ALK inhibitor compound and preparation method of intermediate thereof

Abstract

The invention discloses a preparation method of an ALK inhibitor compound and an intermediate thereof, and particularly provides a preparation method of a compound A9, which comprises the following reaction steps: (1) in a solvent, in the presence of a metal catalyst, a ligand and alkali, carrying out coupling reaction on a compound A2 or a salt thereof and a compound B3 or a salt thereof to obtain a compound A4; the metal catalyst is a palladium catalyst; and (2) in a solvent, in the presence of an acid, carrying out a coupling reaction on the compound A4 and a compound A8 to obtain a compound A9. The preparation method disclosed by the invention has the advantages of proper reaction steps, simplicity and convenience in operation, cheap and easily available reaction raw materials, environment friendliness, simplicity and convenience in post-treatment, low safety risk, shorter production period, lower production cost and the like. # imgabs0 #

Description

[0001] This application claims the priority of Chinese Patent Application No. 2024100195681 with a filing date of January 5, 2024. This application incorporates the entire text of the above-mentioned Chinese patent application by reference. 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 hematopoietic and non-hematopoietic tumors. Abnormal expression of the full-length ALK receptor protein has been reported in neuroblastoma and glioblastoma; and ALK fusion proteins are present in anaplastic large cell lymphoma. The study of ALK fusion proteins also presents the possibility of new treatment options 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 as an ALK inhibitor, and the preparation route is as follows:

[0005]

[0006] This route has a long production cycle, uses a large amount of palladium catalyst, high production cost, and a complex synthesis route. Summary of the Invention

[0007] The technical problem to be solved by the present invention is that the existing methods for preparing ALK inhibitors have a long production cycle, high production cost, and a complex synthesis route. The present invention provides a method for preparing an ALK inhibitor compound and an intermediate thereof, and the preparation method has advantages such as appropriate reaction steps, simple operation, inexpensive and easily available reaction raw materials, environmental friendliness, simple post-treatment, low safety risk, reduced production cycle, and reduced production cost.

[0008] 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, coupling "compound A2 or its salt" with "compound B3 or its salt" to obtain compound A4; the metal catalyst is a palladium catalyst;

[0009]

[0010] (2) In a solvent, in the presence of an acid, coupling compound A4 with compound A8 to obtain compound A9;

[0011]

[0012] X1 is a halogen, such as F, Cl, Br or I;

[0013] X2 and X3 are each independently H or C 1-6 alkyl; or, X2 and X3 are connected to form -C(CH3)2-C(CH3)2-.

[0014] In some embodiments, X1 is Cl.

[0015] In some embodiments, the palladium catalyst is palladium acetate, tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride; preferably palladium acetate.

[0016] In some embodiments, X2 and X3 are each independently H or C 1-6 alkyl.

[0017] In some embodiments, X2 and X3 are connected to form -C(CH3)2-C(CH3)2-, that is is

[0018] 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.

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

[0020] In some embodiments, in step (1), the ether solvent is dioxane and / or methyl ether.

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

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

[0023] In some embodiments, in step (1), the sulfoxide solvent is dimethyl sulfoxide.

[0024] In some embodiments, in step (1), the amide solvent is N,N-dimethylformamide.

[0025] 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.

[0026] In some embodiments, in step (1), the salt of compound A2 is the hydrochloride form of compound A2.

[0027] In some embodiments, in step (1), when the salt of compound A2 is the hydrochloride form of compound A2, the molar ratio of compound A2 to hydrochloric acid is 1:1.

[0028] In some embodiments, in step (1), "the salt of compound A2" and "compound B3" are subjected to a coupling reaction to obtain compound A4.

[0029] In some embodiments, in step (1), compound B3 is in the free form.

[0030] In some embodiments, 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.

[0031] 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

[0032] CyPF-t-Bu Josiphos

[0033] BINAP tBuXphos Me4tBuXphos tBuBrettPhos DavePhos JohnPhos JackiePhos (R)-(S)-Cy2PF-PtBu2 XantPhos or PCy3HBF4; preferably RuPhos, Sphos, Xphos or PCy3HBF4, more preferably RuPhos.

