A preparation method of ALK inhibitor compound and intermediate thereof

Abstract

The present invention discloses a method for preparing an ALK inhibitor compound and an intermediate thereof. Specifically, the present invention discloses a method for preparing compound A9, which comprises the following reaction steps: (1) in a solvent, in the presence of a metal catalyst and a base, coupling reaction of "compound A2 or a salt thereof" with "compound B3 or a salt thereof" to obtain compound A4; (2) in a solvent, in the presence of an organic acid, coupling reaction of compound A4 with compound A8 to obtain compound A9. The preparation method described in the present invention has the advantages of suitable reaction steps, simple operation, inexpensive and readily available reaction raw materials, environmental friendliness, simple post-processing, low safety risks, and reduced production cycle and production costs. #imgabs0#

Description

Technical Field

[0001] The present invention relates to a preparation method of an ALK inhibitor compound and an intermediate thereof. Background Art

[0002] Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor superfamily of receptor tyrosine kinases and has been implicated in the development of both hematopoietic and non-hematopoietic tumors. Aberrant expression of the full-length ALK receptor protein has been reported in neuroblastoma and glioblastoma; and ALK fusion proteins appear in anaplastic large cell lymphoma. The study of ALK fusion proteins also raises the possibility of new treatments for patients with ALK-positive malignancies. Small molecule ALK inhibitors have therapeutic potential for treating diseases and conditions in which ALK plays a role, including cancer.

[0003] The prior art discloses a method for preparing compound A9, an ALK inhibitor, and the preparation route is as follows:

[0004]

[0005] This route has a long production cycle, requires more palladium catalyst, has high production costs, and a complex synthesis route. Summary of the Invention

[0006] The technical problem to be solved by the present invention is that the existing ALK inhibitor preparation method has a long production cycle, high production cost, and a complex synthesis route. The present invention provides a preparation method of an ALK inhibitor compound and its intermediates. The preparation method has the advantages of suitable reaction steps, simple operation, cheap and easy to obtain reaction raw materials, environmental friendliness, simple post-processing, low safety risk, and reduced production cycle and production cost.

[0007] The present invention provides a method for preparing compound A9, which comprises the following reaction steps: (1) in a solvent, in the presence of a metal catalyst and a base, subjecting "compound A2 or a salt thereof" to a coupling reaction with "compound B3 or a salt thereof" to obtain compound A4;

[0008]

[0009] (2) coupling reaction of compound A4 with compound A8 in a solvent in the presence of an organic acid to obtain compound A9;

[0010]

[0011] X1 is OTf, Cl, Br or I;

[0012] X2 and X3 are each independently H or C 1-6Alkyl; or, X2 and X3 are linked to form -C(CH3)2-C(CH3)2-.

[0013] In some embodiments, X1 is Br, i.e. for

[0014] In some embodiments, X1 is OTf, Cl or I; preferably Cl.

[0015] In some embodiments, X2 and X3 are each independently H or C 1-6 alkyl.

[0016] In some embodiments, X2 and X3 are linked to form -C(CH3)2-C(CH3)2-, i.e. for

[0017] In some embodiments, in step (1), the solvent is one or more of an alcohol solvent, an ether solvent, an aromatic solvent, a nitrile solvent, a sulfoxide solvent, an amide solvent and water, for example, a combination of an alcohol solvent and water, a combination of an ether solvent and water, an aromatic solvent, a nitrile solvent, a sulfoxide solvent or an amide solvent.

[0018] In some embodiments, in step (1), the alcohol solvent is isopropanol.

[0019] In some embodiments, in step (1), the ether solvent is dioxane and / or dimethyl ether.

[0020] In some embodiments, in step (1), the aromatic solvent is toluene.

[0021] In some embodiments, in step (1), the nitrile solvent is acetonitrile.

[0022] In some embodiments, in step (1), the sulfoxide solvent is dimethyl sulfoxide.

[0023] In some embodiments, in step (1), the amide solvent is N,N-dimethylformamide.

[0024] In some embodiments, in step (1), when the solvent is a combination of an alcohol solvent and water, the volume ratio of the alcohol solvent to the water is (4-20):1, for example, 4.5:1, 19.9:1 or 10.0:1.

[0025] In some embodiments, in step (1), the salt of Compound A2 is in the form of hydrochloride salt of Compound A2.

[0026] In some embodiments, in step (1), when the salt of Compound A2 is in the form of hydrochloride of Compound A2, the molar ratio of Compound A2 to hydrochloric acid is 1:1.

[0027] In some embodiments, in step (1), the salt of compound B3 is the hydrochloride form of compound B3.

[0028] In some embodiments, in step (1), when the salt of compound B3 is in the form of hydrochloride of compound B3, the molar ratio of compound B3 to hydrochloric acid is 1:1.

