removal conditions are cumbersome. Therefore, the production cycle is long, the cost is high, and the process control is difficult.

[0005]

[0006] The preparation method disclosed in Patent CN108699063B uses Compound 3 to obtain Compound 4 through the Vilsmeier formylation reaction, and then reacts with the chiral fragment 5 to prepare Compound 6. Finally, the carboxylic acid functional group is converted into a cyano group to prepare ruxolitinib phosphate. This method avoids chiral column separation, but involves multiple steps of functional group transformation. At the same time, the preparation of Compound 3 requires the use of a palladium catalyst and water-sensitive methylmagnesium reagent, which is not easy to operate and has safety risks.

[0007]

[0008] Patent CN116761792A also discloses a similar preparation method, but still requires the use of water-sensitive methylmagnesium reagent, has high requirements for production scale-up, and a relatively large cost share.

[0009]

[0010] The above methods also have problems such as difficulty in preparing chiral products, low atomic utilization rate, and complex operations, which are not suitable for industrial production. The present invention aims to provide a preparation method of a key intermediate of ruxolitinib phosphate that is safer, more environmentally friendly, lower in cost, and more suitable for industrial production. Summary of the Invention

[0011] In view of the deficiencies and defects of the prior art, the present invention provides a preparation method of a ruxolitinib phosphate intermediate, which is Compound II. This method eliminates heavy metals and Grignard reagents in the prior art and has the advantages of green efficiency, low cost, and simple operation.

[0012] To achieve the above-mentioned invention objectives, the present invention provides the following technical solutions.

[0013] The present invention provides a preparation method of a Compound II, which comprises the following steps: Under acidic conditions, Compound III reacts to obtain Compound IV.

[0014]

[0015] In the formula, R is hydrogen or an amino protecting group, R1 and R2 are each independently hydrogen or a C1-6 alkyl group or an aryl group, or R1 and R2 together with the atoms to which they are commonly attached form a 4-6 membered heterocyclic group containing 1 or 2 heteroatoms.

[0016] In some embodiments, in the above preparation method of the present invention, the acidic conditions are provided by adding an acidic reagent, and the acidic reagent is sulfuric acid, hydrochloric acid, or hydrobromic acid, or a mixture thereof, preferably hydrochloric acid.

[0017] In some embodiments, in the preparation method of the present invention described above, the mass ratio (value) of the acidic reagent to Formula I is 1.5 to 10, preferably 2.0.

[0018] In some embodiments, in the preparation method of the present invention described above, the reaction is completed in a solvent selected from N,N-dimethylformamide, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, water, and any mixture thereof, and the preferred solvent is water.

[0019] In some embodiments, in the preparation method of the present invention described above, the reaction temperature is 80 - 100 °C, preferably 90 - 100 °C.

[0020] In some embodiments, in the preparation method of the present invention described above, preferably, R1 and R2 are each independently ethyl or methyl, and R is an amino protecting group selected from benzyloxycarbonyl, acetyl, pivaloyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, phenylsulfonyl, methanesulfonyl, and trifluoromethanesulfonyl.

[0021] The preparation method of the present invention does not use precious metals such as palladium, reducing the production cost. At the same time, it avoids using unstable Grignard reagents, making the operation simpler; and in the preparation method of the present invention, the reaction product only needs to be simply treated and filtered to obtain a high-purity product, with lower cost, high yield, and being more suitable for industrial production. Description of the Drawings

[0022] Figure 1 1H-NMR spectrum of the compound II-1 sample of Example 1 1 1H-NMR spectrum; Figure 2 1H-NMR spectrum of the compound II-1 sample of Example 1 13 13C-NMR spectrum; Figure 3 1H-NMR spectrum of the compound II-2 sample of Example 3 1 1H-NMR spectrum; Figure 4 1H-NMR spectrum of the compound II-2 sample of Example 3 13 13C-NMR spectrum. Detailed Description of the Embodiments

[0023] The following examples provide further non-limiting detailed descriptions of the technical solutions of the present application. They should not be considered as limiting the scope of the present application, but only as exemplary illustrations and typical representatives of the present application. Solvents, reagents, raw materials, etc. used in the present application are all commercially available chemically pure or analytically pure products.

