A method for preparing a tinib drug intermediate

Abstract

The invention discloses a method for preparing a tinib drug intermediate, which can be used for the synthesis of multiple drugs, including ensartinib, crizotinib, etc. The method comprises a transition metal salt / chiral phosphine ligand catalytic system, and an asymmetric hydrogenation reaction to achieve asymmetric synthesis of a chiral alcohol intermediate. The method of the invention has simple steps, simple operation, mild conditions, rapid reaction, low pollution, high efficiency, and provides a new method for the efficient and green asymmetric hydrogenation synthesis of drugs such as ensartinib and crizotinib, and has great industrial application value.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemical synthesis, and specifically relates to a method for preparing a tinib drug intermediate, which can be used for the synthesis of multiple drugs, including ensartinib, crizotinib, etc. Background Art

[0002] Crizotinib, CAS No.: 877399-52-5 Molecular formula: C 21 H 22 Cl2FN5O molecular weight: 450.34, chemical name is 3-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine. Ensartinib, CAS No.: 1365267-27-1, molecular formula:

[0003] C 25 H 25 C l2 FN6O3, molecular weight: 547.41, chemical name is 6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-N-(4-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]carbonyl}phenyl)-3-pyridazinecarboxamide. The structural formulas are:

[0004]

[0005] Crizotinib and Ensartinib are both small molecule tyrosine kinase inhibitors (TKIs) targeting anaplastic lymphoma kinase (ALK), ROS1 and another oncogene receptor tyrosine kinase MET, used to treat locally advanced or metastatic non-small cell lung cancer (NSCLC) that is positive for anaplastic lymphoma kinase (ALK). Crizotinib is a targeted therapy for non-small cell lung cancer developed by Pfizer Pharmaceuticals in the United States. Its trade name is It was approved for marketing in the United States in August 2011 and was included in the international lung cancer treatment guidelines at the end of the year as a first-line drug for ALK-positive patients. The second-generation ALK inhibitor Ensartinib is superior to the first-generation crizotinib in all aspects. In June 2016, a global multicenter Phase 3 clinical trial was launched.

[0006] Currently, how to greenly and efficiently synthesize a single-configuration chiral alcohol intermediate (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol is the key to more effective synthesis of drugs such as ensartinib and crizotinib. Summary of the invention

[0007] The invention provides a method for preparing a tinib drug intermediate, which can be used for the synthesis of multiple drugs, including ensartinib, crizotinib and the like.

[0008] The invention proposes a new scheme for preparing chiral alcohol, a key intermediate for synthesizing crizotinib and ensartinib.

[0009] The present invention is implemented by the following technical solutions:

[0010] A method for preparing an intermediate by catalytic asymmetric hydrogenation, the reaction formula is as follows:

[0011]

[0012] Specifically, through the action of a chiral catalyst, in the presence of a base and hydrogen, 2,6-dichloro-3-fluoroacetophenone [Formula (1)] is subjected to an asymmetric hydrogenation reaction in a suitable solvent to generate a chiral alcohol intermediate (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol [Formula (2)];

[0013] The catalyst is obtained by complexing a chiral phosphine ligand with a transition metal precursor in a solvent, wherein the chiral phosphine ligand includes but is not limited to the following ligands L1-L12, and the structure is as follows:

[0014]

[0015] Among them, Ar represents phenyl, 4-methylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-dimethyl-4-methoxyphenyl, 3,4,5-trimethylphenyl, 3,5-di-tert-butylphenyl, 3,5-di-tert-butyl-4-methoxy, 3,5-di-tert-butyl-4-methyl; preferably L4.

[0016] As a preferred technical solution of the present invention, the solvent is one or more of methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, toluene, and 1,2-dichloroethane; preferably ethanol.

[0017] As a preferred technical solution of the present invention, the base is one or a mixture of any proportion of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate; preferably sodium carbonate.