[0029] In some embodiments, in step (1), the metal catalyst is a palladium catalyst, such as one or more of Pd(PPh3)2Cl2, Pd(dppf)2Cl2, Pd(OAc)2 and Pd(PPh3)4, preferably Pd(PPh3)4 and / or Pd(OAc)2; more preferably Pd(PPh3)4.

[0030] In some embodiments, in step (1), the base is an alkali metal carbonate and / or an alkali metal phosphate, such as potassium carbonate and / or potassium phosphate; preferably potassium carbonate.

[0031] In some embodiments, in step (1), the molar ratio of the compound B3 to the compound A2 is (1-1.1):1, for example, 1.1:1, 1.05:1 or 1.0:1.

[0032] In some embodiments, in step (1), the molar ratio of the metal catalyst to the compound A2 is (0.01-0.02):1, for example, 0.01:1 or 0.02:1.

[0033] In some embodiments, in step (1), the molar ratio of the base to the compound A2 is (3.0-5.0):1, for example, 3.0:1, 4.0:1 or 5.0:1.

[0034] In some embodiments, in step (1), when the solvent is a combination of an alcohol solvent and water, the molar ratio of the water to the compound A2 is (9-24):1, for example, 9:1 or 9.5:1.

[0035] In some embodiments, in step (1), the reaction temperature of the coupling reaction is 80-120°C, preferably 80-85°C.

[0036] In some embodiments, in step (1), the coupling reaction is carried out under the protection of an inert gas, for example, under the protection of nitrogen.

[0037] In some embodiments, in step (1), the coupling reaction further comprises the following post-treatment steps: concentration (e.g., spin drying), extraction (e.g., using ethyl acetate and 10% sodium carbonate solution), filtration, removal of metal catalyst (e.g., using N-acetyl-L-cysteine), concentration of the filtrate (e.g., concentration under reduced pressure), washing (e.g., washing with 10% sodium carbonate solution), drying (e.g., drying with anhydrous magnesium sulfate), and recrystallization (e.g., recrystallization using n-heptane).

[0038] In some embodiments, in step (2), the solvent is an alcohol solvent, such as isopropyl alcohol.

[0039] In some embodiments, in step (2), the organic acid is p-toluenesulfonic acid, such as p-toluenesulfonic acid monohydrate.

[0040] In some embodiments, in step (2), the molar ratio of compound A8 to compound A4 is (1-1.5):1, for example, 1.05:1.

[0041] In some embodiments, in step (2), the molar ratio of the organic acid to the compound A4 is (1-1.5):1, for example, 1.2:1.

[0042] In some embodiments, in step (2), the mass volume ratio of the compound A4 to the solvent is 1 g: (6-15) ml, for example, 1 g: 8 ml.

[0043] In some embodiments, in step (2), the coupling reaction temperature is 70-90°C, preferably 77-83°C.

[0044] In some embodiments, in step (2), the coupling reaction is carried out under the protection of an inert gas, for example, under the protection of nitrogen.

[0045] In some embodiments, in step (2), the coupling reaction further comprises the following post-treatment steps: crystallization (e.g., crystallization using ethyl acetate), filtration, washing (e.g., dissolution using dichloromethane, followed by washing with 10% sodium carbonate solution), extraction (e.g., extraction of the aqueous phase using dichloromethane), concentration under reduced pressure, crystallization (e.g., crystallization using acetonitrile), and drying.

[0046] In some embodiments, the method for preparing compound A9 further comprises the following steps: subjecting compound A1 to a reduction reaction in a solvent under the action of a reducing agent to obtain compound A2 or a salt thereof;

[0047]

[0048] In some embodiments, X1 is Br, i.e. for for

[0049] In some embodiments, X1 is OTf, Cl or I; preferably Cl.

[0050] In some embodiments, in the reduction reaction, the solvent is an alcohol solvent and water.

[0051] In some embodiments, in the reduction reaction, the alcohol solvent is methanol.

[0052] In some embodiments, in the reduction reaction, the volume ratio of the alcohol solvent to the water is (5-20):1, for example, 5:1.

[0053] In some embodiments, the salt of Compound A2 is the hydrochloride salt form of Compound A2.

[0054] In some embodiments, when the salt of Compound A2 is in the form of hydrochloride salt of Compound A2, the molar ratio of Compound A2 to hydrochloric acid is 1:1.

[0055] In some embodiments, in the reduction reaction, the mass volume ratio of the compound A1 to the alcohol solvent is 1 g:(3-15) ml, for example, 1 g:5 ml.

[0056] In some embodiments, in the reduction reaction, the reducing agent is SnCl2·2H2O and HCl.

[0057] In some embodiments, the temperature of the reduction reaction is 45-55°C, for example 50°C.

[0058] In some embodiments, in the reduction reaction, the molar ratio of the reducing agent to the compound A1 is (3-10): 1, for example, 4: 1. When the reducing agent is SnCl2·2H2O and HCl, the amount of the reducing agent in the molar ratio of the reducing agent to the compound A1 is calculated as SnCl2·2H2O.

