Method for synthesizing rusotinib intermediate through asymmetric hydrogenation

Abstract

The invention provides a method for synthesizing a rusotinib intermediate through asymmetric hydrogenation, which comprises the following specific steps: complexing a metal precursor and a ligand in a second solvent in an inert atmosphere to generate a catalyst; in a hydrogen atmosphere, in a first solvent, a compound shown as a formula (I) reacts under the catalysis of a catalyst to prepare a compound shown as a formula (II). The rusotinib is prepared through efficient asymmetric catalysis of an Rh reagent, the conversion rate reaches 99%, the ee value reaches 99% or above, the usage amount of the catalyst is small, the TON of the catalyst is high, high regioselectivity and high enantioselectivity are achieved, and reference is provided for industrialization of rusotinib bulk drugs. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of hydrogenation catalysis and relates to a method for synthesizing a ruxolitinib intermediate by asymmetric hydrogenation. Background Art

[0002] Ruxolitinib is an oral JAK1 and JAK2 tyrosine kinase inhibitor, developed jointly by Incyte and Novartis, and approved by the FDA in 2011 for the treatment of bone marrow cancer (myelofibrosis). Ruxolitinib phosphate is a heteroaryl-substituted pyrrolo[2,3-d]pyrimidine, also known as 3(R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile phosphate, and (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile phosphate, which inhibits Janus-associated kinases (JAKs) JAK1 and JAK2. These kinases mediate the signaling of multiple cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves the recruitment of cytokine receptors, activation of STATs (signal transducers and activators of transcription), and subsequent localization of STATs to the nucleus, leading to the regulation of gene expression.

[0003] Ruxolitinib is (R)-3-cyclopentyl-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-H-pyrazol-1-yl)propionitrile, and its structural formula is: It is of great significance to develop an efficient, economical, green and industrially scalable synthetic method to prepare ruxolitinib and even ruxolitinib intermediates.

[0004] Patent W02010083283A2 reports the following synthetic route:

[0005] This route uses cyclopentylcarboxaldehyde as the starting material, and sequentially undergoes seven steps: Witting reaction, Michael addition, oxidation reaction, hydrolysis and amidation, dehydration elimination, Still coupling, and Suzuki coupling to obtain the target product, ruxolitinib. The biggest disadvantage of this route is that the preparation conditions of the catalyst used in the Michael addition step are harsh and the efficiency of the asymmetric addition reaction is low, so it is not suitable for industrial production.

[0006] The document (US2010\0190981A1) reports a method for preparing ruxolitinib, first preparing a mixed ruxolitinib, and then separating ruxolitinib by preparative chromatography. This method cannot be used for industrial production; the document (US2010\0190981A1) also reports a method for preparing (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile by asymmetric hydrogenation, and the route is as follows:

[0007] The route is long, the asymmetric catalyst is difficult to prepare, the conditions are demanding, and the catalyst cost is high.

[0008] A journal article (Org. Lett. 2009, 11, 9, 1999) discloses a method for preparing ruxolitinib, which first prepares a ruxolitinib precursor and then obtains ruxolitinib through asymmetric catalysis. The ee value and conversion rate obtained are not ideal, as follows:

[0009] Therefore, it is of great significance to develop an efficient synthetic method to prepare ruxolitinib intermediates. Summary of the invention

[0010] In view of this, the purpose of the present invention is to provide a method for synthesizing a ruxolitinib intermediate by asymmetric hydrogenation, which is prepared by highly efficient asymmetric catalysis using an Rh reagent, with a conversion rate of 99%, and an ee value of more than 99%, a small amount of catalyst used, and a high turnover number (TON) of the catalyst, achieving high regioselectivity and high enantioselectivity, providing a reference for the industrialization of ruxolitinib API.

[0011] In order to achieve the above technical objectives, on the one hand, the present invention provides a method for synthesizing a Ruxolitinib intermediate by asymmetric hydrogenation, and the specific steps are as follows:

[0012] Under a hydrogen atmosphere, in a first solvent, the compound represented by formula (I) is reacted under the catalysis of a catalyst to obtain a compound represented by formula (II).