[0018] As a preferred technical solution of the present invention, the reaction temperature of the asymmetric hydrogenation reaction is 20 to 120° C., the hydrogen pressure is 10 to 100 standard atmospheres (atm), and the reaction time is 1 to 120 hours.

[0019] As a preferred technical solution of the present invention, the catalyst is obtained by complexing a chiral phosphine ligand with a transition metal precursor in a solvent; the molar ratio of the transition metal salt to the chiral phosphine ligand is 0.5:1.0-1.2, the complex reaction temperature is 10-40°C, and the complex reaction time is 0.5-3 hours.

[0020] As a preferred technical solution of the present invention, the catalyst obtained by complexation is not separated but directly used for catalyzing asymmetric hydrogenation reaction.

[0021] As a preferred technical solution of the present invention, the transition metals include: Rh, Ru, Ir and Mn.

[0022] As a preferred technical solution of the present invention, suitable transition metal complexes include:

[0023] (Rh(NBD)2) + BF4 - ; [Rh(NBD)Cl]2; [Rh(COD)Cl]2; [Rh(COD)2]X; Rh(acac)(CO)2; Rh(ethylene)2(acac); (Rh(ethylene)2Cl)2; RhCl(PPh3)3; Rh(CO)2Cl2; (arene)X2(diphosphine); Ru(arylgroup)X2; Ru(R'COO)2(diphosphine); Ru(methallyl)2(diphosphine); Ru(arylgroup) n ; Ru(arylgroup)X2(diphosphine); RuCl2(COD); (Ru(COD)2) X ; (Ir(COD)Cl)2; Ir(COD))X; MnX2; Mn(acac)2.

[0024] In the above transition metal complexes, R' and R" can be alkyl, alkoxy or substituted alkyl, aryl is aryl, Ar can be 3,5-ditrifluoromethylbenzene or fluorobenzene; X is a counter anion, such as BF4 - , ClO4- , SbF6 - , PF6 - , CF3SO3 - ,RCOO - ,B(C6H3(CF3)2)4 - , Cl - ,Br - , I - ; L is the solvent.

[0025] As a preferred technical solution of the present invention, the usage amount of the base is 4%, when the substrate is 1 mmol, 0.04 mmol of the base is added.

[0026] As a preferred technical solution of the present invention, S / C = 2,000-100,000, when the substrate is 1 mmol, the amount of catalyst added is 0.5×10 -3 mmol-1×10 -5 mmol.

[0027] It is worth noting that the hydrogenation product can be directly subjected to subsequent reactions by removing the solvent, and then subjected to conventional post-treatment to obtain (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol [Formula (2)] with high yield and high optical purity.

[0028] In summary, the above technical solution has the characteristics of simple operation, fast reaction, low cost, high conversion rate and selectivity, atom economy, and environmental friendliness, and has extremely high industrial value. The tridentate ligand catalyst system using transition metal salt / chiral ferrocenylphosphine ligand has high stability and reactivity, which can improve or overcome the occurrence of catalyst deactivation caused by the coordination of the product to the catalyst metal center. Compared with other current technologies, the process is significantly advanced, the generation of intermediates and waste is significantly reduced, it is efficient and green, and suitable for industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Schematic diagram of the synthesis route of the present invention;

[0030] Figure 2 (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol 1 HNMR (600MHz,CDCl3) nuclear magnetic spectrum;

[0031] Figure 3 (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol 13 C NMR (151MHz,CDCl3) nuclear magnetic spectrum;

[0032] Figure 4(S)-1-(2,6-dichloro-3-fluorophenyl)ethanol 31 F NMR (243MHz, CDCl3) nuclear magnetic spectrum;

[0033] Figure 5 The liquid chromatography separation diagram is a diagram of racemic 1-(2,6-dichloro-3-fluorophenyl)ethanol and (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol. Specific implementation methods

[0034] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention more clear, the embodiments of the present invention will be explained below, but the present invention is not limited thereto.

[0035] The technical effect of the synthesis method of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol [Formula (2)] of the present invention is further illustrated by specific examples below.