[0059] In some embodiments, the reduction reaction further comprises the following post-processing steps: concentration after adding water (e.g., concentration under reduced pressure after adding water), extraction (e.g., extraction with methyl tert-butyl ether), washing (e.g., washing with saturated brine), concentration, filtration, and drying.

[0060] In some embodiments, when the hydrochloride salt form of the compound A2 is obtained, the post-treatment step further comprises adding acid (eg, adding 4 M hydrogen chloride ethyl acetate solution).

[0061] In some embodiments, the method for preparing compound A9 further comprises the following steps: in a solvent, under the action of a reducing agent, subjecting "compound B2 or its salt" to a reductive amination reaction with tetrahydropyrone and acetic acid to obtain compound B3 or its salt;

[0062]

[0063] In some embodiments, X2 and X3 are each independently H or C 1-6 alkyl.

[0064] In some embodiments, X2 and X3 are linked to form -C(CH3)2-C(CH3)2-, i.e. for for

[0065] In some embodiments, in the reductive amination reaction, the solvent is a halogenated alkane solvent, such as dichloromethane.

[0066] In some embodiments, the salt of Compound B2 is the hydrochloride salt form of Compound B2.

[0067] In some embodiments, when the salt of Compound B2 is in the form of hydrochloride salt of Compound B2, the molar ratio of Compound B2 to hydrochloric acid is 1:1.

[0068] In some embodiments, the salt of Compound B3 is the hydrochloride salt form of Compound B3.

[0069] In some embodiments, when the salt of Compound B3 is in the form of hydrochloride salt of Compound B3, the molar ratio of Compound B3 to hydrochloric acid is 1:1.

[0070] In some embodiments, in the reductive amination reaction, the reducing agent is sodium triacetoxyborohydride.

[0071] In some embodiments, in the reductive amination reaction, the molar ratio of the tetrahydropyrone to the compound B2 is (2-5):1, for example, 3:1.

[0072] In some embodiments, in the reductive amination reaction, the molar ratio of the acetic acid to the compound B2 is (0.5-2):1, for example, 0.85:1.

[0073] In some embodiments, in the reductive amination reaction, the molar ratio of the reducing agent to the compound B2 is (2-5):1, for example, 3:1.

[0074] In some embodiments, in the reductive amination reaction, the mass volume ratio of the compound B2 to the solvent is 1 g:(5-20) ml, for example, 1 g:10 ml.

[0075] In some embodiments, the reductive amination reaction may further include the use of an organic acid, such as acetic acid.

[0076] In some embodiments, the reductive amination reaction further comprises the following post-treatment steps: extraction (e.g., extraction with dichloromethane and 15% sodium carbonate solution), filtration (e.g., filtration through a pad of celite), drying (e.g., drying over anhydrous magnesium sulfate), concentration (e.g., concentration under reduced pressure), and washing (e.g., washing with n-heptane).

[0077] In some embodiments, the temperature of the reductive amination reaction is room temperature.

[0078] In some embodiments, the method for preparing compound A9 further comprises the following steps: performing a deprotection reaction on compound B1 in a solvent under acidic conditions to obtain compound B2 or a salt thereof;

[0079]

[0080] X4 is an amino protecting group; X2 and X3 are as defined in any one of the present invention.

[0081] In some embodiments, the amino protecting group is a group conventionally used in the art to protect amino groups, such as -Boc.

[0082] In some embodiments, X2 and X3 are linked to form -C(CH3)2-C(CH3)2-, i.e. for

[0083] In some embodiments, X2 and X3 are each independently H or C 1-6 alkyl.

[0084] In some embodiments, for

[0085] In some embodiments, in the deprotection reaction, the solvent is an ester solvent, such as ethyl acetate.

[0086] In some embodiments, the salt of Compound B2 is the hydrochloride salt form of Compound B2.

[0087] In some embodiments, when the salt of Compound B2 is in the form of hydrochloride salt of Compound B2, the molar ratio of Compound B2 to hydrochloric acid is 1:1.

[0088] In some embodiments, in the deprotection reaction, the acid in the acidic condition is hydrogen chloride. The hydrogen chloride can be added in the form of a hydrogen chloride ethyl acetate solution. The concentration of the hydrogen chloride ethyl acetate solution can be 4M.

[0089] In some embodiments, in the deprotection reaction, the mass volume ratio of the compound B1 to the solvent is 1 g: (3-20) ml, for example, 1 g: 4.8 ml.

[0090] In some embodiments, in the deprotection reaction, the molar ratio of the acid to the compound B1 is (3-10):1, for example, 6:1.

[0091] In some embodiments, the deprotection reaction is performed at room temperature.

