Method for preparing ALK inhibitor compound and intermediate thereof

Abstract

Disclosed in the present invention is a method for preparing an ALK inhibitor compound and an intermediate thereof. Specifically, the present invention provides a method for preparing compound A9, comprising the following reaction steps: (1) carrying out a coupling reaction on "compound A2 or a salt thereof" and "compound B3 or a salt thereof" in a solvent in the presence of a metal catalyst, a ligand, and a base to obtain compound A4, wherein the metal catalyst is a palladium catalyst; and (2) carrying out a coupling reaction on compound A4 and compound A8 in a solvent in the presence of an acid to obtain compound A9. The preparation method of the present invention has the advantages of proper reaction steps, simple operation, cheap and easily available reaction raw materials, environmental friendliness, simple post-treatment, low safety risk, reduced production cycle and production cost, etc.

Description

A preparation method of ALK inhibitor compound and intermediate thereof

[0001] This application claims priority to Chinese patent application No. 2024100195681, filed on January 5, 2024. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a method for preparing an ALK inhibitor compound and an intermediate thereof. Background Art

[0003] 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.

[0004] The prior art discloses a method for preparing compound A9, an ALK inhibitor, and the preparation route is as follows:

[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, a ligand 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; the metal catalyst is a palladium catalyst;

[0008] (2) coupling reaction of compound A4 with compound A8 in a solvent in the presence of an acid to obtain compound A9;

[0009] X1 is halogen, such as F, Cl, Br or I;

[0010] 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-.

[0011] In some embodiments, X1 is Cl.

[0012] In some embodiments, the palladium catalyst is palladium acetate, tetrakis(triphenylphosphine)palladium or bistriphenylphosphine palladium dichloride; preferably palladium acetate.

[0013] In some embodiments, X2 and X3 are each independently H or C 1-6 alkyl.

[0014] In some embodiments, X2 and X3 are linked to form -C(CH3)2-C(CH3)2-, i.e. for

[0015] 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, a combination of an aromatic solvent and water, a combination of a nitrile solvent and water, a combination of an amide solvent and water, an aromatic solvent, a nitrile solvent, a sulfoxide solvent or an amide solvent; preferably a combination of an alcohol solvent and water, a combination of an aromatic solvent and water, a combination of a nitrile solvent and water, or a combination of an amide solvent and water.

[0016] In some embodiments, in step (1), the alcohol solvent is isopropanol.

[0017] In some embodiments, in step (1), the ether solvent is dioxane and / or dimethyl ether.

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

[0019] In some embodiments, in step (1), the nitrile solvent is acetonitrile.

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

[0021] In some embodiments, in step (1), the amide solvent is N,N-dimethylformamide.

[0022] In some embodiments, in step (1), when the solvent is a combination of an alcohol solvent and water, the mass ratio of the alcohol solvent to the water is (4-20):1, preferably 11.9:1.

[0023] In some embodiments, in step (1), the salt of Compound A2 is in the form of hydrochloride salt of Compound A2.

[0024] 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.

[0025] In some embodiments, in step (1), the "salt of compound A2" and "compound B3" undergo a coupling reaction to obtain compound A4.

[0026] In some embodiments, in step (1), the compound B3 is in free form.

[0027] 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 phosphate.

[0028] In some embodiments, in step (1), the ligand is a bidentate phosphine ligand or a biaryl phosphine ligand, such as BrettPhos RuPhos Xphos SPhos Bippyphos CyPF-t-Bu Josiphos 、BINAP tBuXphos Me4tBuXphos tBuBrettPhos DavePhos JohnPhos JackiePhos (R)-(S)-Cy2PF-PtBu2 XantPhos or PCy3HBF4; preferably RuPhos, Sphos, Xphos or PCy3HBF4, more preferably RuPhos.

[0029] In some embodiments, in step (1), the molar ratio of the compound B3 to the compound A2 is (1-1.1):1, such as 1.1:1, 1.05:1 or 1.0:1, preferably 1.1:1.

[0030] In some embodiments, in step (1), the molar ratio of the metal catalyst to the compound A2 is (0.01-0.02):1, such as 0.01:1 or 0.02:1, preferably 0.01:1.

[0031] In some embodiments, in step (1), the molar ratio of the base to the compound A2 is (3.0-5.0):1, such as 3.0:1, 4.0:1 or 5.0:1, preferably 3.0:1.

[0032] In some embodiments, in step (1), the molar ratio of the ligand to the compound A2 is 0.01:1 to 0.03:1, preferably 0.02:1.

[0033] In some embodiments, in step (1), when the solvent is a combination of an alcohol solvent and water, the volume molar ratio of the water to the compound A2 is 0.20 L / mol to 0.40 L / mol, preferably 0.35 L / mol.

[0034] In some embodiments, in step (1), the reaction temperature of the coupling reaction is 80-120°C, preferably 75-85°C.

[0035] In some embodiments, in step (1), the reaction time of the coupling reaction is 4-8 hours, preferably 6 hours.

[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 a palladium removal step, preferably using both N-acetyl-L-cysteine ​​and activated carbon for palladium removal; the molar ratio of the N-acetyl-L-cysteine ​​to the compound A2 is preferably 0.1:1; and the mass percentage of the activated carbon in the reaction system is preferably 10%.