[0034] In some embodiments, 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, preferably 1.1:1.

[0035] In some embodiments, 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, preferably 0.01:1.

[0036] In some embodiments, 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, preferably 3.0:1.

[0037] In some embodiments, in step (1), the molar ratio of the ligand to compound A2 is 0.01:1 to 0.03:1, preferably 0.02:1.

[0038] In some embodiments, in step (1), when the solvent is a combination of an alcohol solvent and water, the molar ratio of water to compound A2 is 0.20 L / mol to 0.40 L / mol, preferably 0.35 L / mol.

[0039] In some embodiments, in step (1), the reaction temperature of the coupling reaction is 80 - 120 °C, preferably 75 - 85 °C.

[0040] In some embodiments, in step (1), the reaction time of the coupling reaction is 4 - 8 hours, preferably 6 hours.

[0041] In some embodiments, in step (1), the coupling reaction is carried out under the protection of an inert gas, such as under nitrogen protection.

[0042] In some embodiments, in step (1), the coupling reaction further includes a palladium removal step, preferably using N-acetyl-L-cysteine and activated carbon to remove palladium simultaneously; the molar ratio of N-acetyl-L-cysteine to compound A2 is preferably 0.1:1; the mass percentage of activated carbon in the reaction system is preferably 10%.

[0043] In some embodiments, in step (1), the coupling reaction includes the following post-treatment steps: liquid separation (for example, using purified water for liquid separation), concentration (for example, first concentrating the organic phase and then adding ethyl acetate for concentration), extraction (for example, using ethyl acetate and water), palladium removal, filtration, washing (for example, washing with an aqueous sodium carbonate solution and saturated brine), concentration (for example, first concentrating, then adding methyl tert-butyl ether and n-heptane for concentration, and then adding n-heptane for concentration), and recrystallization (for example, recrystallizing with n-heptane and / or methyl tert-butyl ether).

[0044] In some embodiments, in step (2), the solvent is an alcohol solvent, such as isopropyl alcohol.

[0045] In some embodiments, 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 (picric acid), 2,4,6-trinitrobenzoic acid (pyro picric acid), trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, cyclohexanethiol sulfonic acid, or p-toluenesulfonic acid; the inorganic strong acid can be concentrated hydrochloric acid, an organic solution of hydrogen chloride (such as hydrogen chloride in isopropyl alcohol, hydrogen chloride in ethyl acetate, hydrogen chloride in methanol, hydrogen chloride in ethanol, hydrogen chloride in dioxane solution), perchloric acid, hydroiodic acid, hydrobromic acid, sulfuric acid, or nitric acid, and preferably concentrated hydrochloric acid.

[0046] In some embodiments, in step (2), the molar ratio of compound A8 to compound A4 is (1 - 1.5):1, such as 1.05:1.

[0047] In some embodiments, in step (2), the molar ratio of the acid to compound A4 is (1 - 1.5):1, such as 1.2:1.

[0048] In some embodiments, in step (2), the molar volume ratio of compound A4 to the solvent is 1:(6 - 15) mol / L, such as 1:8 mol / L.

[0049] In some embodiments, in step (2), the temperature of the coupling reaction is 70 - 90 °C, preferably 75 - 85 °C.

[0050] In some embodiments, in step (2), the coupling reaction is carried out under the protection of an inert gas, such as under the protection of nitrogen.

[0051] In some embodiments, in step (2), the reaction time of the coupling reaction is 12 - 24 h, such as 24 h.

[0052] In some embodiments, in step (2), the coupling reaction further includes the following post-treatment steps: crystallization (e.g., crystallization using ethyl acetate), filtration, washing (e.g., washing with ethyl acetate, dichloromethane, and 10% sodium carbonate solution), liquid separation, washing the organic phase (e.g., washing with 10% sodium carbonate solution), concentration under reduced pressure, crystallization (e.g., crystallization using acetonitrile), and drying.

[0053] In some embodiments, the method for preparing 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 a salt thereof;

[0054]

[0055] X1 is F, Cl, Br, or I.

[0056] In some embodiments, compound A1 undergoes a reduction reaction to obtain a salt of compound A2.

[0057] 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.