[0092] In some embodiments, the deprotection reaction further comprises the following post-processing steps: concentration under reduced pressure, slurrying (eg, slurrying with methyl tert-butyl ether), filtration, and drying.

[0093] The present invention also provides a method for preparing compound A4, comprising the following reaction steps: in a solvent, in the presence of a metal catalyst and a base, coupling reaction of "compound A2 or a salt thereof" with "compound B3 or a salt thereof" to obtain compound A4;

[0094]

[0095] X1 is OTf, Cl, Br or I;

[0096] X2 and X3 are each independently H or C 1-6 Alkyl; or, X2 and X3 are linked to form -C(CH3)2-C(CH3)2-.

[0097] In some embodiments, X1 is Br, i.e. for

[0098] In some embodiments, X1 is OTf, Cl or I; preferably Cl.

[0099] In some embodiments, X2 and X3 are each independently H or C 1-6 alkyl.

[0100] In some embodiments, X2 and X3 are linked to form -C(CH3)2-C(CH3)2-, i.e. for

[0101] In some embodiments, the steps and reaction conditions in the preparation method of compound A4 are as described in any of the above items.

[0102] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0103] The reagents and raw materials used in the present invention are commercially available.

[0104] The positive progress of the present invention is that the preparation method of the present invention has the advantages of appropriate reaction steps, simple operation, cheap and easy to obtain reaction raw materials, environmental friendliness, simple post-processing, low safety risk, and reduced production cycle and production cost. DETAILED DESCRIPTION

[0105] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0106] Example 1

[0107]

[0108] To a 1L reaction flask, add stannous chloride dihydrate (65.86g), methanol (100ml), water (20ml), concentrated hydrochloric acid (12ml) and compound Al' (20.0g) in sequence, heat to an internal temperature of 50°C, and stir for 4 hours to complete the reaction. The reaction system was cooled to room temperature, water (100ml) was added, and the mixture was concentrated under reduced pressure until about 100g remained. Methyl tert-ether (200ml) was added and stirred, and 20% sodium hydroxide solution was added dropwise until the pH of the aqueous phase reached 11-12. The liquid was separated and the organic phase was collected. The aqueous phase was back-extracted once with methyl tert-ether (100ml). The organic phases were combined and washed once with 15% sodium chloride solution (100ml). The organic phase was concentrated with ethyl acetate (100 ml*2) to replace the solvent until about 50 g remained. 4 M hydrogen chloride ethyl acetate solution (70 ml) was added dropwise. After stirring at room temperature for 1 hour, the mixture was concentrated with ethyl acetate (100 ml*2) to replace the solvent until about 100 g remained. The mixture was filtered and dried to obtain compound A2' (18.05 g) with a purity of 99.51% and a yield of 87%.

[0109] MS: [M+H]+=244.0

[0110] 1 H NMR (400MHz, DMSO-d6) δ7.37 (s, 1H), 7.28 (s, 1H), 4.78-4.67 (m, 1H), 2.26 (d, J=1.28Hz, 3H), 1.29 (dd, J=6.04, 1.31Hz, 6H).

[0111] Example 2

[0112]

[0113] To a 2 L reaction flask, add the compound of formula B1' (61.9 g) and ethyl acetate (300 ml) sequentially. After stirring until dissolved, add a 4 M solution of hydrogen chloride in ethyl acetate (300 ml) dropwise at room temperature and stir for 2 hours to terminate the reaction. The reaction solution is concentrated to dryness under reduced pressure, and methyl tert-butyl ether (200 ml) is added and concentrated to dryness. Methyl tert-butyl ether (300 ml) is added and the mixture is beaten at room temperature for 2 hours. The mixture is filtered and dried to obtain the compound of formula B2' (48.81 g) with a purity of 97.9% and a yield of 99%.

[0114] 1 H NMR (400MHz, DMSO-d6) δ9.29 (s, 2H), 6.36 (td, J=3.10, 1.53Hz, 1H), 3.58 (dp, J=5 .08, 2.47Hz, 2H), 3.13-3.03 (m, 2H), 2.28 (tq, J=4.66, 2.15Hz, 2H), 1.22 (s, 12H).

[0115] Example 3

[0116]

[0117] To a 2L reaction flask, add the compound of formula B2' (36.13g), dichloromethane (360ml), tetrahydropyrone (51.58g), and acetic acid (8.84g) in sequence. Stir until dissolved. Then, add sodium triacetoxyborohydride (109.17g) in portions. Stir at room temperature for 2.5 hours to complete the reaction. Add dichloromethane (360ml) to the system, slowly add 15% sodium carbonate solution (900ml), and add 20% sodium hydroxide solution (150ml). Adjust the pH to approximately 10-11, filter through celite, separate the layers, and collect the organic phase. Back-extract the aqueous phase three times with dichloromethane (360ml x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and dried, ethyl acetate was added, and the mixture was concentrated under reduced pressure to constant weight. n-heptane (90 g) was added dropwise at room temperature, and the mixture was cooled to 0-5°C and stirred for 2 hours. The mixture was filtered and dried to obtain the compound of formula B3' (32.52 g) with a purity of 99.68% and a yield of 75%.