[0013] Furthermore, the catalyst is configured in a manner that a ligand and a metal precursor are complexed in a second solvent.

[0014] Furthermore, the ligand is selected from at least one of Zhaophos and its derivatives.

[0015] Further, the ligand is selected from at least one of Zhaophos, N-Me-zhaophos, 4-F-ph-zhangphos, Cy-zhaophos, 2-Nap-zhaophos, and DTBM-zhaophos. Further, the ligand can also be selected from at least one of (S)-binap, (Sc,Rp)-DuanPhos, (R,S)-JosiPhos, (S,S)-Me-DuPhos, (S)-SePhos, (S)-C3-tunePhos, (R,R)-QuinoxP, (R,S,R,R)-ZhangPhos, (S)-BINAP, (R,R)-DIOP, (R,R)-Ph-BPE, (S,S)-QuinoxP*, and (R)-(+)-SEGPhos.

[0016] Furthermore, the first solvent is selected from at least one of dichloromethane, tetrahydrofuran, methanol, dioxane, toluene, ethyl acetate, isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, and dioxane.

[0017] Further, the gas pressure of the hydrogen is 50-85 bar. Further, the gas pressure of the hydrogen is selected from at least one of 50, 55, 60, 65, 70 and 85 bar.

[0018] Furthermore, the catalyst is configured in an inert atmosphere, and the inert atmosphere refers to an argon atmosphere or a nitrogen atmosphere.

[0019] Furthermore, the second solvent is selected from at least one of dichloromethane, tetrahydrofuran, methanol, dioxane, toluene, ethyl acetate, isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, and dioxane.

[0020] Furthermore, the metal precursor is selected from at least one of [Rh(COD)2]BF4, [Rh(NBD)2]BF4, [Ir(COD)Cl]2, [Rh(COD)CH3]2, [Rh(COD)2]OTf, [Rh(COD)2BArF, and [Rh(COD)Cl]2.

[0021] Furthermore, the molar ratio of the metal precursor to the ligand is 1:1-1.5, preferably 1:1.1.

[0022] Furthermore, the molar ratio of the compound represented by formula (I) to the metal precursor is 100:1-10, preferably 100:1, 50:1, 20:1.

[0023] Furthermore, during the reaction of the compound represented by formula (I), a boron trifluoride tetrahydrofuran complex needs to be added to increase the conversion rate of the product.

[0024] Furthermore, the reaction temperature is 25-60°C, preferably 35, 40 or 50°C.

[0025] Furthermore, the reaction time is 10 to 30 hours, preferably 24 hours.

[0026] Furthermore, after the reaction is completed, post-treatment is performed to obtain the compound represented by formula (II). Furthermore, the post-treatment refers to filtering the mixture after the reaction is completed through diatomaceous earth and then removing the solvent.

[0027] Compared with the prior art, the present invention has the following beneficial effects The preparation strategy of the present invention uses Rh catalyst to catalyze hydrogenation in one step to prepare the stereochirality of the ruxolitinib intermediate, avoids difficult-to-obtain ligands, reduces production costs, and avoids the risk of heavy metal residues in post-treatment. At the same time, the prepared product has high conversion rate, high ee value, high stereoselectivity, simple purification, low process difficulty, mild reaction conditions, almost no by-products, high product quality, and is suitable for industrial production.

[0028] The substrate conversion rate of the invention reaches more than 99%, the ee reaches more than 99%, the reaction steps are few, the post-treatment is simple, the reaction conditions are mild, and no extremely cold or extremely hot conditions are required. While effectively simplifying the preparation process, the production efficiency and yield are greatly improved, and the invention is environmentally friendly and meets the requirements of green environmental protection.