[0024] Example 1 Preparation of Compound II-1

[0025] 10.00 g of Compound I-1 was added to 15 mL of water, and then 20.00 g of concentrated hydrochloric acid was added. After the addition, the temperature was raised to 90 - 100 °C and the reaction was carried out for 3 h. After 3 h, the temperature was lowered to room temperature, and the pH was adjusted to 12 with 20% aqueous sodium hydroxide solution. Stirring was continued for 0.5 h and then filtration was carried out. The wet product was mixed with 100 mL of water at room temperature and stirred for 0.5 h, followed by filtration. Drying at 80 °C gave Compound II-1, 6.00 g, with a yield of 90% and a liquid phase purity of 99%.

[0026] Example 2 Preparation of Compound II-1

[0027] 10.00 g of Compound I-2 was added to 15 mL of water, and then 20.00 g of concentrated hydrochloric acid was added. After the addition, the temperature was raised to 90 - 100 °C and the reaction was carried out for 3 h. After 3 h, the temperature was lowered to room temperature, and the pH was adjusted to 12 with 20% aqueous sodium hydroxide solution. Stirring was continued for 0.5 h and then filtration was carried out. The wet product was mixed with 100 mL of water at room temperature and stirred for 0.5 h, followed by filtration. Drying at 80 °C gave Compound II-1, 6.34 g, with a yield of 89% and a liquid phase purity of 99%.

[0028] Example 3 Preparation of Compound II-1

[0029] 10.00 g of Compound I-3 was added to 15 mL of water, and then 20.00 g of concentrated hydrochloric acid was added. After the addition, the temperature was raised to 90 - 100 °C and the reaction was carried out for 3 h. After 3 h, the temperature was lowered to room temperature, and the pH was adjusted to 12 with 20% aqueous sodium hydroxide solution. Stirring was continued for 0.5 h and then filtration was carried out. The wet product was mixed with 100 mL of water at room temperature and stirred for 0.5 h, followed by filtration. Drying at 80 °C gave Compound II-1, 6.21 g, with a yield of 90% and a liquid phase purity of 99%.

[0030] Example 4 Preparation of Compound II-2

[0031] 10.00 g of Compound I-4 was added to 15 mL of water, and then 20.00 g of concentrated hydrochloric acid was added. After the addition, the temperature was raised to 90 - 100 °C and the reaction was carried out for 3 h. After 3 h, the temperature was lowered to room temperature, and the pH was adjusted to 6 - 7 with 20% aqueous sodium hydroxide solution. Stirring was continued for 0.5 h and then filtration was carried out. Drying at 60 °C gave Compound II-2, 3.36 g, with a yield of 75% and a liquid phase purity of 99%.

[0032] Example 5 Preparation of Compound II-3

[0033] 10.00 g of Compound I-5 was added to 15 mL of water, and then 20.00 g of concentrated hydrochloric acid was added. After the addition, the temperature was raised to 90 - 100 °C and the reaction was carried out for 3 h. After 3 h, the temperature was lowered to room temperature, the pH was adjusted to 12 with 20% aqueous sodium hydroxide solution, and stirring was continued for 0.5 h followed by suction filtration. The product was dried at 60 °C to obtain 4.67 g of Compound II-3 with a yield of 85% and a liquid phase purity of 99%.

[0034] Example 6 Preparation of Compound II-1

[0035] 10.00 g of Compound I-I was added to 30 mL of water, and then 10.00 g of sulfuric acid was added. After the addition, the temperature was raised to 90 - 100 °C and the reaction was carried out for 3 h. After 3 h, the temperature was lowered to room temperature, the pH was adjusted to 12 with 20% aqueous sodium hydroxide solution, and stirring was continued for 0.5 h followed by suction filtration. The product was dried at 80 °C to obtain 5.60 g of Compound II-I with a yield of 84% and a liquid phase purity of 99%.