[0038] In some embodiments, in step (1), the coupling reaction includes the following post-treatment steps: separation (e.g., separation using purified water), concentration (e.g., first concentrating the organic phase and then adding ethyl acetate to concentrate), extraction (e.g., using ethyl acetate and water), palladium removal, filtration, washing (e.g., washing with aqueous sodium carbonate solution and saturated brine), concentration (e.g., first concentrating and then adding methyl tert-butyl ether and n-heptane to concentrate, and then adding n-heptane to concentrate) and recrystallization (e.g., recrystallization using n-heptane and / or methyl tert-butyl ether).

[0039] In some embodiments, in step (2), the solvent is an alcohol solvent, such as isopropyl alcohol.

[0040] In some embodiments, in step (2), the acid is an organic strong acid or an inorganic strong acid, and the organic strong acid may be 2,4,6-trinitrophenol (picric acid), 2,4,6-trinitrobenzoic acid (pyropicric acid), trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, cyclohexanethiolsulfonic acid or p-toluenesulfonic acid; the inorganic strong acid may be concentrated hydrochloric acid, an organic solution of hydrogen chloride (such as hydrogen chloride isopropanol, hydrogen chloride ethyl acetate, hydrogen chloride methanol, hydrogen chloride ethanol, hydrogen chloride dioxane solution), perchloric acid, hydroiodic acid, hydrobromic acid, sulfuric acid or nitric acid, preferably concentrated hydrochloric acid.

[0041] 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.

[0042] In some embodiments, in step (2), the molar ratio of the acid to the compound A4 is (1-1.5):1, for example, 1.2:1.

[0043] In some embodiments, in step (2), the molar volume ratio of the compound A4 to the solvent is 1:(6-15) mol / L, for example, 1:8 mol / L.

[0044] In some embodiments, in step (2), the coupling reaction temperature is 70-90°C, preferably 75-85°C.

[0045] 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.

[0046] In some embodiments, in step (2), the reaction time of the coupling reaction is 12 to 24 hours, for example, 24 hours.

[0047] In some embodiments, in step (2), the coupling reaction further comprises the following post-treatment steps: crystallization (e.g., using ethyl acetate for crystallization), filtration, washing (e.g., using ethyl acetate, dichloromethane, and washing with 10% sodium carbonate solution), separation, washing the organic phase (e.g., using 10% sodium carbonate solution for washing), concentration under reduced pressure, crystallization (e.g., using acetonitrile for crystallization), and drying.

[0048] 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;

[0049] X1 is F, Cl, Br or I.

[0050] In some embodiments, Compound A1 is subjected to a reduction reaction to obtain a salt of Compound A2.

[0051] In some embodiments, the reducing agent is iron powder and concentrated hydrochloric acid, stannous chloride dihydrate and concentrated hydrochloric acid, hydrazine hydrate and ferric chloride, Pd / C and H2, or Pt / C and H2, preferably Pt / C and H2.

[0052] In some embodiments, during the reduction reaction, the hydrogen pressure of the reaction system is 0.05-0.6 MPa, preferably 0.2-0.4 MPa, and more preferably normal pressure.

[0053] In some embodiments, in the reduction reaction, the reaction system is first replaced with nitrogen and then with hydrogen.

[0054] In some embodiments, in the reduction reaction, the solvent is an organic solvent, or a combination of an organic solvent and water, and the organic solvent is an ether solvent (such as tetrahydrofuran), an ester solvent (such as ethyl acetate) or an alcohol solvent (such as methanol or isopropanol); preferably, the solvent is an ester solvent, or a combination of an ester solvent and water; more preferably, the solvent is ethyl acetate, or a combination of ethyl acetate and water.

[0055] In some embodiments, in the reduction reaction, the molar volume ratio of the compound A1 to the organic solvent is (1-3):10 mol / L, for example, 2:10 mol / L.

[0056] In some embodiments, in the reduction reaction, when the solvent is a combination of an organic solvent and water, the mass ratio of the water to the compound A1 is 2% to 4%, for example, 3%.

[0057] In some embodiments, in the reduction reaction, the Pt / C is 3% Pt / C.

[0058] In some embodiments, in the reduction reaction, the mass percentage of the reducing agent to the compound A1 is 4% to 6%, for example, 5%.

[0059] In some embodiments, in the reduction reaction, the mass percentage of the Pt / C to the compound A1 is 4% to 6%, for example, 5%.

[0060] In some embodiments, the salt of Compound A2 is the hydrochloride salt form of Compound A2.

[0061] 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.

[0062] In some embodiments, the temperature of the reduction reaction is 40-70°C, such as 40-50°C.

[0063] In some embodiments, the reaction time of the reduction reaction is 18-20 h, for example 20 h.

[0064] In some embodiments, the reduction reaction further comprises the following post-processing steps: filtration, concentration (e.g., concentration under reduced pressure, or concentration under reduced pressure after adding ethyl acetate), cooling crystallization (e.g., cooling to -5 to 5°C), washing (e.g., eluting with ethyl acetate), and drying.