[0029] Compared with the existing technology, the preparation process is simple and the cost is lower. The ee value of the obtained product is high. The reaction process is stable and controllable, and side reactions are not easy to occur. After the reaction is completed, it can be separated and purified by simple filtration. It is simple, efficient, and conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Proton spectrum of Ruxolitinib intermediate; Figure 2 Carbon spectrum of ruxolitinib intermediates. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0032] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0033] The technical solution of the present invention is illustrated below by way of example, and the scope of protection requested by the present invention includes but is not limited to the following embodiments.

[0034] Example 1 Screening of metal catalyst precursors and ligands Under argon atmosphere, catalyst precursor, ligand and dichloromethane (DCM, 0.5 mL) were added to a 4.0 mL bottle. The mixture was stirred at 25 ° C for 30 min in a glove box filled with argon to obtain an orange-red solution, which can be used directly for catalytic reaction. After that, 41.8 mg of ruxolitinib precursor (0.1 mmol) and 2 μL of boron trifluoride tetrahydrofuran complex were added to a glass test tube with a magnet, 1 ml of dichloromethane was added under nitrogen protection, 100 microliters of 0.01M catalyst (S / C=100) was added, and 65 bar of hydrogen was filled, and the reaction was carried out at 50 ° C for 24 hours. After the reaction was completed, it was cooled to room temperature naturally, the hydrogen was carefully released, and the diatomaceous earth was filtered. After the filtrate was removed from the organic solvent, the specific conversion rate and ee value of the product were obtained as shown in Table 1.

[0035]

[0036]

[0037] Table 1

[0038] From the results in Table 1, it can be seen that when the metal catalyst precursor [Rh(NBD)2]BF4 is combined with the ligand Zhaophos or N-Me-zhaophos, a high ee value can be obtained when the metal catalyst precursor molar ratio is 0.2mmol, but the conversion rate is not high. When the metal catalyst precursor molar ratio is increased by 1mmol, not only the conversion rate is increased, but also the ee value is higher, and when the metal catalyst precursor [Rh(NBD)2]BF4 is combined with the ligand N-Me-zhaophos, the conversion rate reaches 43%.

[0039] Example 2 Screening of solvents In an argon atmosphere, catalyst precursor Rh(nbd)2BF4 (0.2 mol%, 1eq), ligand N-Me-Zhaophos (0.22 mol%, 1.1eq) and solvent (0.5 mL) were added to a 4.0 mL bottle. The mixture was stirred at 25°C for 30 min in a glove box filled with argon to obtain an orange-red solution, which can be used directly for catalytic reaction. After that, 41.8 mg of ruxolitinib precursor (0.1 mmol) and 2 μL of boron trifluoride tetrahydrofuran complex were added to a glass test tube with a magnet, 1 ml of dichloromethane was added under nitrogen protection, 100 microliters of 0.01M catalyst (S / C=100) was added, and 50 bar of hydrogen was filled, and the reaction was carried out at 35°C for 24 hours. After the reaction was completed, it was cooled to room temperature naturally, the hydrogen was carefully released, and the diatomaceous earth was filtered. The filtrate was freed of organic solvent to obtain the product. The results are shown in Table 2 below.

[0040]

[0041] Table 2

[0042] From the results in Table 2, it can be seen that when DCM is selected as the solvent, the conversion rate and ee value of the obtained product are the highest.

[0043] Example 3 Catalyst dosage screening Under argon atmosphere, catalyst precursor Rh(cod)2OTf, ligand N-Me-Zhaophos and dichloromethane (DCM, 0.5 mL) were added to a 4.0 mL bottle. The mixture was stirred at 25°C for 30 min in a glove box filled with argon to obtain an orange-red solution, which can be used directly for catalytic reaction. After that, 41.8 mg of ruxolitinib precursor (0.1 mmol) and 2 μL of boron trifluoride tetrahydrofuran complex were added to a glass test tube with a magnet, 1 ml of dichloromethane was added under nitrogen protection, 100 microliters of 0.01M catalyst (S / C=100) was added, and 65 bar of hydrogen was filled, and the reaction was carried out at 50°C for 24 hours. After the reaction was completed, it was cooled naturally to room temperature, the hydrogen was carefully released, and the diatomaceous earth was filtered. The filtrate was freed of organic solvent to obtain the product, as shown in Table 3.

