Preparation method for Anti-tumor drug intermediate

Abstract

A preparation method for an anti-tumor drug intermediate, comprising the following step: when a monovalent copper salt is used as a catalyst and a pyrrolidinol compound is used as a ligand, a compound of formula II reacts with a compound of formula III, i.e., 4-morpholinopiperidine, to prepare a compound of formula I or a salt thereof. Compared with the prior art, the present application uses a monovalent copper catalyst and uses a pyrrolidinol compound as a ligand, thereby reducing the cost of a catalytic system, and increasing the yield. In addition, the reaction achieves a high purity and fewer impurities.

Description

A method for preparing an antitumor drug intermediate Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a method for preparing an alectinib intermediate compound of formula I or a salt thereof. Background Art

[0002] Alectinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) developed by Roche, USA, for the treatment of patients with ALK-positive locally advanced or metastatic non-small cell lung cancer.

[0003] Compound I is a key intermediate in the process route reported by the original research company (US9126931B2). This intermediate is prepared by the palladium-catalyzed carbon-nitrogen coupling reaction of an aryl iodide (II) and 4-morpholinopiperidine (III).

[0004] The amount of metal palladium catalyst used in the above reaction is 1.5% to 2.0%, which is relatively large, and metal palladium is expensive, which makes the preparation cost of compound (I) relatively large, thereby increasing the production cost of alectinib. In addition, the palladium catalytic system has strict requirements on anhydrous and oxygen-free conditions, and the industrial production operation is relatively difficult. In view of the defects of the existing process, a catalytic system with low cost and industrial application value is needed to prepare the key intermediate (I) of alectinib.

[0005] Patent CN115677659A discloses a reaction for preparing intermediate (I) from intermediate (II) using a copper catalyst. However, the yield of the product prepared using the copper catalyst and ligand in the patent is low and the reaction time is long, and a more efficient copper catalytic system is needed.

[0006] Summary of the Invention

[0007] In order to address the deficiencies of the prior art, the present invention provides a method for preparing an anti-tumor drug intermediate. This method can use a monovalent copper salt as a catalyst and a pyrrolidone compound as a ligand, thereby reducing the cost of the precious metal catalyst and improving the yield of the intermediate. Moreover, the process is simple, environmentally friendly, and easy to industrialize.

[0008] The technical solutions of the present invention are as follows:

[0009] A method for preparing an anti-tumor drug intermediate comprises the following steps:

[0010] Under the conditions of monovalent copper salt as catalyst and pyrrolidone compound as ligand, the compound of formula II reacts with the compound of formula III 4-morpholinopiperidine to prepare the compound of formula I or its salt.

[0011] Furthermore, the pyrrolidone compound has the following structure:

[0012] wherein R1 is H, methyl, ethyl, linear or branched C3-C5 alkyl, benzyl, phenyl, naphthyl, or substituted phenyl; the substituted phenyl has one of methyl, methoxy, and isopropyl at the ortho, meta, or para position;

[0013] R2 is H, methyl, ethyl, linear or branched C3-C5 alkyl, phenyl, benzyl, methoxy, ethoxy, and R2 is at any substitutable position of the pyrrole ring.

[0014] Furthermore, R1 is H, methyl, ethyl, linear or branched C3-C5 alkyl, or phenyl; R2 is H, methyl, ethyl, or phenyl, and R2 is located at any position among the 3-position, 4-position, and 5-position of the pyrrole ring.

[0015] Further, pyrrolidone compounds include:

[0016] Furthermore, the monovalent copper salt includes cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide or copper thiophene-2-carboxylate.

[0017] Furthermore, the molar ratio of the monovalent copper salt to the compound of formula II is 1:1-20.

[0018] Furthermore, the molar ratio of the monovalent copper salt to the compound of formula II is 1:1-15.

[0019] Furthermore, the reaction temperature is 80-130° C., and the reaction time is 1-15 hours.

[0020] Furthermore, the reaction temperature is 90-125° C., and the reaction time is 1-12 hours.

[0021] Furthermore, the reaction conditions also include a base, which includes triethylamine, diisopropylethylamine and 1,8-diazobispiro[5.4.0]undec-7-ene, potassium phosphate, potassium carbonate, cesium carbonate or potassium hydroxide, and the molar ratio of the base to the compound of formula II is 1 to 6:1.