[0118] 1H NMR (400MHz, Chloroform-d) δ6.53 (tt, J=3.52, 1.87Hz, 1H), 4.11-3.97 (m, 2H), 3.40 (td, J=11.88, 1.99Hz, 2H), 3.20 (q, J=3.03Hz, 2H), 2.64 (t, J=5 .62Hz, 2H), 2.53 (tt, J=11.57, 3.89Hz, 1H), 2.34-2.25 (m, 2H), 1.81 (ddd, J=12.50, 4.19, 2.09Hz, 2H), 1.64 (qd, J=12.18, 4.51Hz, 2H), 1.26 (s, 12H).

[0119] Example 4

[0120]

[0121] Compound A2' (20.0 g), Compound B3' (20.09 g), isopropyl alcohol (230 ml), water (11.55 g), and potassium carbonate (39.41 g) were added to the reaction flask in sequence. Stirring was initiated and the atmosphere was purged with nitrogen three times. Tetrakistriphenylphosphine palladium (0.8237 g) was added and the atmosphere was purged with nitrogen three times. Under nitrogen protection, the temperature was raised to 80-85°C and stirred for 24 hours to complete the reaction. The reaction system was cooled to 50-55°C and N-acetyl-L-cysteine ​​(1.16 g) was added. After stirring for 1 hour, the temperature was lowered to room temperature. The system was concentrated to a residual volume of approximately 130 g. The volume was then concentrated and purged twice with ethyl acetate (100 ml x 2) to a residual volume of approximately 130 g. Ethyl acetate (200 ml) was added and the solution was washed once with 10% sodium carbonate solution (200 ml). The filtrate was then filtered and collected. The filtrate is subjected to liquid separation, and N-acetyl-L-cysteine ​​(1.16 g) is added to the organic phase, and the mixture is heated to 50-55 ° C, stirred for 1 hour, cooled to room temperature, and washed once with 10% sodium carbonate solution (150 ml). N-acetyl-L-cysteine ​​(1.16 g) is added to the organic phase, and the mixture is heated to 50-55 ° C, stirred for 1 hour, cooled to room temperature, and washed once with 10% sodium carbonate solution (150 ml). The organic phase is concentrated under reduced pressure to a residue of approximately 60 g. At 20-25 ° C, methyl tert-butyl ether (40 g) is added dropwise, and normal heptane (100 g) is added dropwise. After stirring for 30 minutes, the mixture is concentrated under reduced pressure to a residue of approximately 100 g. Normal heptane (100 g) is added dropwise, and the mixture is concentrated under reduced pressure to a residue of approximately 100 g. The mixture is cooled to 0-5 ° C, stirred for 4 hours, filtered, and dried to obtain compound A4 (20.22 g). The purity is 97.6%, and the yield is 86%.

[0122] MS: [M+H]+=331.20

[0123] 1H NMR (400MHz, DMSO-d6) δ6.49 (s, 1H), 6.44 (s, 1H), 5.42 (dq, J=3.54, 1.65Hz, 1H), 4.47 (s, 2 H), 4.38 (h, J=6.05Hz, 1H), 3.95-3.86 (m, 2H), 3.13 (q, J=2.95Hz, 2H), 2.66 (t, J=5.51Hz, 2 H), 2.46 (dt, J=11.17, 3.71Hz, 1H), 2.23 (dq, J=6.10, 3.43, 2.92Hz, 2H), 2.07 (s, 3H), 1.75 (ddd, J=12.26, 4.11, 1.98Hz, 2H), 1.46 (qd, J=12.16, 4.44Hz, 2H), 1.23 (d, J=6.01Hz, 6H).

[0124] Example 5

[0125] Referring to the synthesis method of the compound in Example 4, the reaction parameters were optimized and adjusted to obtain the following results.

[0126]

[0127] Example 6

[0128]

[0129] To the reaction flask, add isopropyl alcohol (120 ml), A4 (15.0 g), A8 (16.5 g), and p-toluenesulfonic acid monohydrate (10.36 g) in sequence, stir, and replace with nitrogen three times. Heat to 80 ± 3°C under nitrogen, stir and react for 24 hours, and the reaction is complete. Cool to 60-65°C, add ethyl acetate (120 ml) dropwise, slowly cool to 15 ± 5°C, stir for 2 hours, and filter. Add dichloromethane (90 ml) to the filter cake and stir to dissolve. Wash twice with 10% aqueous sodium carbonate solution (75 ml x 2). Combine the aqueous phases and extract once with dichloromethane (45 ml). The organic phases were combined and concentrated under reduced pressure to a residual weight of approximately 37.5 g. Acetonitrile (75 ml) was added dropwise, and the mixture was concentrated under reduced pressure to a residual weight of approximately 67.5 g. The temperature was controlled at 30±10°C, and acetonitrile (75 ml) was added dropwise. The temperature was lowered to 20±5°C, stirred for 6 hours, and filtered. Drying afforded compound A9 (23.0 g) with a purity of 99.74% and a yield of 79%.