[0065] In some embodiments, when the hydrochloride form of the compound A2 is obtained, the post-treatment step further includes adding acid (for example, adding ethyl hydrochloride, the molar ratio of ethyl hydrochloride to the compound A1 is preferably 3:1 to 5:1, more preferably 4:1).

[0066] 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;

[0067] X2 and X3 are as defined in any one of the present invention.

[0068] In some embodiments, X2 and X3 are each independently H or C 1-6 alkyl.

[0069] In some embodiments, X2 and X3 are linked to form -C(CH3)2-C(CH3)2-, i.e. for for

[0070] In some embodiments, the "salt of compound B2" undergoes a reductive amination reaction with tetrahydropyrone and acetic acid.

[0071] In some embodiments, in the reductive amination reaction, the solvent is a halogenated alkane solvent, such as dichloromethane.

[0072] In some embodiments, the salt of Compound B2 is the hydrochloride salt form of Compound B2.

[0073] In some embodiments, when the salt of Compound B2 is in the form of a hydrochloride salt of Compound B2, the molar ratio of Compound B2 to hydrochloric acid is 1:1.

[0074] In some embodiments, the salt of Compound B3 is the hydrochloride salt form of Compound B3.

[0075] 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.

[0076] In some embodiments, in the reductive amination reaction, the reducing agent is sodium triacetoxyborohydride.

[0077] In some embodiments, in the reductive amination reaction, the molar ratio of the tetrahydropyrone to the compound B2 is (2-5):1, for example, 3.4:1.

[0078] 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, 1:1.

[0079] 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, 2.5:1.

[0080] In some embodiments, in the reductive amination reaction, the molar volume ratio of the compound B2 to the solvent is 1:(5-20) mol / L, for example, 1:10 mol / L.

[0081] In some embodiments, the reductive amination reaction further comprises the following post-treatment steps: concentration (e.g., concentration under reduced pressure, or first concentration under reduced pressure followed by addition of methyl tert-butyl ether and concentration under reduced pressure), crystallization (e.g., crystallization in methyl tert-butyl ether);

[0082] Furthermore, the reductive amination reaction further comprises the following post-treatment steps: quenching (e.g., quenching with a 10% NaOH aqueous solution), filtration (e.g., filtration with diatomaceous earth), extraction (e.g., extraction with dichloromethane and water), drying (e.g., drying with anhydrous sodium sulfate), filtration, washing (e.g., washing with methyl tert-butyl ether), and drying.

[0083] In some embodiments, the temperature of the reductive amination reaction is room temperature (eg, 15-25° C.).

[0084] In some embodiments, the reaction time of the reductive amination reaction is 6-12 h, for example 6 h.

[0085] 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;

[0086] X4 is an amino protecting group; X2 and X3 are as defined in any one of the present invention.

[0087] In some embodiments, the amino protecting group is a group conventionally used in the art to protect amino groups, such as -Boc.

[0088] In some embodiments, X2 and X3 are linked to form -C(CH3)2-C(CH3)2-, i.e. for

[0089] In some embodiments, X2 and X3 are each independently H or C 1-6 alkyl.

[0090] In some embodiments, for

[0091] In some embodiments, Compound B1 is subjected to a deprotection reaction to obtain a salt of Compound B2.

[0092] In some embodiments, in the deprotection reaction, the solvent is an ester solvent, such as ethyl acetate.

[0093] In some embodiments, the salt of Compound B2 is the hydrochloride salt form of Compound B2.

[0094] In some embodiments, when the salt of Compound B2 is in the form of a hydrochloride salt of Compound B2, the molar ratio of Compound B2 to hydrochloric acid is 1:1.

[0095] In some embodiments, in the deprotection reaction, the acid in the acidic conditions 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 4 M. The mass ratio of the hydrogen chloride ethyl acetate solution to the compound B1 is (3-10):1, for example, 3.7:1.

[0096] In some embodiments, in the deprotection reaction, the mass ratio of the compound B1 to the solvent is 1:(3-20), for example, 1:3.2.

[0097] In some embodiments, the deprotection reaction is performed at room temperature (eg, 25-35° C.).

[0098] In some embodiments, the deprotection reaction time is 2 to 6 hours.

[0099] In some embodiments, the deprotection reaction further comprises the following post-treatment steps: concentration under reduced pressure (e.g., concentrating the reaction solution under reduced pressure to ≤2.5-3.5 v / w), crystallization (e.g., stirring and crystallizing in methyl tert-butyl ether), filtration, washing (e.g., washing with methyl tert-butyl ether), and drying.

[0100] The present invention also provides a method for preparing compound A4, which comprises the following reaction steps: in a solvent, in the presence of a metal catalyst, a ligand and a base, coupling reaction of "compound A2 or a salt thereof" with "compound B3 or a salt thereof" to obtain compound A4; the metal catalyst is a palladium catalyst;

[0101] X1 is halogen, such as F, Cl, Br or I;

[0102] 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-.

[0103] In some embodiments, X2 and X3 are linked to form -C(CH3)2-C(CH3)2-, i.e. for

[0104] In some embodiments, the steps and reaction conditions in the preparation method of compound A4 are as described in any of the above items.