[0022] Compared with the prior art, the present invention uses a monovalent copper catalyst and a pyrrolidone compound as a ligand, which reduces the cost of the catalytic system and improves the yield. Moreover, the reaction has high purity and relatively few impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 Hydrochloride of Formula I 1 H NMR spectrum;

[0024] Figure 2: Hydrochloride of Formula I Compound 13 C NMR spectrum;

[0025] Figure 3 HPLC spectrum of Example 1. DETAILED DESCRIPTION

[0026] A method for preparing an anti-tumor drug intermediate comprises the following steps:

[0027] Under the conditions of monovalent copper salt as catalyst and pyrrolidone compound as ligand, the compound of formula II reacts with the compound of formula III 4-morpholinopiperidine to prepare the compound of formula I or its salt.

[0028] Furthermore, the pyrrolidone compound has the following structure:

[0029] wherein R1 is H, methyl, ethyl, linear or branched C3-C5 alkyl, benzyl, phenyl, naphthyl, or substituted phenyl; the substituted phenyl has one of methyl, methoxy, and isopropyl at the ortho, meta, or para position;

[0030] R2 is H, methyl, ethyl, linear or branched C3-C5 alkyl, phenyl, benzyl, methoxy, ethoxy, and R2 is at any substitutable position of the pyrrole ring.

[0031] Preferably, R1 is H, methyl, ethyl, linear or branched C3-C5 alkyl, or phenyl; R2 is H, methyl, ethyl, or phenyl, and R2 is located at any position among the 3-position, 4-position, and 5-position of the pyrrole ring.

[0032] Preferably, the pyrrolidone compounds include:

[0033] Furthermore, the monovalent copper salt includes cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide or copper thiophene-2-carboxylate.

[0034] Furthermore, the molar ratio of the monovalent copper salt to the compound of formula II is 1:1 to 20. Preferably, the molar ratio of the monovalent copper salt to the compound of formula II is 1:1 to 15. Preferably, the molar ratio of the monovalent copper salt to the compound of formula II is 1:2 to 14. Further, the molar ratio of the monovalent copper salt to the compound of formula II is 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, or 1:14. If the amount of the monovalent copper salt and the pyrrolidone ligand is too small, the reaction of the compound of formula II may be incomplete.

[0035] The molar ratio of the monovalent copper salt to the pyrrolidone ligand is 1:1-5, preferably 1:1-3, further preferably 1:1, 1:2, or 1:3.

[0036] Furthermore, if the temperature is too low, the reaction of the compound of formula II is incomplete, and the yield is reduced. If the temperature is too high, the pyrrolidone compound A will decompose, resulting in incomplete reaction of the compound of formula II and an increase in by-products. The reaction temperature is 80-130°C, the reaction temperature is 90-125°C, and further, the reaction temperature is 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, and 125°C.

[0037] The reaction time is 1 to 15 hours. Preferably, the reaction time is 1 to 12 hours. The reaction time is 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours.

[0038] Furthermore, the reaction conditions also include a base, which includes triethylamine, diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene, potassium phosphate, potassium carbonate, cesium carbonate, or potassium hydroxide, and the molar ratio of the base to the compound of Formula II is 1 to 6:1. Preferably, the base is triethylamine, potassium phosphate, potassium carbonate, cesium carbonate, or potassium hydroxide. Preferably, the molar ratio of the base to the compound of Formula II is 2 to 5:1, and further molar ratios are 2:1, 3:1, 4:1, and 5:1. If the amount of inorganic base used is too small, the reaction of the compound of Formula II may be incomplete, and if the amount of inorganic base used is too large, a large amount of impurities will be generated.

[0039] Furthermore, the organic solvent used is a polar aprotic solvent including acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropylene urea, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, or sulfolane. Preferably, N,N-dimethylacetamide, dimethyl sulfoxide, or sulfolane. These solvents are widely available and inexpensive.

[0040] Example 1

[0041] Cuprous iodide (1.14 g, 6.0 mmol), pyrrolidine ligand 2,2,2-trifluoro-1-(1H-pyrrol-2-yl)ethane-1-ol L1 (0.99 g, 6.0 mmol), tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylate (10.29 g, 20.0 mmol), 4-morpholinopiperidine (4.26 g, 25.0 mmol), and potassium carbonate (11.06 g, 80.0 mmol) were placed in a dry reaction flask under nitrogen protection. N,N-dimethylacetamide (120 mL) was added to the reaction flask, and the reaction solution was heated to 120°C and stirred for 12 hours. The reaction solution was cooled to room temperature, and isopropyl acetate (480 mL) and aqueous ammonium chloride solution (15%, 120 mL) were added and stirred at room temperature for 1 hour. The aqueous layer was removed, and a saturated aqueous sodium chloride solution (120 mL) was added to the organic phase, and the mixture was stirred at room temperature for 0.5 hours. The aqueous layer was removed, and the obtained organic phase was concentrated under reduced pressure at an external temperature of 50°C. The residue was dissolved in acetone (200 mL) and the internal temperature of the solution was raised to 35°C. Over 30 minutes, a mixture of ethanol (3.0 mL) of pyridine hydrochloride (2.54 g, 22.0 mmol) and acetone (6.0 mL) was added dropwise to crystallize the target product. The obtained slurry was placed at 0°C and stirred for 3 hours. The wet powder was filtered through a Buchner funnel and washed with acetone (50 mL). The wet powder was dried under reduced pressure at 40°C for 8 hours to obtain the hydrochloride salt of compound formula I (10.3 g, yield 86.8%, HPLC purity 99.1%). See Figure 1.