[0058] In some embodiments, 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.

[0059] In some embodiments, in the reduction reaction, the reaction system is first purged with nitrogen and then with hydrogen.

[0060] In some embodiments, in the reduction reaction, the solvent is an organic solvent or a combination of an organic solvent and water. The organic solvent is an ether solvent (e.g., tetrahydrofuran), an ester solvent (e.g., ethyl acetate), or an alcohol solvent (e.g., 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.

[0061] In some embodiments, in the reduction reaction, the molar volume ratio of compound A1 to the organic solvent is (1 - 3):10 mol / L, e.g., 2:10 mol / L.

[0062] In some embodiments, in the reduction reaction, when the solvent is a combination of an organic solvent and water, the mass ratio of water to compound A1 is 2% - 4%, e.g., 3%.

[0063] In some embodiments, in the reduction reaction, the Pt / C is 3% Pt / C.

[0064] In some embodiments, in the reduction reaction, the mass percentage of the reducing agent to the compound A1 is 4% to 6%, such as 5%.

[0065] In some embodiments, in the reduction reaction, the mass percentage of Pt / C to the compound A1 is 4% to 6%, such as 5%.

[0066] In some embodiments, the salt of the compound A2 is the hydrochloride form of the compound A2.

[0067] In some embodiments, when the salt of the compound A2 is the hydrochloride form of the compound A2, the molar ratio of the compound A2 to hydrochloric acid is 1:1.

[0068] In some embodiments, the temperature of the reduction reaction is 40 to 70 °C, such as 40 to 50 °C.

[0069] In some embodiments, the reaction time of the reduction reaction is 18 - 20 h, such as 20 h.

[0070] In some embodiments, the reduction reaction further includes the following post-treatment steps: filtration, concentration (such as concentration under reduced pressure, or concentration under reduced pressure after adding ethyl acetate), cooling crystallization (such as cooling to -5 to 5 °C), washing (such as rinsing with ethyl acetate), and drying.

[0071] In some embodiments, when obtaining the hydrochloride form of the compound A2, the post-treatment step further includes adding an acid (such as adding ethyl acetate solution of hydrogen chloride, and the molar ratio of the ethyl acetate solution of hydrogen chloride to the compound A1 is preferably 3:1 to 5:1, more preferably 4:1).

[0072] In some embodiments, the preparation method of the compound A9 further includes 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;

[0073]

[0074] X2 and X3 are defined as described in any one of the present invention.

[0075] In some embodiments, X2 and X3 are each independently H or C 1-6 alkyl group.

[0076] In some embodiments, X2 and X3 are connected to form -C(CH3)2-C(CH3)2-, that is is For

[0077] In some embodiments, the "salt of compound B2" undergoes a reductive amination reaction with tetrahydropyranone and acetic acid.

[0078] In some embodiments, in the reductive amination reaction, the solvent is a halogenated alkane solvent, such as dichloromethane.

[0079] In some embodiments, the salt of compound B2 is in the form of the hydrochloride salt of compound B2.

[0080] In some embodiments, when the salt of compound B2 is in the form of the hydrochloride salt of compound B2, the molar ratio of compound B2 to hydrochloric acid is 1:1.

[0081] In some embodiments, the salt of compound B3 is in the form of the hydrochloride salt of compound B3.

[0082] In some embodiments, when the salt of compound B3 is in the form of the hydrochloride salt of compound B3, the molar ratio of compound B3 to hydrochloric acid is 1:1.

[0083] In some embodiments, in the reductive amination reaction, the reducing agent is sodium triacetoxyborohydride.

[0084] In some embodiments, in the reductive amination reaction, the molar ratio of tetrahydropyranone to compound B2 is (2 - 5):1, such as 3.4:1.

[0085] In some embodiments, in the reductive amination reaction, the molar ratio of acetic acid to compound B2 is (0.5 - 2):1, such as 1:1.

[0086] In some embodiments, in the reductive amination reaction, the molar ratio of the reducing agent to compound B2 is (2 - 5):1, such as 2.5:1.

[0087] In some embodiments, in the reductive amination reaction, the molar volume ratio of compound B2 to the solvent is 1:(5 - 20) mol / L, such as 1:10 mol / L.