[0036] Example 7 Preparation of Compound II-1

[0037] 10.00 g of Compound I-1 was added to 10 mL of water, and then 20.00 g of concentrated hydrochloric acid was added. After the addition, the temperature was raised to 80 °C and the reaction was carried out for 10 h. After 10 h, the temperature was lowered to room temperature, the pH was adjusted to 12 with 20% aqueous sodium hydroxide solution, and stirring was continued for 0.5 h followed by suction filtration. The wet product was mixed with 100 mL of water at room temperature and stirred for 0.5 h followed by suction filtration. The product was dried at 80 °C to obtain 4.87 g of Compound II-1 with a yield of 73% and a liquid phase purity of 98%.

[0038] Example 8 Preparation of Compound II-1

[0039] 10.00 g of Compound I-1 was added to 40 mL of water, and then 80.00 g of concentrated hydrochloric acid was added. After the addition, the temperature was raised to 90 - 100 °C and the reaction was carried out for 3 h. After 3 h, the temperature was lowered to room temperature, the pH was adjusted to 12 with 20% aqueous sodium hydroxide solution, and stirring was continued for 0.5 h followed by suction filtration. The wet product was mixed with 100 mL of water at room temperature and stirred for 0.5 h followed by suction filtration. The product was dried at 80 °C to obtain 6.00 g of Compound II-1 with a yield of 90% and a liquid phase purity of 99%.

[0040] Example 9 Preparation of Compound II-1

[0041] 10.00 g of Compound I-1 was added to 5.0 mL of 1,4-dioxane, and then 20.00 g of concentrated hydrochloric acid was added. After the addition, the temperature was raised to 90 - 100 °C and the reaction was carried out for 3 h. After 3 h, the temperature was lowered to room temperature, and the pH was adjusted to 12 with 20% aqueous sodium hydroxide solution. Stirring was continued for 0.5 h and then filtration was carried out. The wet product was mixed with 100 mL of water at room temperature and stirred for 0.5 h, followed by filtration. Drying at 80 °C gave 5.53 g of Compound II-1 in 83% yield with a liquid phase purity of 99%.

Claims

1. A preparation method of a ruxolitinib phosphate intermediate of formula II, comprising, The compound of formula I is reacted under acidic conditions to obtain the compound of formula II, ， wherein R is selected from hydrogen or an amino protecting group, R1 and R2 are each independently selected from hydrogen, C1-6 alkyl and aryl, or, R1 and R2 together with the atoms to which they are commonly attached form a 4-6 membered heterocyclic group containing 1 or 2 heteroatoms.

2. The preparation method according to claim 1, wherein the acidic conditions are provided by an acidic reagent.

3. The preparation method according to claim 2, wherein the acidic reagent is selected from one or more of sulfuric acid, hydrochloric acid and bromic acid.

4. The preparation method according to claim 3, wherein the acidic reagent is hydrochloric acid.

5. The preparation method according to any one of claims 2-4, wherein the mass ratio of the acidic reagent to the compound of formula I is 1.5 to 10.

6. The preparation method according to claim 5, wherein the mass ratio of the acidic reagent to the compound of formula I is 2.

0.

7. The preparation method according to claim 1, wherein the reaction is completed in a solvent selected from one or more of N,N-dimethylformamide, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide and water, and the preferred solvent is water.

8. The preparation method according to claim 1, wherein the reaction temperature is 80 to 100 °C, preferably 90 to 100 °C.

9. The preparation method according to claim 1, wherein R1 and R2 are each independently ethyl or methyl.

10. The preparation method according to claim 1, wherein the amino protecting group is selected from benzyloxycarbonyl, acetyl, pivaloyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, phenylsulfonyl, methanesulfonyl, trifluoromethanesulfonyl.

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