[0042] 1 H NMR (400MHz, DMSO): δ12.22(s,1H),11.50(s,1H),8.02-7.99(m,2H),7.45(dd,J1=8.4Hz,J 2=1.2Hz,1H),7.07(d,J=8.0Hz,1H),6.85(dd,J1=8.0Hz,J2=1.6Hz,1H),6.81(s,1H),3.94 (d,J=3.2Hz,4H),3.42(s,4H),3.20(t,J=11.6Hz,1H),3.01-2.98(m,4H),2.51-2.48(m,2H ), 2.15 (d, J = 10.80Hz, 2H), 1.88-1.81 (m, 8H), 1.18 (s, 9H), 1.13 (t, J = 7.60Hz, 3H) ppm; see Figure 1

[0043] 13C NMR (100 MHz, DMSO): δ 163.4, 155.6, 150.2, 147.1, 136.0, 133.4, 131.7, 128.6, 123.9, 121.8, 121.6, 120.8, 117.5, 117.1, 106.2, 103.2, 79.8, 63.6, 62.9, 51.5, 48.6, 42.2, 30.4, 28.1, 26.8, 22.8, 15.2 ppm; see Figure 2

[0044] ESI HRMS:C 34 H 44 The theoretical value of N4O3+H is 557.3492, and the measured value is 557.3496.

[0045] Example 2

[0046] Cuprous iodide (0.76 g, 4.0 mmol), pyrrolidine ligand 1,1,1-trifluoro-2-(1H-pyrrol-2-yl)propan-2-ol L2 (0.72 g, 4.0 mmol), tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylate (10.29 g, 20.0 mmol), 4-morpholinopiperidine (4.09 g, 24.0 mmol), and potassium phosphate (16.98 g, 80.0 mmol) were placed in a dry reaction flask under nitrogen protection. Sulfolane (100 mL) was added to the reaction flask, and the reaction solution was then heated to 110°C and stirred for 8 hours. The reaction solution was cooled to room temperature, and isopropyl acetate (400 mL) and aqueous ammonium chloride solution (15%, 60 mL) were added and stirred at room temperature for 1 hour. The aqueous layer was removed, and a saturated aqueous sodium chloride solution (100 mL) was added to the organic phase. The mixture was stirred at room temperature for 0.5 hours. The aqueous layer was removed, and the resulting organic phase was concentrated under reduced pressure at an external temperature of 50°C. The residue was dissolved in acetone (180 mL) and the internal temperature of the solution was raised to 35°C. A mixture of pyridine hydrochloride (2.54 g, 22.0 mmol) in ethanol (3.0 mL) and acetone (6.0 mL) was added dropwise over 30 minutes to crystallize the target compound. The resulting slurry was placed at 0°C and stirred for 3 hours. The mixture was filtered through a Buchner funnel to obtain a wet powder, which was then washed with acetone (40 mL). The wet powder was dried under reduced pressure at 40°C for 6 hours to obtain the hydrochloride salt of compound Formula I (11.6 g, yield 97.8%, HPLC purity 98.7%).

[0047] Example 3

[0048] Cuprous iodide (0.57 g, 3.0 mmol), pyrrolidine ligand 2,2,2-trifluoro-1-phenyl-1-(1H-pyrrol-2-yl)ethane-1-ol L3 (0.73 g, 3.0 mmol), tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylate (6.17 g, 12.0 mmol), 4-morpholinopiperidine (3.07 g, 18.0 mmol), and potassium phosphate (10.19 g, 48.0 mmol) were placed in a dry reaction flask under nitrogen protection. Cyclopentane (60.0 mL) was added to the reaction flask, and the reaction solution was heated to 105°C and stirred for 5 hours. The reaction solution was cooled to room temperature, and isopropyl acetate (300 mL) and aqueous ammonium chloride solution (15%, 40 mL) were added and stirred at room temperature for 1 hour. The aqueous layer was removed, and a saturated aqueous sodium chloride solution (40 mL) was added to the organic phase, and the mixture was stirred at room temperature for 1 hour. The aqueous layer was removed, and the obtained organic phase was concentrated under reduced pressure at an external temperature of 50°C. The residue was dissolved in acetone (90 mL) and the internal temperature of the solution was raised to 35°C. Over 30 minutes, a mixture of ethanol (1.5 mL) of pyridine hydrochloride (1.53 g, 13.2 mmol) and acetone (3.0 mL) was added dropwise to crystallize the target product. The obtained slurry was placed at 0°C and stirred for 3 hours. The wet powder was filtered through a Buchner funnel and washed with acetone (30 mL). The wet powder was dried under reduced pressure at 50°C for 8 hours to obtain the hydrochloride salt of compound formula I (6.73 g, yield 94.5%, HPLC purity 99.0%).