[0130] MS: [M+H] + =640.10

[0131] 1H NMR(400MHz,Chloroform-d)δ9.51(s,1H),8.59(dd,J=8.41,1.08Hz,1H),8.18(s,1H),8.05(s,1H),7.95(dd,J=8.00,1.63Hz,1H),7.65(ddd,J=8.60,7.38,1.67Hz,1H),7.60(s,1H),6.72(s,1H),5.59(dt,J=3.64,1.96Hz,1H),4.55(hept,J=6.17Hz,1H),4.09(dd,J=11.28,4.24Hz,2H),3.45(td,J=11.88,1.93Hz,2H),3.36-3.21(m,3H),2.80(t,J=5.56Hz,2H),2.43(s,2H),2.14(s,3H),1.88(d,J=12.42Hz,2H),1.78-1.69(m,2H),1.36(dd,J=17.08,6.47Hz,13H)。

Claims

1. A method for preparing compound A9, comprising the following reaction steps: (1) In a solvent, in the presence of a metal catalyst and a base, coupling reaction is performed on "Compound A2 or a salt thereof" and "Compound B3 or a salt thereof" to obtain Compound A4; (2) Compound A4 is subjected to a coupling reaction with Compound A8 in a solvent in the presence of p-toluenesulfonic acid monohydrate to obtain Compound A9; X1 is OTf, Cl, Br or I; X2 and X3 are each independently H or C 1-6 Alkyl; or, X2 and X3 are linked to form -C(CH3)2-C(CH3)2-.

2. The method for preparing compound A9 according to claim 1, wherein The preparation method meets one or more of the following conditions: (1) X1 is Br, that is for (2) X2 and X3 are connected to form -C(CH3)2-C(CH3)2-, that is, for 3. The method for preparing compound A9 according to claim 1, wherein The preparation method meets one or more of the following conditions: (1) X1 is OTf, Cl or I; (2) X2 and X3 are independently H or C 1-6 alkyl.

4. The method for preparing compound A9 according to claim 1, wherein X1 is Cl.

5. The method for preparing compound A9 according to any one of claims 1 to 3, wherein: The preparation method meets one or more of the following conditions: (1) In step (1), the solvent is one or more of an alcohol solvent, an ether solvent, an aromatic solvent, a nitrile solvent, a sulfoxide solvent, an amide solvent, and water; (2) In step (1), the salt of compound A2 is the hydrochloride form of compound A2; (3) In step (1), the salt of compound B3 is the hydrochloride form of compound B3; (4) In step (1), the metal catalyst is a palladium catalyst; (5) In step (1), the base is an alkali metal carbonate and / or an alkali metal phosphate; (6) In step (1), the molar ratio of compound B3 to compound A2 is (1-1.1):1; (7) In step (1), the molar ratio of the metal catalyst to the compound A2 is (0.01-0.02):1; (8) In step (1), the molar ratio of the base to the compound A2 is (3.0-5.0):1; (9) In step (1), when the solvent is a combination of an alcohol solvent and water, the molar ratio of the water to the compound A2 is (9-24):1; (10) In step (1), the reaction temperature of the coupling reaction is 80-120°C; (11) In step (1), the coupling reaction is carried out under the protection of an inert gas; (12) In step (1), the coupling reaction further comprises the following post-processing steps: concentration, extraction, filtration, removal of metal catalyst, concentration of the filtrate, washing, drying and recrystallization; (13) In step (2), the solvent is an alcohol solvent; (14) In step (2), the molar ratio of compound A8 to compound A4 is (1-1.5):1; (15) In step (2), the molar ratio of the monohydrated p-toluenesulfonic acid to the compound A4 is (1-1.5):1; (16) In step (2), the mass volume ratio of the compound A4 to the solvent is 1 g: (6-15) ml; (17) In step (2), the coupling reaction temperature is 70-90°C; (18) In step (2), the coupling reaction is carried out under the protection of an inert gas; (19) In step (2), the coupling reaction further comprises the following post-treatment steps: crystallization, filtration, washing, extraction, concentration under reduced pressure, crystallization and drying.