[0105] The present invention also provides a method for preparing compound A2, comprising 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;

[0106] X1 is F, Cl, Br or I;

[0107] The reducing agent is iron powder and concentrated hydrochloric acid, hydrazine hydrate and ferric chloride, Pd / C and H2, or Pt / C and H2.

[0108] In some embodiments, the steps and reaction conditions in the preparation method of compound A2 are as described in any of the previous items.

[0109] 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.

[0110] The reagents and raw materials used in the present invention are commercially available.

[0111] 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

[0112] 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.

[0113] In the following examples, w / w refers to the mass ratio of the substance to the reaction standard; V refers to the volume mass ratio of the solvent to the reaction standard; in the following examples, the reaction standard substances are B1', B2', B5a', B5' and B6', respectively.

[0114] Example 1—Preparation of Intermediate B2'

[0115] Ethyl acetate (357.55 kg, 3.2 w / w) was added to the reaction flask, stirring was started, and the reaction material B1' (111.40 kg, 1.0 w / w) was added. The temperature was raised to 25-35°C, and stirring was performed to dissolve the solids completely. A 4M HCl / EA solution (421.85 kg, 3.7 w / w) was then added dropwise. After the addition was complete, the temperature was controlled at 25-35°C, and the mixture was stirred for 2-6 hours before sampling. After the reaction was complete, the reaction solution was concentrated under reduced pressure to ≤ 2.5-3.5 v / w. Methyl tert-butyl ether (410.70 kg, 3.7 w / w) was added, the system temperature was controlled at 20-30°C, and crystallization was stirred for 6-10 hours. The mixture was filtered, and the filter cake was washed with methyl tert-butyl ether (83.45 kg, 0.75 w / w) and dried. 87.20 kg of the product was obtained, with a yield of 99% and a purity of 98.8%.

[0116] Example 2—Preparation of Intermediate B4'

[0117] To the reaction flask, dichloromethane (915.95 kg, 10.7 w / w), acetic acid (20.65 kg, 0.9 eq), B2' (85.26 kg, 1.0 eq), B3' (119.60 kg, 3.4 eq) were added in sequence, stirred evenly, and the temperature was controlled at 15±5°C. Sodium triacetoxyborohydride (185.70 kg, 2.5 eq) was added in batches. After the addition was completed, the temperature was controlled at 20±5°C, and the reaction was stirred for 6 h. After the reaction was completed, the reaction was continued. The reaction mixture was quenched by adding a 10% aqueous solution of NaOH, stirred, allowed to stand, separated, and the organic phase was filtered (diatomaceous earth). The aqueous phase was extracted with dichloromethane. The organic phases were combined, and anhydrous sodium sulfate (17.20 kg) was added in sequence. The mixture was concentrated under reduced pressure. Methyl tert-butyl ether was added, and the mixture was concentrated under reduced pressure. The temperature was controlled at 20±5°C, and methyl tert-butyl ether was added dropwise with stirring. After the addition was complete, the temperature was lowered to -5 to 5°C, and crystallization was stirred for 2 to 4 hours. The mixture was filtered, and the filter cake was washed with methyl tert-butyl ether and dried to obtain 88.7 kg of the product as a white solid with a yield of 87% and a purity of 99.5%.

[0118] When the inventors began to study the process, they found that in the post-processing vacuum concentration and purification steps, slurrying with ethyl acetate and n-heptane resulted in a granular, light yellow product, which was not conducive to product quality control. Therefore, they developed a recrystallization method for purifying B4' using methyl tert-butyl ether.

[0119] Example 3 - Preparation of Intermediate B5'

[0120] Ethyl acetate (587.1 kg, 9.0 w / w), B5a' (65.05 kg, 1.0 eq), 3% Pt / C (3.3 kg, 0.05 w / w), purified water (1.90 kg, 0.029 w / w) were added to the autoclave, and the atmosphere was replaced with nitrogen and then hydrogen. The hydrogen pressure was controlled at 0.2-0.4 MPa and the temperature was 40-50°C. After the reaction was completed for 18-20 h, a sample was taken for control. After the reaction was completed, the system was cooled to 20 The reaction mixture was stirred at 15-30°C, filtered to remove the platinum carbon, and concentrated under reduced pressure to a remaining 3V. The temperature was controlled at 15-30°C, and 3.8eq of ethyl acetate was added dropwise to the system. After the addition was complete, the mixture was stirred at controlled temperature for 8-10 hours, controlled at ≤50°C, and concentrated under reduced pressure to a remaining 3V. 3V of ethyl acetate was added to the system, controlled at ≤50°C, and concentrated under reduced pressure to a remaining 3V. The system was further cooled to -5-5°C, stirred for 2-4 hours, filtered, and the filter cake was rinsed with ethyl acetate and dried to obtain 60.20kg. The reaction yield was 90% and the purity was 99.5%.

[0121] The inventors further studied the hydrogen pressure, the stability of the reaction system at high temperature, the type of reducing agent and the type of solvent, as follows:

[0122] (1) The inventors further screened the pressure of hydrogen, and the results were as follows:

[0123] As shown in the table above, when the hydrogen pressure was adjusted to 1.0-1.5 MPa and the reaction time was 20 h, the product purity was only 89.84%. Considering the large production system, the reaction time may need to be extended. At a pressure of 0.2-0.4 MPa, the reaction was stable for 70 h, with no significant change in the system purity, still reaching over 99%.