[0049] Example 4

[0050] Cuprous iodide (0.38 g, 2.0 mmol), 1,1,1-trifluoro-3-phenyl-2-(1H-pyrrol-2-yl)propan-2-ol L5 (0.51 g, 2.0 mmol), 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylic acid tert-butyl ester (10.29 g, 20.0 mmol), 4-morpholinopiperidine (3.75 g, 22.0 mmol), and cesium carbonate (26.07 g, 80.0 mmol) were placed in a dry reaction flask under nitrogen protection. Dimethyl sulfoxide (80 mL) was added to the reaction flask, and then the reaction solution was heated to 110°C and stirred for 5 hours. The reaction solution was cooled to room temperature, and isopropyl acetate (320 mL) and aqueous ammonium chloride solution (15%, 40 mL) were added and stirred at room temperature for 1 hour. The aqueous layer was removed, and a saturated aqueous sodium chloride solution (80 mL) was added to the organic phase, and the mixture was stirred at room temperature for 0.5 hours. The aqueous layer was removed, and the obtained organic phase was concentrated under reduced pressure at an external temperature of 50°C. The residue was dissolved in acetone (180 mL) and the internal temperature of the solution was raised to 35°C. Over 30 minutes, a mixture of ethanol (3.0 mL) of pyridine hydrochloride (2.54 g, 22.0 mmol) and acetone (6.0 mL) was added dropwise to crystallize the target product. The obtained slurry was placed at 0°C and stirred for 3 hours. The wet powder was filtered through a Buchner funnel and washed with acetone (40 mL). The wet powder was dried under reduced pressure at 40°C for 5 hours to obtain the hydrochloride salt of compound formula I (11.4 g, yield 96.1%, HPLC purity 99.2%).

[0051] Example 5

[0052] Cuprous iodide (0.29 g, 1.5 mmol), 2,2,2-trifluoro-1-phenyl-1-(5-phenyl-1H-pyrrol-2-yl)ethane-1-ol L7 (0.48 g, 1.5 mmol), tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylate (10.29 g, 20.0 mmol), 4-morpholinopiperidine (3.75 g, 22.0 mmol), and potassium hydroxide (3.37 g, 60.0 mmol) were placed in a dry reaction flask under nitrogen protection. Dimethyl sulfoxide (70 mL) was added to the reaction flask, and the reaction solution was then heated to 100°C and stirred for 4 hours. The reaction solution was cooled to room temperature, and isopropyl acetate (280 mL) and aqueous ammonium chloride solution (15%, 40 mL) were added and stirred at room temperature for 1 hour. The aqueous layer was removed, and a saturated aqueous sodium chloride solution (70 mL) was added to the organic phase, and the mixture was stirred at room temperature for 0.5 hours. The aqueous layer was removed, and the obtained organic phase was concentrated under reduced pressure at an external temperature of 50°C. The residue was dissolved in acetone (150 mL) and the internal temperature of the solution was raised to 35°C. Over 30 minutes, a mixture of ethanol (3.0 mL) of pyridine hydrochloride (2.54 g, 22.0 mmol) and acetone (6.0 mL) was added dropwise to crystallize the target product. The obtained slurry was placed at 0°C and stirred for 3 hours. The wet powder was filtered through a Buchner funnel and washed with acetone (40 mL). The wet powder was dried under reduced pressure at 40°C for 5 hours to obtain the hydrochloride salt of compound formula I (10.8 g, yield 91.0%, HPLC purity 99.4%).