6. The method for preparing compound A9 according to claim 5, wherein The preparation method meets one or more of the following conditions: (1) In step (1), the solvent is a combination of an alcohol solvent and water, a combination of an ether solvent and water, an aromatic solvent, a nitrile solvent, a sulfoxide solvent, or an amide solvent; (2) In step (1), when the solvent is a combination of an alcohol solvent and water, the volume ratio of the alcohol solvent to the water is (4-20):1; (3) In step (1), the alcohol solvent is isopropyl alcohol; (4) In step (1), the ether solvent is dioxane and / or dimethyl ether; (5) In step (1), the aromatic solvent is toluene; (6) In step (1), the nitrile solvent is acetonitrile; (7) In step (1), the sulfoxide solvent is dimethyl sulfoxide; (8) In step (1), the amide solvent is N,N-dimethylformamide; (9) In step (1), when the salt of the compound A2 is in the form of the hydrochloride of the compound A2, the molar ratio of the compound A2 to hydrochloric acid is 1:1; (10) In step (1), when the salt of compound B3 is in the form of a hydrochloride salt of compound B3, the molar ratio of compound B3 to hydrochloric acid is 1:1; (11) In step (1), the metal catalyst is one or more of Pd(PPh3)2Cl2, Pd(dppf)2Cl2, Pd(OAc)2 and Pd(PPh3)4; (12) In step (1), the base is potassium carbonate and / or potassium phosphate; (13) In step (1), the molar ratio of compound B3 to compound A2 is 1.1:1, 1.05:1 or 1.0:1; (14) In step (1), the molar ratio of the metal catalyst to the compound A2 is 0.01:1 or 0.02:1; (15) In step (1), the molar ratio of the base to the compound A2 is 3.0:1, 4.0:1 or 5.0:1; (16) In step (1), when the solvent is a combination of an alcohol solvent and water, the molar ratio of the water to the compound A2 is 9:1 or 9.5:1; (17) In step (1), the reaction temperature of the coupling reaction is 80-85°C; (18) In step (1), the coupling reaction is carried out under nitrogen protection; (19) In step (2), the solvent is isopropyl alcohol; (20) In step (2), the molar ratio of compound A8 to compound A4 is 1.05:1; (21) In step (2), the molar ratio of the monohydrated p-toluenesulfonic acid to the compound A4 is 1.2:1; (22) In step (2), the mass volume ratio of the compound A4 to the solvent is 1 g:8 ml; (23) In step (2), the coupling reaction temperature is 77-83°C; (24) In step (2), the coupling reaction is carried out under nitrogen protection.

7. The method for preparing compound A9 according to claim 6, wherein The preparation method meets one or more of the following conditions: (1) In step (1), the metal catalyst is Pd(PPh3)4 and / or Pd(OAc)2; (2) In step (1), the base is potassium carbonate; (3) In step (1), when the solvent is a combination of an alcohol solvent and water, the volume ratio of the alcohol solvent to the water is 4.5:1, 19.9:1 or 10.0:

1.

8. The method for preparing compound A9 according to claim 7, wherein In step (1), the metal catalyst is Pd(PPh3)4.

9. The method for preparing compound A9 according to any one of claims 1 to 3, wherein: In step (1), further The method comprises the following steps: subjecting compound A1 to a reduction reaction in a solvent under the action of a reducing agent to obtain compound A2 or a salt thereof; X1 is defined as in any one of claims 1 to 3.

10. The method for preparing compound A9 according to claim 9, wherein The preparation method meets one or more of the following conditions: (1) In the reduction reaction, the solvent is an alcohol solvent and water; (2) The salt of the compound A2 is the hydrochloride form of the compound A2; (3) In the reduction reaction, when the solvent is an alcohol solvent and water, the mass volume ratio of the compound A1 to the alcohol solvent is 1 g: (3-15) ml; (4) In the reduction reaction, the reducing agent is SnCl2·2H2O and HCl; (5) The temperature of the reduction reaction is 45 to 55° C.; (6) In the reduction reaction, the molar ratio of the reducing agent to the compound A1 is (3-10):1; when the reducing agent is SnCl2·2H2O and HCl, the amount of the reducing agent in the molar ratio of the reducing agent to the compound A1 is calculated as SnCl2·2H2O; (7) The reduction reaction further includes the following post-processing steps: concentration after adding water, extraction, washing, concentration, filtration and drying; (8) In the reduction reaction, when the solvent is an alcohol solvent and water, the volume ratio of the alcohol solvent to the water is (5-20):

1.

11. The method for preparing compound A9 according to claim 10, wherein The preparation method meets one or more of the following conditions: (1) In the reduction reaction, the alcohol solvent is methanol; (2) In the reduction reaction, when the solvent is an alcohol solvent and water, the volume ratio of the alcohol solvent to the water is 5:1; (3) When the salt of the compound A2 is in the form of the hydrochloride of the compound A2, the molar ratio of the compound A2 to hydrochloric acid is 1:1; (4) In the reduction reaction, when the solvent is an alcohol solvent and water, the mass volume ratio of the compound A1 to the alcohol solvent is 1 g:5 ml; (5) The temperature of the reduction reaction is 50°C; (6) In the reduction reaction, the molar ratio of the reducing agent to the compound A1 is 4:1; (7) When the hydrochloride form of the compound A2 is obtained, the post-treatment step further comprises adding acid.