[0124] (2) The reaction system was reacted at 60-70°C for 72 hours, and the reaction purity did not change significantly, indicating that under this condition, the reaction system was stable within 72 hours. (3) The inventors further optimized and adjusted the type of reducing agent, and obtained the following results.

[0125] (4) The inventors further screened the types of solvents, and the results were as follows:

[0126] Example 4 - Preparation of Intermediate B6'

[0127] Add isopropanol (653.0 kg, 11.9 w / w), water (55.10 kg, 1.0 w / w), potassium phosphate (149.10 kg, 3.0 eq) to the reaction bottle, start stirring, control the temperature at 15 ~ 30 ° C, add B4' (73.30 kg, 1.10 eq), B5' (55.10 kg, 1.00 eq) in sequence, replace with nitrogen, control the temperature of the system at 15 ~ 30 ° C, add palladium acetate (0.525 kg, 0.01 eq), RuPhos (2.10 kg, 0.02 eq), replace with nitrogen, heat to 80 ± 5 ° C, react for 4 ~ 8 h, take samples and control, wait until the reaction is completed, and cool down. The mixture was cooled to ≤50°C, purified water was added, the temperature was controlled at 20-30°C, stirring was continued for 0.5-1 hour, the liquid phase was separated, the organic phase was retained, concentrated, ethyl acetate was added, concentrated, ethyl acetate and water were added, the mixture was allowed to stand, the liquid phase was separated, N-acetyl-L-cysteine ​​(0.1 eq) and activated carbon (10% w / w) were added simultaneously, the mixture was stirred at 50°C for 1-3 hours, filtered, washed with aqueous sodium carbonate solution and saturated brine in sequence, concentrated, methyl tert-butyl ether and n-heptane were added dropwise at 20-30°C with stirring, the mixture was kept stirring for 1-2 hours, concentrated again, n-heptane was added, the temperature was cooled to -5-5°C, stirred and crystallized for 4 hours, filtered, the filter cake was rinsed with n-heptane, and dried to obtain 67.7 kg. The reaction yield was 87% and the purity was 99.4%.

[0128] Referring to the above preparation method, the ligand types were optimized and adjusted, and the obtained results are as follows.

[0129] Furthermore, the inventors optimized the palladium removal process in the post-processing step, and the results are as follows.

[0130] When N-acetyl-L-cysteine ​​is used to remove palladium, the impurities in the system will increase. Therefore, the number of palladium removal operations with N-acetyl-L-cysteine ​​needs to be reduced. Combining the activated carbon palladium removal operation with the N-acetyl-L-cysteine ​​palladium removal operation can reduce the operation time and the possibility of liquid separation and emulsification, and at the same time, the Pd residue can be controlled to below 200 ppm.

[0131] Example 5 - Preparation of Intermediate B8'

[0132] Under nitrogen protection, B6' (30.1 kg, 1.0 eq), B7' (37.85 kg, 1.05 eq) and isopropanol (192.64 kg, 6.4 w / w) were added to a three-necked flask. Concentrated hydrochloric acid (1.2 eq) was added dropwise to the system under nitrogen protection. The temperature was raised to 75-85°C with stirring and the reaction was stirred for 24 h. After the reaction was completed, the temperature was lowered to 60-70°C, and ethyl acetate (240 L, 8 V) was added dropwise. The system temperature was lowered to room temperature, stirred at room temperature for 12-16 h, filtered, and the filter cake was washed with ethyl acetate and collected.

[0133] Add dichloromethane (180L, 6V) to the filter cake and stir for 30 minutes. Add 10% sodium carbonate solution under stirring and stir for 30 to 60 minutes to ensure that the system is dissolved clearly. Let it stand and separate the layers. Collect the organic phase and wash the organic phase with 10% sodium carbonate solution. Stir for 30 minutes to ensure that the pH of the water layer is greater than 8. Let it stand and separate the layers. Collect the organic phase and wash the organic phase with water. Let it stand and separate the layers. Collect the organic phase and concentrate the organic phase under reduced pressure. Add acetonitrile to the concentrated residue and stir overnight at room temperature. Filter and wash the filter cake with acetonitrile and collect the filter cake.

[0134] Add acetonitrile to the filter cake, replace with nitrogen while stirring, and protect with nitrogen (note: avoid light), stir and heat to 75-85°C, stir for 0.5-1.5h, cool to room temperature, stir overnight, filter, wash the filter cake with acetonitrile, collect the filter cake, and vacuum dry to obtain 51.78kg, with a yield of about 89% and a purity of 99.84%.

[0135] Example 5 was repeated, except that concentrated hydrochloric acid was replaced with p-toluenesulfonic acid, resulting in a product yield of 74%. Since p-toluenesulfonic acid and alcohol solvents easily form genotoxic impurities during heating, which is not conducive to subsequent process development, a process using concentrated hydrochloric acid as the acid catalyst was developed.