[0036] Among them, O-SpiroPAP was obtained by the following literature method.

[0037] G.-Q.Chen, B.-J.Lin, J.-M.Huang, L.-Y.Zhao, Q.-S.Chen, S.-P.Jia, Q.Yin andX.Zhang, Journal of the American Chemical Society, 2018, 140, 8064-8068.

[0038] Example 1: Preparation of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol [Formula (2)]

[0039]

[0040] Reference Figure 1 , Synthesis of catalyst:

[0041] In a glove box, weigh (R)-O-SpiroPAP (L4, 8.3 mg, 0.011 mmol, 2.2 equiv.), [Ir(COD)Cl]2 (3.4 mg, 0.005 mmol, 1 equiv.), add 1 mL of ethanol, stir at room temperature for 1 hour, and prepare a catalyst (ligand metal complex) with a concentration of 0.01 mol / L;

[0042] Take the molar ratio of substrate to catalyst S / C = 10,000 as an example:

[0043] In a glove box, weigh the substrate 2,6-dichloro-3-fluoroacetophenone [Formula (1)] (207 mg, 1 mmol), add Na2CO3 (5.5 mg, 0.04 mmol), 1 mL ethanol (concentration 1 mmol / mL), and stir at room temperature for 1 hour to fully dissolve the substrate and base. In the glove box, add the above catalyst (10 μL, 1×10 -4 mmol), then the reaction bottle was transferred to the autoclave, the autoclave was tightened, and the autoclave was removed from the glove box. After replacing the autoclave body with 10atm H2 three times, 60atm H2 was filled into the autoclave and the autoclave was immediately sealed. After stirring at 60°C for 48 hours, the reaction was terminated. In the fume hood, the vent valve was opened and the hydrogen in the autoclave was slowly released. After simple purification, 205 mg of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol [Formula (2)] was obtained with a yield of 99%. The reaction solution was analyzed by liquid chromatography, and the ee value was>99%.

[0044] Example 2: Screening of asymmetric hydrogenation conditions for preparing (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol [Formula (2)]

[0045] According to the operation mode of Example 1, the reaction conditions for preparing (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol [Formula (2)] by asymmetric hydrogenation were screened, and the conditions such as ligand, base, solvent, etc. were optimized respectively. The results obtained are shown in Table 1:

[0046] Table 1 Asymmetric hydrogenation conditions screening a

[0047]

[0048]

[0049]

[0050] a Reaction conditions: 1 (1.0mmol), [Ir(COD)Cl]2 (0.25μmol), ligand (0.55μmol), base (0.04mmol), solvent (1mL); b Determined by 1 H NMR analysis of the crude reaction mixture; c Determined by HPLC analysis using a chiral stationary phase; dS / C=10,000, reaction temperature=30℃, time=24h; e S / C=10,000, reactiontemperature=60℃, time=48h.

[0051] Example 3: 200 g scale preparation of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol [Formula (2)] (S / C=50,000)

[0052] In a glove box, weigh the substrate 2,6-dichloro-3-fluoroacetophenone [Formula (1)] (207 g, 1 mol), add Na2CO3 (4.24 g, 0.04 mol), 500 mL ethanol (concentration 2 M), and stir at room temperature for 1 hour to fully dissolve the substrate and the base. In the glove box, use a syringe to add the catalyst (2 mL, 0.01 mmol) prepared in Example 1 to the substrate solution, then transfer the reaction bottle to the autoclave, tighten the autoclave, and move the autoclave out of the glove box. After replacing the autoclave body with 10 atm H2 three times, fill the autoclave with 80 atm H2 and then seal the autoclave. After stirring at 60 ° C for 48 hours, terminate the reaction. In a fume hood, open the vent valve and slowly release the hydrogen in the autoclave. After simple purification, 208 g of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol [Formula (2)] was obtained with a yield of 99.5%. The reaction solution was analyzed by liquid chromatography, and the ee value was >99%.