[0053] Example 6

[0054] Cuprous chloride (1.19 g, 12.0 mmol), 1,1,1-trifluoro-2-(1H-pyrrol-2-yl)propan-2-ol L2 (2.15 g, 12.0 mmol), tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylate (20.58 g, 40.0 mmol), 4-morpholinopiperidine (8.17 g, 48.0 mmol), and potassium carbonate (19.35 g, 140.0 mmol) were placed in a dry reaction flask under nitrogen protection. Dimethyl sulfoxide (120 mL) was added to the reaction flask, and the reaction solution was then heated to 105°C and stirred for 3 hours. The reaction solution was cooled to room temperature, and isopropyl acetate (360 mL) and aqueous ammonium chloride solution (15%, 60 mL) were added and stirred at room temperature for 1 hour. The aqueous layer was removed, and a saturated aqueous sodium chloride solution (120 mL) was added to the organic phase, and the mixture was stirred at room temperature for 0.5 hours. The aqueous layer was removed, and the obtained organic phase was concentrated under reduced pressure at an external temperature of 50°C. The residue was dissolved in acetone (250 mL) and the internal temperature of the solution was raised to 35°C. Over 30 minutes, a mixture of pyridine hydrochloride (5.08 g, 44.0 mmol) in ethanol (6.0 mL) and acetone (12.0 mL) was added dropwise to crystallize the target product. The obtained slurry was placed at 0°C and stirred for 3 hours. The wet powder was filtered through a Buchner funnel and washed with acetone (50 mL). The wet powder was dried under reduced pressure at 40°C for 6 hours to obtain the hydrochloride salt of compound formula I (22.2 g, yield 93.6%, HPLC purity 99.2%).

[0055] Example 7

[0056] Thiophene-2-carboxylate copper (0.76 g, 4.0 mmol), pyrrolidine ligand 1,1,1-trifluoro-2-(1H-pyrrol-2-yl)propan-2-ol L2 (0.72 g, 4.0 mmol), tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylate (20.58 g, 40.0 mmol), 4-morpholinopiperidine (8.17 g, 48.0 mmol), and triethylamine (14.17 g, 140.0 mmol) were placed in a dry reaction flask under nitrogen. N,N-dimethylacetamide (120 mL) was added to the reaction flask, and the reaction solution was heated to 115°C and stirred for 6 hours. The reaction solution was cooled to room temperature, and isopropyl acetate (360 mL) and aqueous ammonium chloride solution (15%, 60 mL) were added. The mixture was stirred at room temperature for 1 hour. The aqueous layer was removed, and a saturated aqueous sodium chloride solution (120 mL) was added to the organic phase, and the mixture was stirred at room temperature for 0.5 hours. The aqueous layer was removed, and the obtained organic phase was concentrated under reduced pressure at an external temperature of 50°C. The residue was dissolved in acetone (250 mL) and the internal temperature of the solution was raised to 35°C. Over 30 minutes, a mixture of pyridine hydrochloride (5.08 g, 44.0 mmol) in ethanol (6.0 mL) and acetone (12.0 mL) was added dropwise to crystallize the target product. The obtained slurry was placed at 0°C and stirred for 3 hours. The wet powder was filtered through a Buchner funnel and washed with acetone (50 mL). The wet powder was dried under reduced pressure at 40°C for 6 hours to obtain the hydrochloride salt of compound formula I (21.5 g, yield 90.6%, HPLC purity 98.7%).

[0057] Example 8

[0058] Cuprous oxide (1.72 g, 12.0 mmol), pyrrolidine ligand 1,1,1-trifluoro-2-(1H-pyrrol-2-yl)propan-2-ol L2 (2.15 g, 12.0 mmol), tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylate (20.58 g, 40.0 mmol), 4-morpholinopiperidine (8.17 g, 48.0 mmol), and triethylamine (14.17 g, 140.0 mmol) were placed in a dry reaction flask under nitrogen protection. Dimethyl sulfoxide (120 mL) was added to the reaction flask, and the reaction solution was heated to 105°C and stirred for 3 hours. The reaction solution was cooled to room temperature, and isopropyl acetate (360 mL) and aqueous ammonium chloride solution (15%, 60 mL) were added and stirred at room temperature for 1 hour. The aqueous layer was removed, and a saturated aqueous sodium chloride solution (120 mL) was added to the organic phase, and the mixture was stirred at room temperature for 0.5 hours. The aqueous layer was removed, and the obtained organic phase was concentrated under reduced pressure at an external temperature of 50°C. The residue was dissolved in acetone (250 mL) and the internal temperature of the solution was raised to 35°C. Over 30 minutes, a mixture of pyridine hydrochloride (5.08 g, 44.0 mmol) in ethanol (6.0 mL) and acetone (12.0 mL) was added dropwise to crystallize the target product. The obtained slurry was placed at 0°C and stirred for 3 hours. The wet powder was filtered through a Buchner funnel and washed with acetone (50 mL). The wet powder was dried under reduced pressure at 40°C for 6 hours to obtain the hydrochloride salt of compound formula I (22.8 g, yield 96.1%, HPLC purity 99.1%).