[0044]

[0045] Table 3

[0046] From the results in Table 3, it can be seen that when the amount of catalyst increases, the conversion rate of the substrate is improved, and the ee value can be maintained above 98%. When the amount of catalyst reaches 2 mmol%, the conversion rate reaches a maximum of 99%, and the ee value no longer increases.

[0047] Example 4 Screening of Hydrogen Pressure In an argon atmosphere, catalyst precursor (2 mol%, 1eq), ligand N-Me-Zhaophos (2.2 mmol%, 1.1eq) and dichloromethane (DCM, 0.5 mL) were added to a 4.0 mL bottle. The mixture was stirred at 25°C for 30 min in a glove box filled with argon to obtain an orange-red solution, which can be used directly for catalytic reaction. After that, 41.8 mg of ruxolitinib precursor (0.1 mmol) and 2 μL of boron trifluoride tetrahydrofuran complex were added to a glass test tube with a magnet, 1 ml of dichloromethane was added under nitrogen protection, 100 microliters of 0.01M catalyst (S / C=100) was added, and hydrogen was charged, and the reaction was carried out at 50°C for 24 hours. After the reaction was completed, it was naturally cooled to room temperature, the hydrogen was carefully released, and the diatomaceous earth was filtered. The filtrate was freed of organic solvent to obtain the product. The specific results are shown in Table 4.

[0048]

[0049] Table 4

[0050] It can be seen from Table 4 that when the metal catalyst precursor is [Rh(NBD)2]BF4, the conversion rate is improved with the increase of hydrogen pressure, but when the increase value is 65bar, it is not much different from 80bar. When replaced with other metal catalyst precursors, it is more economical to use a pressure value of 65bar. When the metal catalyst precursor is [Rh(COD)2]OTf, the conversion rate reaches more than 99%, and the ee value is also more than 99%.

[0051] Example 5 Preparation of the compound of formula (I)

[0052] The synthesis was carried out with reference to the description in paragraphs

[0242] -

[0243] of the specification of patent CN116348467A. The obtained product is as follows: (E)-(4-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate: white solid. 1H NMR (600 MHz, CDCl3) δ8.97 (s, 1H), 8.92 (s, 1H), 8.46 (s, 1H), 7.50 (d, J = 3.7 Hz, 1H), 6.81 (d,J = 3.7 Hz, 1H), 6.25 (s, 2H), 5.22 (s, 1H), 3.59 (p, J = 8.5 Hz, 1H), 2.13 –2.04 (m, 2H), 1.83 – 1.69 (m, 4H), 1.57 – 1.48 (m, 2H), 1.15 (s, 9H). 13 C NMR (151 MHz, CDCl3) δ 178.3, 160.6, 152.1, 152.0, 149.8, 141.5, 129.9, 129.8,123.4, 116.5, 114.8, 101.0, 82.2, 65.7, 43.7, 38.8, 31.6, 26.8, 24.8. LC-MS(ESI) m / z: [M+H] + = 419.27 Example 6 Preparation of the compound of formula (II)

[0053] In an argon atmosphere, the catalyst precursor Rh(cod)2OTf (2.35 mg, 5×10 -3 mmol, 1eq), ligand N-Me-Zhaophos (5.5×10 -3 mmol, 1.1eq) and dichloromethane (DCM, 0.5 mL). The mixture was stirred at 25 ° C for 30 min in a glove box filled with argon to obtain an orange-red solution, which can be used directly for catalytic reaction. After that, 41.8 mg of ruxolitinib precursor (0.1 mmol) and 2 μL of boron trifluoride tetrahydrofuran complex were added to a glass test tube with a magnet, 1 ml of dichloromethane was added under nitrogen protection, 100 microliters of 0.01M catalyst (S / C=100) was added, and 65 bar of hydrogen was filled, and the reaction was carried out at 50 ° C for 24 hours. After the reaction was completed, it was cooled to room temperature naturally, the hydrogen was carefully released, and the diatomaceous earth was filtered. After removing the organic solvent from the filtrate, 42.0 mg of the product was obtained, with a yield of 99% and an enantioselectivity of 98% ee.