Claims

1. A preparation method of compound A9, which comprises the following reaction steps: (1) In a solvent, in the presence of a metal catalyst, a ligand and a base, coupling "compound A2 or its salt" with "compound B3 or its salt" to obtain compound A4; the metal catalyst is a palladium catalyst; (2) In a solvent, in the presence of an acid, compound A4 is coupled with compound A8 to obtain compound A9; X1 is Cl, Br or I; X2 and X3 are each independently H or C 1-6 alkyl; or, X2 and X3 are joined to form -C(CH3)2-C(CH3)2-.

2. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1)X2 and X3 are connected to form -C(CH3)2-C(CH3)2-, that is For (2) X1 is Cl or I; preferably Cl; (3) The palladium catalyst is palladium acetate, tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride; preferably palladium acetate; (4) In step (1), the solvent is one or more of alcohol solvents, ether solvents, aromatic solvents, nitrile solvents, sulfoxide solvents, amide solvents and water. For example, a combination of an alcohol solvent and water, a combination of an ether solvent and water, a combination of an aromatic solvent and water, a combination of a nitrile solvent and water, a combination of an amide solvent and water, an aromatic solvent, a nitrile solvent, a sulfoxide solvent or an amide solvent; preferably a combination of an alcohol solvent and water, a combination of an aromatic solvent and water, a combination of a nitrile solvent and water, or a combination of an amide solvent and water; (5) In step (1), the salt of compound A2 is the hydrochloride form of compound A2; (6) In step (1), compound B3 is in the free form; (7) In step (1), the base is a carbonate of an alkali metal and / or a phosphate of an alkali metal, such as potassium carbonate and / or potassium phosphate; preferably potassium phosphate; (8) In step (1), the ligand is a bidentate phosphine ligand or a biarylphosphine ligand, such as BrettPhos, RuPhos, Xphos, SPhos, Bippyphos, CyPF-t-Bu, Josiphos, BINAP, tBuXphos, Me4tBuXphos, tBuBrettPhos, DavePhos, JohnPhos, JackiePhos, (R)-(S)-Cy2PF-PtBu2, XantPhos or PCy3HBF4; preferably RuPhos, Sphos, Xphos or PCy3HBF4; (9) In step (1), the molar ratio of compound B3 to compound A2 is (1 - 1.1):1, such as 1.1:1, 1.05:1 or 1.0:1; (10) In step (1), the molar ratio of the metal catalyst to compound A2 is (0.01 - 0.02):1, such as 0.01:1 or 0.02:1; (11) In step (1), the molar ratio of the base to compound A2 is (3.0 - 5.0):1, such as 3.0:1, 4.0:1 or 5.0:1; (12) In step (1), the molar ratio of the ligand to compound A2 is 0.01:1 to 0.03:1; (13) In step (1), the reaction temperature of the coupling reaction is 80 - 120 °C; (14) In step (1), the reaction time of the coupling reaction is 4 - 8 hours; (15) In step (1), the coupling reaction is carried out under inert gas protection; (16) In step (1), the coupling reaction further includes a step of removing palladium, such as using one or more of N-acetyl-L-cysteine, activated carbon and L-cysteine, preferably using N-acetyl-L-cysteine and activated carbon simultaneously to remove palladium; (17) In step (1), the coupling reaction includes the following post-treatment steps: liquid separation, concentration, extraction, palladium removal, filtration, washing, concentration, and recrystallization; (18) In step (1), "the salt of compound A2" reacts with "compound B3" through a coupling reaction to obtain compound A4.

3. The preparation method according to claim 2, characterized in that, One or more of the following conditions are satisfied: (1) In step (1), the alcohol solvent is isopropanol; (2) In step (1), the ether solvent is dioxane and / or methyl ether; (3) In step (1), the aromatic solvent is toluene; (4) In step (1), the nitrile solvent is acetonitrile; (5) In step (1), the sulfoxide solvent is dimethyl sulfoxide; (6) In step (1), the amide solvent is N,N-dimethylformamide; (7) In step (1), when the solvent is a combination of an alcohol solvent and water, the mass ratio of the alcohol solvent to the water is (4 - 20):1, preferably 11.9:1; (8) In step (1), when the salt of compound A2 is in the form of the hydrochloride of compound A2, the molar ratio of compound A2 to hydrochloric acid is 1:1; (9) In step (1), the ligand is RuPhos; (10) In step (1), the molar ratio of compound B3 to compound A2 is 1.1:1; (11) In step (1), the molar ratio of the metal catalyst to compound A2 is 0.01:1; (12) In step (1), the molar ratio of the base to compound A2 is 3.0:1; (13) In step (1), the molar ratio of the ligand to compound A2 is 0.02:1; (14) In step (1), when the solvent is a combination of an alcohol solvent and water, the volume molar ratio of water to compound A2 is 0.20 L / mol to 0.40 L / mol, preferably 0.35 L / mol; (15) In step (1), the reaction temperature of the coupling reaction is 75 - 85 °C; (16) In step (1), the reaction time of the coupling reaction is 6 hours; (17) In step (1), the coupling reaction is carried out under nitrogen protection; (18) In step (1), when the coupling reaction also includes the step of removing palladium using N-acetyl-L-cysteine and activated carbon simultaneously; the molar ratio of N-acetyl-L-cysteine to compound A2 is 0.1:1; the mass percentage of activated carbon in the reaction system is 10%.