[0053] Example 4: Kilogram-scale preparation of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol [Formula (2)] (S / C = 100,000)

[0054] In a 5L hydrogenation kettle, weigh the substrate 2,6-dichloro-3-fluoroacetophenone [Formula (1)] (1035g, 5mol), add Na2CO3 (21.2g, 0.20mol), 2500mL ethanol (concentration 2M), and stir at room temperature for 1 hour to fully dissolve the substrate and the base. Close the reaction kettle, fully replace the argon in the hydrogenation kettle, and when the oxygen analyzer shows that the oxygen content is less than 100ppm, add the catalyst (5mL, 0.01mmol) prepared in Example 1 to the reaction system through a pipeline, replace the kettle body with 5atm H2 three times, fill the autoclave with 80atm H2, stir at 60°C for 72 hours, and take samples to track the reaction until the raw material is completely converted. Carefully open the vent valve to slowly release the hydrogen in the kettle. After discharging the materials and concentrating the solvent under reduced pressure, and then simply purifying, 1025 g of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol [Formula (2)] was obtained with a yield of 98%. The reaction solution was analyzed by liquid chromatography, and the ee value was >99%.

[0055] The NMR and optical rotation data of the product (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol [Formula (2)] are as follows:

[0056] (S)-1-(2,6-dichloro-3-fluorophenyl)ethan-1-ol

[0057]

[0058] 1 H NMR (600MHz, CDCl3) δ7.29–7.24(m,1H),7.05–7.00(m,1H),5.58(dq,J=9.5,6.9Hz,1H),2.92(d,J=9.9Hz,1H),1.65(d,J=6.9Hz,3H). 13 C NMR (151MHz, CDCl3) δ158.13,156.48,140.55,129.67,129.62,128.30,128.28,121.47,121.34,115.77,115.61,68.45,68.44,21.37.

[0059] For details of NMR spectra, see Figure 2-4 .

[0060] Optical rotation:[α] D 25 = +5.2 (c = 1.00, MeOH).

[0061] The UPLC determination method is as follows: Chiral AD-3 column, 254 nm, 25° C., n-hexane:i-PrOH=95:5; flow 0.5 mL / min; t R (major) = 3.37min. For its liquid chromatogram, see Figure 5 .

[0062] The above description is only the preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention includes but is not limited to various changes and variations in specific implementation conditions such as reaction temperature and reaction time. Any modification, equivalent substitution, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing an intermediate by catalytic asymmetric hydrogenation, characterized in that: The reaction formula is as follows: Specifically, through the action of a chiral catalyst, in the presence of a base and hydrogen, 2,6-dichloro-3-fluoroacetophenone [Formula (1)] is subjected to an asymmetric hydrogenation reaction in a solvent to generate a chiral alcohol intermediate (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol [Formula (2)]; The catalyst is obtained by complexing a chiral phosphine ligand with a transition metal precursor in a solvent, wherein the chiral phosphine ligand includes ligand L4 or L9, and the structure is as follows: Wherein, Ar represents phenyl, 3,5-di-tert-butylphenyl; The solvent is methanol, ethanol or toluene; The base is sodium carbonate, potassium carbonate or cesium carbonate; The transition metal complex is (Ir(COD)Cl)2.

2. The preparation method according to claim 1, characterized in that: The reaction temperature of the asymmetric hydrogenation reaction is 20 to 120° C., the hydrogen pressure is 10 to 100 atmospheres, and the reaction time is 1 to 120 hours.

3. The preparation method according to claim 1, characterized in that: The catalyst is obtained by complexing a chiral phosphine ligand with a transition metal precursor in a solvent, the molar ratio of the transition metal precursor to the chiral phosphine ligand is 0.5:1.0-1.2, the complexing reaction temperature is 10-40°C, and the complexing reaction time is 0.5-3 hours.

4. The method according to claim 3, characterized in that The catalyst obtained by complexation is not separated and is directly used for catalyzing asymmetric hydrogenation reaction.

5. The method according to any one of claims 1 to 4, characterized in that: S / C = 2,000-100,000.

Images