12. The method for preparing Compound A9 according to any one of claims 1 to 3, wherein: In step (1), the method further comprises the following steps: in a solvent, under the action of a reducing agent, subjecting "Compound B2 or its salt" to a reductive amination reaction with tetrahydropyrone and acetic acid to obtain Compound B3 or its salt; X2 and X3 are as defined in any one of claims 1 to 3.

13. The method for preparing compound A9 according to claim 12, wherein: The preparation method meets one or more of the following conditions: (1) In the reductive amination reaction, the solvent is a halogenated alkane solvent; (2) the salt of the compound B2 is the hydrochloride form of the compound B2; (3) the salt of the compound B3 is the hydrochloride form of the compound B3; (4) In the reductive amination reaction, the reducing agent is sodium triacetoxyborohydride; (5) In the reductive amination reaction, the molar ratio of the tetrahydropyrone to the compound B2 is (2-5):1; (6) In the reductive amination reaction, the molar ratio of the acetic acid to the compound B2 is (0.5-2):1; (7) In the reductive amination reaction, the molar ratio of the reducing agent to the compound B2 is (2-5):1; (8) In the reductive amination reaction, the mass volume ratio of the compound B2 to the solvent is 1 g:(5-20) ml; (9) The reductive amination reaction may further comprise the use of an organic acid; (10) The reductive amination reaction further comprises the following post-processing steps: extraction, filtration, drying, concentration and washing; (11) The temperature of the reductive amination reaction is room temperature.

14. The method for preparing compound A9 according to claim 13, wherein The preparation method meets one or more of the following conditions: (1) In the reductive amination reaction, the solvent is dichloromethane; (2) When the salt of the compound B2 is in the form of the hydrochloride of the compound B2, the molar ratio of the compound B2 to hydrochloric acid is 1:1; (3) When the salt of the compound B3 is in the form of the hydrochloride of the compound B3, the molar ratio of the compound B3 to hydrochloric acid is 1:1; (4) In the reductive amination reaction, the molar ratio of the tetrahydropyrone to the compound B2 is 3:1; (5) In the reductive amination reaction, the molar ratio of the acetic acid to the compound B2 is 0.85:1; (6) In the reductive amination reaction, the molar ratio of the reducing agent to the compound B2 is 3:1; (7) In the reductive amination reaction, the mass volume ratio of the compound B2 to the solvent is 1 g:10 ml; (8) The organic acid is acetic acid.

15. The method for preparing compound A9 according to claim 12, wherein: In step (1), the method further comprises the following steps: performing a deprotection reaction on compound B1 in a solvent under acidic conditions to obtain compound B2 or a salt thereof; X4 is an amino protecting group; X2 and X3 are as defined in claim 12.

16. The method for preparing compound A9 according to claim 15, wherein The preparation method meets one or more of the following conditions: (1) The amino protecting group is -Boc; (2) X2 and X3 are connected to form -C(CH3)2-C(CH3)2-, that is, for 17. The method for preparing compound A9 according to claim 15, wherein The preparation method meets the following conditions: X2 and X3 are each independently H or C 1-6 alkyl.

18. The method for preparing Compound A9 according to any one of claims 15 to 17, wherein: The preparation method meets one or more of the following conditions: (1) In the deprotection reaction, the solvent is an ester solvent; (2) the salt of the compound B2 is the hydrochloride form of the compound B2; (3) In the deprotection reaction, the acid in the acidic condition is hydrogen chloride; (4) In the deprotection reaction, the mass volume ratio of the compound B1 to the solvent is 1 g: (3-20) ml; (5) In the deprotection reaction, the molar ratio of the acid to the compound B1 is (3-10):1; (6) the deprotection reaction is carried out at room temperature; (7) The deprotection reaction further includes the following post-processing steps: concentration under reduced pressure, slurrying, filtration and drying.

19. The method for preparing compound A9 according to claim 18, wherein The preparation method meets one or more of the following conditions: (1) In the deprotection reaction, the solvent is ethyl acetate; (2) When the salt of the compound B2 is in the form of the hydrochloride of the compound B2, the molar ratio of the compound B2 to hydrochloric acid is 1:1; (3) the hydrogen chloride is added in the form of an ethyl acetate solution of hydrogen chloride; (4) When the hydrogen chloride is added in the form of an ethyl acetate solution of hydrogen chloride, the concentration of the ethyl acetate solution of hydrogen chloride is 4M; (5) In the deprotection reaction, the mass volume ratio of the compound B1 to the solvent is 1 g:4.8 ml; (6) In the deprotection reaction, the molar ratio of the acid to the compound B1 is 6:1.

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