4. The preparation method according to claim 1, characterized in that, One or more of the following conditions are satisfied: (1) In step (2), the solvent is an alcohol solvent; (2) In step (2), the acid is an organic strong acid or an inorganic strong acid; the organic strong acid can be 2,4,6-trinitrophenol, 2,4,6-trinitrobenzoic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, cyclohexanethiol sulfonic acid, or p-toluenesulfonic acid, preferably p-toluenesulfonic acid; the inorganic strong acid can be concentrated hydrochloric acid, an organic solution of hydrogen chloride, perchloric acid, hydroiodic acid, hydrobromic acid, sulfuric acid, or nitric acid, preferably concentrated hydrochloric acid; (3) In step (2), the molar ratio of the compound A8 to the compound A4 is (1 - 1.5):1; (4) In step (2), the molar ratio of the acid to the compound A4 is (1 - 1.5):1; (5) In step (2), the molar volume ratio of the compound A4 to the solvent is 1:(6 - 15) mol / L; (6) In step (2), the temperature of the coupling reaction is 70 - 90 °C; (7) In step (2), the coupling reaction is carried out under the protection of an inert gas; (8) In step (2), the reaction time of the coupling reaction is 12 - 24 h; (9) In step (2), the coupling reaction further includes the following post-treatment steps: crystallization, filtration, washing, liquid separation, washing the organic phase, concentration under reduced pressure, crystallization, and drying.

5. The preparation method according to claim 4, characterized in that, It satisfies one or more of the following conditions: (1) When the inorganic strong acid is an organic solution of hydrogen chloride, the organic solution of hydrogen chloride is hydrogen chloride in isopropanol, hydrogen chloride in ethyl acetate, hydrogen chloride in methanol, hydrogen chloride in ethanol, or hydrogen chloride in dioxane solution; (2) In step (2), the molar ratio of the compound A8 to the compound A4 is 1.05:1; (3) In step (2), the molar ratio of the acid to the compound A4 is 1.2:1; (4) In step (2), the molar volume ratio of the compound A4 to the solvent is 1:8 mol / L; (5) In step (2), the temperature of the coupling reaction is 75 - 85 °C; (6) In step (2), the coupling reaction is carried out under the protection of nitrogen; (7) In step (2), the reaction time of the coupling reaction is 24 h.

6. The preparation method according to claim 1, wherein, The preparation method of the said compound A9 further comprises the following steps: in a solvent, under the action of a reducing agent, compound A1 undergoes a reduction reaction to obtain compound A2 or its salt; X1 is Cl, Br, or I.

7. The preparation method according to claim 6, characterized in that, It satisfies one or more of the following conditions: (1) The reducing agent is iron powder and concentrated hydrochloric acid, stannous chloride dihydrate and concentrated hydrochloric acid, hydrazine hydrate and ferric chloride, Pd / C and H2, or Pt / C and H2; (2) In the reduction reaction, the hydrogen pressure of the reaction system is 0.05 - 0.6 MPa; preferably 0.2 - 0.4 MPa, more preferably atmospheric pressure; (3) In the reduction reaction, the reaction system is first purged with nitrogen and then with hydrogen; (4) In the reduction reaction, the solvent is an organic solvent, or a combination of an organic solvent and water, and the organic solvent is an ether solvent, an ester solvent, or an alcohol solvent; preferably, the solvent is an ester solvent, or a combination of an ester solvent and water; more preferably, the solvent is ethyl acetate, or a combination of ethyl acetate and water; (5) In the reduction reaction, the molar volume ratio of the compound A1 to the organic solvent is (1 - 3):10 mol / L; (6) In the reduction reaction, when the solvent is a combination of an organic solvent and water, the mass ratio of water to the compound A1 is 2% - 4%; (7) In the reduction reaction, when the reducing agent is Pt / C and hydrogen, the Pt / C is 3% Pt / C; (8) In the reduction reaction, the mass percentage of the reducing agent to the compound A1 is 4% - 6%; (9) The salt of the compound A2 is the hydrochloride form of the compound A2; (10) The temperature of the reduction reaction is 40 to 70 °C; (11) The reaction time of the reduction reaction is 18 - 20 h; (12) The reduction reaction further includes the following post-treatment steps: filtration, concentration, cooling crystallization, washing, and drying.

8. The preparation method according to claim 7, characterized in that, It satisfies one or more of the following conditions: (1) In the reduction reaction, the ether solvent is tetrahydrofuran; (2) In the reduction reaction, the ester solvent is ethyl acetate; (3) In the reduction reaction, the alcohol solvent is methanol or isopropanol; (4) In the reduction reaction, the molar volume ratio of the compound A1 to the organic solvent is 2:10 mol / L; (5) In the reduction reaction, when the solvent is a combination of an organic solvent and water, the mass ratio of water to the compound A1 is 3%; (6) In the reduction reaction, the mass percentage of the reducing agent to the compound A1 is 5%; (7) 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; (8) The temperature of the reduction reaction is 40 to 50 °C; (9) The reaction time of the reduction reaction is 20 h; (10) When obtaining the hydrochloride form of the compound A2, the post-treatment step further includes adding an acid, such as adding ethyl acetate hydrochloride, and the molar ratio of the ethyl acetate hydrochloride to the compound A1 is preferably 3:1 to 5:1, more preferably 4:

1.