[0059] Example 9

[0060] Cuprous chloride (0.60 g, 6.0 mmol), pyrrolidine ligand 2,2,2-trifluoro-1-(1H-pyrrol-2-yl)ethane-1-ol L1 (0.99 g, 6.0 mmol), tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylate (20.58 g, 40.0 mmol), 4-morpholinopiperidine (8.17 g, 48.0 mmol), and potassium carbonate (16.59 g, 120.0 mmol) were placed in a dry reaction flask under nitrogen protection. Cyclopentane (120 mL) was added to the reaction flask, and the reaction solution was then heated to 105°C and stirred for 3 hours. The reaction solution was cooled to room temperature, and isopropyl acetate (360 mL) and aqueous ammonium chloride solution (15%, 60 mL) were added and stirred at room temperature for 1 hour. The aqueous layer was removed, and a saturated aqueous sodium chloride solution (120 mL) was added to the organic phase, and the mixture was stirred at room temperature for 0.5 hours. The aqueous layer was removed, and the obtained organic phase was concentrated under reduced pressure at an external temperature of 50°C. The residue was dissolved in acetone (250 mL) and the internal temperature of the solution was raised to 35°C. Over 30 minutes, a mixture of pyridine hydrochloride (5.08 g, 44.0 mmol) in ethanol (6.0 mL) and acetone (12.0 mL) was added dropwise to crystallize the target product. The obtained slurry was placed at 0°C and stirred for 3 hours. The wet powder was filtered through a Buchner funnel and washed with acetone (50 mL). The wet powder was dried under reduced pressure at 40°C for 6 hours to obtain the hydrochloride salt of compound formula I (23.1 g, yield 97.4%, HPLC purity 98.9%).

[0061] Example 10

[0062] Cuprous chloride (0.60 g, 6.0 mmol), pyrrol alcohol ligand 2,2,2-trifluoro-1-(1H-pyrrol-2-yl)ethane-1-ol L1 (0.99 g, 6.0 mmol), tert-butyl 6-cyano-2-(2-(4-ethyl-3-(((trifluoromethyl)sulfonyl)oxy)phenyl)propan-2-yl)-1H-indole-3-carboxylate (21.46 g, 40.0 mmol), 4-morpholinopiperidine (8.17 g, 48.0 mmol), and potassium carbonate (16.59 g, 120.0 mmol) were placed in a dry reaction flask under nitrogen protection. Cyclopentane (120 mL) was added to the reaction flask, and the reaction solution was then heated to 105°C and stirred for 3 hours. The reaction solution was cooled to room temperature, and isopropyl acetate (360 mL) and aqueous ammonium chloride solution (15%, 60 mL) were added, and stirred at room temperature for 1 hour. The aqueous layer was removed, and a saturated aqueous sodium chloride solution (120 mL) was added to the organic phase, and the mixture was stirred at room temperature for 0.5 hours. The aqueous layer was removed, and the obtained organic phase was concentrated under reduced pressure at an external temperature of 50°C. The residue was dissolved in acetone (250 mL) and the internal temperature of the solution was raised to 35°C. Over 30 minutes, a mixture of pyridine hydrochloride (5.08 g, 44.0 mmol) in ethanol (6.0 mL) and acetone (12.0 mL) was added dropwise to crystallize the target product. The obtained slurry was placed at 0°C and stirred for 3 hours. The wet powder was filtered through a Buchner funnel and washed with acetone (50 mL). The wet powder was dried under reduced pressure at 40°C for 6 hours to obtain the hydrochloride salt of compound formula I (22.7 g, yield 95.7%, HPLC purity 98.3%).