[0054] (R) -(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate: white solid, 99% NMR yield, 99% ee. 1 HNMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.30 (d, J = 11.5 Hz, 2H), 7.46 (d, J =3.7 Hz, 1H), 6.75 (d, J = 3.7 Hz, 1H), 6.24 (s, 2H), 4.25 (td, J = 9.4, 3.9Hz, 1H), 3.12 (dd, J = 17.0, 8.6 Hz, 1H), 2.94 (dd, J = 17.0, 3.9 Hz, 1H), 2.64 – 2.51 (m, 1H), 1.99 – 1.91 (m, 1H), 1.76 – 1.50 (m, 5H), 1.32 – 1.21 (m, 2H), 1.14 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 178.4, 152.0, 152.0, 150.9,140.0, 130.0, 129.2, 121.3, 116.7, 114.3, 101.2, 65.7, 64.3, 44.3, 38.8,30.1, 30.0, 26.8, 25.4, 24.7, 23.6. LC-MS (ESI) m / z: [M+H] + = 421.27 Comparative Example 1 The difference from entry 17 in Table 1 of Example 1 is that no boron trifluoride tetrahydrofuran complex is added during the preparation process. The conversion rate of the obtained product is only 20%, and the ee value is 99%.

[0055] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a Ruxolitinib intermediate by asymmetric hydrogenation, characterized in that: The steps of the method include: Under a hydrogen atmosphere, in a first solvent, the compound represented by formula (I) is reacted under the action of a catalyst to obtain a compound represented by formula (II), The catalyst is configured in such a way that a ligand is complexed with a metal precursor in a second solvent, wherein the ligand is selected from at least one of Zhaophos, N-Me-zhaophos, 4-F-ph-zhangphos, 2-Nap-zhaophos, DTBM-zhaophos, and Cy-Zhaophos, and the structure of the ligand is as follows: 。 2. The method according to claim 1, characterized in that: The metal precursor is selected from at least one of [Rh(COD)2]BF4, [Rh(NBD)2]BF4, [Ir(COD)Cl]2, [Rh(COD)CH3]2, [Rh(COD)2]OTf, [Rh(COD)2BArF, and [Rh(COD)Cl]2.

3. The method according to claim 1, characterized in that: The first solvent is selected from at least one of dichloromethane, tetrahydrofuran, methanol, dioxane, toluene, ethyl acetate, isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, and dioxane.

4. The method according to claim 1, characterized in that: The gas pressure of the hydrogen is 50-85 bar.

5. The method according to claim 1, characterized in that: The second solvent is selected from at least one of dichloromethane, tetrahydrofuran, methanol, dioxane, toluene, ethyl acetate, isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, and dioxane.

6. The method according to claim 1, characterized in that: The molar ratio of the metal precursor to the ligand is 1:1-1.

5.

7. The method according to claim 1, characterized in that: The molar ratio of the compound represented by formula (I) to the metal precursor is 100:1-10, preferably 100:1, 50:1, 20:

1.

8. The method according to claim 1, characterized in that: When the compound represented by the formula (I) is reacted, a boron trifluoride tetrahydrofuran complex needs to be added.

9. The method according to claim 1, characterized in that: The reaction temperature is 25-60° C.; the reaction time is 10-30 h.

10. The method according to claim 1, characterized in that: After the reaction is completed, post-treatment is performed to obtain the compound represented by formula (II). Furthermore, the post-treatment refers to filtering the mixture after the reaction through diatomaceous earth and removing the solvent.

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