9. The preparation method according to claim 1, characterized in that, The preparation method of the said compound A9 further comprises the following steps: in a solvent, under the action of a reducing agent, "compound B2 or its salt" undergoes a reductive amination reaction with tetrahydropyranone and acetic acid to obtain compound B3 or its salt; 10. The preparation method according to claim 9, characterized in that, It satisfies 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 in the form of the hydrochloride of the compound B2; (3) The compound B3 is in the free form; (4) In the reductive amination reaction, the reducing agent is sodium triacetoxyborohydride; (5) In the reductive amination reaction, the molar ratio of the tetrahydropyranone to the compound B2 is (2 - 5):1; (6) In the reductive amination reaction, the molar ratio of 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 molar volume ratio of the compound B2 to the solvent is 1:(5 - 20) mol / L; (9) The reductive amination reaction further includes the following post-treatment steps: concentration and crystallization; (10) The temperature of the reductive amination reaction is room temperature; (11) The reaction time of the reductive amination reaction is 6 - 12 h.

11. The preparation method according to claim 10, characterized in that, It satisfies 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) In the reductive amination reaction, the molar ratio of the tetrahydropyranone to the compound B2 is 3.4:1; (4) In the reductive amination reaction, the molar ratio of acetic acid to the compound B2 is 1:1; (5) In the reductive amination reaction, the molar ratio of the reducing agent to compound B2 is 2.5:1; (6) In the reductive amination reaction, the molar volume ratio of compound B2 to the solvent is 1:10 mol / L; (7) In the reductive amination reaction, in the post-treatment step, the concentration is carried out under reduced pressure, for example, first concentrated under reduced pressure and then concentrated under reduced pressure after adding methyl tert-butyl ether; (8) In the reductive amination reaction, in the post-treatment step, the crystallization is carried out in methyl tert-butyl ether; (9) The reductive amination reaction further includes the following post-treatment steps: quenching, filtration, extraction, drying, filtration, washing and drying; (10) The temperature of the reductive amination reaction is 15 - 25 °C; (11) The reaction time of the reductive amination reaction is 6 h; (12) "The salt of compound B2" undergoes a reductive amination reaction with tetrahydropyranone and acetic acid.

12. The preparation method according to claim 9, characterized in that, The method for preparing the compound A9 further comprises the following steps: in a solvent and under acidic conditions, the compound B1 undergoes a deprotection reaction to obtain the compound B2 or a salt thereof; X4 is an amino protecting group.

13. The preparation method according to claim 12, characterized in that, It satisfies one or more of the following conditions: (1) The amino protecting group is -Boc; (2) In the deprotection reaction, the solvent is an ester solvent; (3) The salt of compound B2 is the hydrochloride form of compound B2; (4) In the deprotection reaction, the acid in the acidic condition is hydrogen chloride; the hydrogen chloride can be added in the form of an ethyl acetate solution of hydrogen chloride; (5) In the deprotection reaction, the mass ratio of compound B1 to the solvent is 1:(3 - 20); (6) The deprotection reaction is carried out at room temperature; (7) The reaction time of the deprotection reaction is 2 - 6 hours; (8) The deprotection reaction further includes the following post-treatment steps: concentration under reduced pressure, crystallization, filtration, washing and drying.

14. The preparation method according to claim 13, characterized in that, It satisfies one or more of the following conditions: (1) In the deprotection reaction, the solvent is ethyl acetate; (2) When the salt of compound B2 is the hydrochloride form of compound B2, the molar ratio of compound B2 to hydrochloric acid is 1:1; (3) The concentration of the ethyl acetate solution of hydrogen chloride can be 4 M; the mass ratio of the ethyl acetate solution of hydrogen chloride to compound B1 is (3 - 10):1, for example, 3.7:1; (4) In the deprotection reaction, the mass ratio of compound B1 to the solvent is 1:3.2; (5) The reaction temperature of the deprotection reaction is 25 - 35 °C.

15. A method for preparing compound A4, which comprises the following reaction steps: in a solvent, in the presence of a metal catalyst, a ligand and a base, coupling "compound A2 or its salt" with "compound B3 or its salt" to obtain compound A4; the metal catalyst is a palladium catalyst; X1 is Cl, Br or I; X2 and X3 are each independently H or C 1-6 alkyl; or, X2 and X3 are joined to form -C(CH3)2-C(CH3)2-; The steps and reaction conditions in the preparation method of compound A4 are as described in any one of claims 1 - 3.

16. A method for preparing a compound A2, comprising the following steps: In a solvent, under the action of a reducing agent, compound A1 undergoes a reduction reaction to obtain compound A2 or its salt; X1 is Cl, Br or I; The reducing agent is iron powder and concentrated hydrochloric acid, hydrazine hydrate and ferric chloride, Pd / C and H2, or Pt / C and H2; The steps and reaction conditions in the preparation method of compound A2 are as described in any one of claims 6 - 8.

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