[0063] Example 11

[0064] Cuprous chloride (0.60 g, 6.0 mmol), pyrrolidine ligand 1,1,1-trifluoro-2-(1H-pyrrol-2-yl)propan-2-ol L2 (1.07 g, 6.0 mmol), tert-butyl 2-(2-(3-bromo-4-ethylphenyl)propan-2-yl)-6-cyano-1H-indole-3-carboxylate (18.70 g, 40.0 mmol), 4-morpholinopiperidine (8.17 g, 48.0 mmol), and potassium phosphate (33.97 g, 160.0 mmol) were placed in a dry reaction flask under nitrogen protection. Dimethyl sulfoxide (120 mL) was added to the reaction flask, and the reaction solution was heated to 120°C and stirred for 6 hours. The reaction solution was cooled to room temperature, and isopropyl acetate (360 mL) and aqueous ammonium chloride solution (15%, 60 mL) were added and stirred at room temperature for 1 hour. The aqueous layer was removed, and a saturated aqueous sodium chloride solution (120 mL) was added to the organic phase, and the mixture was stirred at room temperature for 0.5 hours. The aqueous layer was removed, and the obtained organic phase was concentrated under reduced pressure at an external temperature of 50°C. The residue was dissolved in acetone (250 mL) and the internal temperature of the solution was raised to 35°C. Over 30 minutes, a mixture of pyridine hydrochloride (5.08 g, 44.0 mmol) in ethanol (6.0 mL) and acetone (12.0 mL) was added dropwise to crystallize the target product. The obtained slurry was placed at 0°C and stirred for 3 hours. The wet powder was filtered through a Buchner funnel and washed with acetone (50 mL). The wet powder was dried under reduced pressure at 40°C for 6 hours to obtain the hydrochloride salt of compound formula I (20.3 g, yield 85.6%, HPLC purity 98.8%).

[0065] Example 12

[0066] Cuprous chloride (1.19 g, 12.0 mmol), pyrrolidine ligand 1,1,1-trifluoro-2-(1H-pyrrol-2-yl)propan-2-ol L2 (2.15 g, 12.0 mmol), 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylic acid tert-butyl ester (20.58 g, 40.0 mmol), 4-morpholinopiperidine (8.17 g, 48.0 mmol), and potassium phosphate (33.97 g, 160.0 mmol) were placed in a dry reaction flask under nitrogen protection. Dimethyl sulfoxide (120 mL) was added to the reaction flask, and the reaction solution was then heated to 110°C and stirred for 3 hours. The reaction solution was cooled to room temperature, and 2M NaOH aqueous solution (6.0 mL) was added to the reaction system and stirred at room temperature for 1 hour. The mixture was then filtered through a Buchner funnel and the filter cake was washed with dimethyl sulfoxide (20 mL). Under stirring at room temperature, 1M aqueous HCl (360 mL) was slowly added dropwise to the filtrate, causing a yellow solid to precipitate. The mixture was stirred at room temperature for 3 hours. The mixture was filtered and the filter cake was washed sequentially with water (100 mL) and acetone (100 mL). The wet powder was dried under reduced pressure at 40°C for 6 hours to obtain the hydrochloride salt of compound I (22.6 g, 95.2% yield, 98.2% HPLC purity).

[0067] Comparative Example

[0068] Subhajit Bhunia et al., "Selected Copper-Based Reactions for CN, CO, CS and CC Bond Formation" (Angew. Chem. Int. Ed. 2017, 56, 16136), discloses the use of a copper-catalyzed reaction system. Eight ligands (1a-1h) were investigated for use in a copper-catalyzed carbon-nitrogen bond coupling system to prepare alectinib intermediates (Formula I) or their salts. The reaction results are shown in Table 1. The complexes formed with cuprous iodide by these ligands were poorly catalytic, and aryl iodide (II) showed little reaction with 4-morpholinopiperidine (III).

[0069] Comparative Example 1

[0070] Cuprous iodide (0.74 g, 3.9 mmol) and L-proline 1a (0.90 g, 7.8 mmol) were placed in a dry reaction flask under nitrogen protection. Dimethyl sulfoxide (60 mL) was added to the reaction flask and stirred at 25°C for 1 hour. Subsequently, tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylate (10.0 g, 19.4 mmol), 4-morpholinopiperidine (6.61 g, 38.8 mmol), and cesium carbonate (19.0 g, 58.2 mmol) were added to the reaction flask under nitrogen protection. The reaction solution was heated to 110°C and stirred for 24 hours. The reaction solution was cooled to room temperature, and isopropyl acetate (240 mL) and aqueous ammonium chloride solution (15%, 60 mL) were added and stirred at room temperature for 1 hour. The aqueous layer was removed, and saturated aqueous sodium chloride solution (60 mL) was added to the organic phase. The mixture was stirred at room temperature for 1 hour. The aqueous layer was removed, and the resulting organic phase was concentrated under reduced pressure at an external temperature of 50°C. The concentrate was purified by column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound of Formula I (2.16 g, 20.0% yield, 98.2% HPLC purity).

[0071] Comparative Example 2

[0072] Cuprous iodide (0.74 g, 3.9 mmol) and 2-acetylcyclohexane-1-one 1f (1.09 g, 7.8 mmol) were placed in a dry reaction flask under nitrogen protection. Dimethyl sulfoxide (30 mL) was added to the reaction flask and stirred at 25°C for 1 hour. Subsequently, tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylate (10.0 g, 19.4 mmol), 4-morpholinopiperidine (6.61 g, 38.8 mmol), and cesium carbonate (12.6 g, 38.8 mmol) were added to the reaction flask under nitrogen protection. The reaction solution was heated to 100°C and stirred for 24 hours. The reaction solution was cooled to room temperature, and isopropyl acetate (120 mL) and aqueous ammonium chloride solution (15%, 30 mL) were added and stirred at room temperature for 1 hour. The aqueous layer was removed, and saturated aqueous sodium chloride solution (30 mL) was added to the organic phase. The mixture was stirred at room temperature for 1 hour. The aqueous layer was removed, and the resulting organic phase was concentrated under reduced pressure at an external temperature of 50°C. The concentrate was purified by column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound of Formula I (0.46 g, 4.3% yield, 98.8% HPLC purity).

[0073] Comparative Example 3

[0074] Cuprous iodide (0.74 g, 3.9 mmol) and N1,N2-bis(2,4,6-trimethoxyphenyl)oxamide 1h (1.64 g, 3.9 mmol) were placed in a dry reaction flask under nitrogen. Dimethyl sulfoxide (50 mL) was added to the reaction flask and stirred at 25°C for 1 hour. Tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylate (10.0 g, 19.4 mmol), 4-morpholinopiperidine (6.61 g, 38.8 mmol), and potassium phosphate (8.2 g, 38.8 mmol) were then added to the reaction flask under nitrogen. The reaction mixture was heated to 110°C and stirred for 24 hours. The reaction mixture was cooled to room temperature, and isopropyl acetate (200 mL) and aqueous ammonium chloride solution (15%, 50 mL) were added and stirred at room temperature for 1 hour. The aqueous layer was removed, and saturated aqueous sodium chloride solution (50 mL) was added to the organic phase. The mixture was stirred at room temperature for 1 hour. The aqueous layer was removed, and the resulting organic phase was concentrated under reduced pressure at an external temperature of 50°C. The concentrate was purified by column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound of Formula I (0.25 g, yield 2.3%, HPLC purity 98.5%).

[0075] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not limiting. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the purpose and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for preparing an anti-tumor drug intermediate, characterized in that: The following steps are involved: Under the condition that monovalent copper salt is used as catalyst and pyrrolidine compound is used as ligand, the compound of formula II reacts with the compound of formula III 4-morpholinopiperidine to obtain the compound of formula I or its salt, 2. The method for preparing an anti-tumor drug intermediate according to claim 1, characterized in that: The pyrrolidine compound has the following structure: Wherein, R1 is H, methyl, ethyl, straight or branched C3-C5 alkyl, benzyl, phenyl, naphthyl, and substituted phenyl; the substituted phenyl has one of methyl, methoxy, and isopropyl in the ortho, meta, or para position; R2 is H, methyl, ethyl, straight or branched C3-C5 alkyl, phenyl, benzyl, methoxy, ethoxy, and R2 is at any substitutable position of the pyrrole ring.

3. The method for preparing an anti-tumor drug intermediate according to claim 2, characterized in that: The R1 is H, methyl, ethyl, straight or branched C3-C5 alkyl, or phenyl; R2 is H, methyl, ethyl, or phenyl, and R2 is at any position of the 3-position, 4-position, or 5-position of the pyrrole ring.

4. The method for preparing an anti-tumor drug intermediate according to claim 3, characterized in that: Pyrrolidone compounds include:

5. The method for preparing an anti-tumor drug intermediate according to claim 1, characterized in that: The monovalent copper salt includes cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide or copper thiophene-2-carboxylate.

6. The method for preparing an anti-tumor drug intermediate according to claim 1, characterized in that: The molar ratio of the monovalent copper salt to the compound of formula II is 1:1-20.

7. The method for preparing an anti-tumor drug intermediate according to claim 6, characterized in that: The molar ratio of the monovalent copper salt to the compound of formula II is 1:1-15.

8. The method for preparing an anti-tumor drug intermediate according to claim 1, characterized in that: The reaction temperature is 80-130° C., and the reaction time is 1-15 hours.

9. The method for preparing an anti-tumor drug intermediate according to claim 8, characterized in that: The reaction temperature is 90-125° C., and the reaction time is 1-12 hours.

10. The method for preparing an anti-tumor drug intermediate according to claim 1, characterized in that: The reaction conditions also include a base, which includes triethylamine, diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene, potassium phosphate, potassium carbonate, cesium carbonate or potassium hydroxide, and the molar ratio of the base to the compound of formula II is 1 to 6:1.

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