[0088] In some embodiments, the reductive amination reaction further includes the following post-treatment steps: concentration (such as concentration under reduced pressure, or first concentration under reduced pressure and then concentration under reduced pressure after adding methyl tert-butyl ether), crystallization (such as crystallization in methyl tert-butyl ether);

[0089] Further, the reductive amination reaction further comprises the following post-treatment steps: quenching (e.g., quenching with 10% aqueous NaOH solution), filtration (e.g., filtration through 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.

[0090] In some embodiments, the temperature of the reductive amination reaction is room temperature (e.g., 15 - 25 °C).

[0091] In some embodiments, the reaction time of the reductive amination reaction is 6 - 12 h, e.g., 6 h.

[0092] In some embodiments, the method for preparing compound A9 further comprises the following steps: in a solvent, under acidic conditions, compound B1 undergoes a deprotection reaction to obtain compound B2 or its salt;

[0093]

[0094] X4 is an amino protecting group; the definitions of X2 and X3 are as described in any one of the present invention.

[0095] In some embodiments, the amino protecting group is a group conventionally used in the art for protecting amino groups, e.g., -Boc.

[0096] In some embodiments, X2 and X3 are connected to form -C(CH3)2 - C(CH3)2 -, i.e., is

[0097] In some embodiments, X2 and X3 are each independently H or C 1-6 alkyl.

[0098] In some embodiments, is

[0099] In some embodiments, compound B1 undergoes a deprotection reaction to obtain a salt of compound B2.

[0100] In some embodiments, in the deprotection reaction, the solvent is an ester solvent, e.g., ethyl acetate.

[0101] In some embodiments, the salt of compound B2 is the hydrochloride form of compound B2.

[0102] In some embodiments, 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.

[0103] 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 an ethyl acetate solution of hydrogen chloride. The concentration of the ethyl acetate solution of hydrogen chloride can be 4M. The mass ratio of the ethyl acetate solution of hydrogen chloride to Compound B1 is (3 - 10):1, for example, 3.7:1.

[0104] In some embodiments, in the deprotection reaction, the mass ratio of Compound B1 to the solvent is 1:(3 - 20), for example, 1:3.2.

[0105] In some embodiments, the deprotection reaction is carried out at room temperature (for example, 25 - 35 °C).

[0106] In some embodiments, the reaction time of the deprotection reaction is 2 - 6 hours.

[0107] In some embodiments, the deprotection reaction further includes the following post-treatment steps: concentration under reduced pressure (for example, concentrating the reaction solution under reduced pressure to ≤2.5 - 3.5 v / w), crystallization (for example, stirring and crystallizing in methyl tert-butyl ether), filtration, washing (for example, washing with methyl tert-butyl ether), and drying.

[0108] The present invention also provides a method for preparing Compound A4, which includes 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;

[0109]

[0110] X1 is a halogen, for example, F, Cl, Br, or I;

[0111] X2 and X3 are each independently H or C 1-6 alkyl; or, X2 and X3 are connected to form -C(CH3)2-C(CH3)2-.

[0112] In some embodiments, X2 and X3 are connected to form -C(CH3)2-C(CH3)2-, that is is

[0113] In some embodiments, each step and reaction condition in the method for preparing Compound A4 are as described in any one of the preceding items.

[0114] The present invention also provides a method for preparing Compound A2, which includes 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;

[0115]

[0116] X1 is F, Cl, Br or I;

[0117] The reducing agent is iron powder and concentrated hydrochloric acid, hydrazine hydrate and ferric chloride, Pd / C and H2, or Pt / C and H2.

[0118] In some embodiments, each step and reaction conditions in the preparation method of the compound A2 are as described in any of the previous items.

[0119] On the basis of conforming to the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0120] The reagents and raw materials used in the present invention are all commercially available.

[0121] The positive and progressive effects of the present invention are as follows: the preparation method of the present invention has the advantages of appropriate 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. Detailed Embodiments

[0122] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the examples described herein. The experimental methods without specific conditions noted in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0123] In the following examples, w / w refers to the mass ratio of the substance to the reaction reference substance; V refers to the volume-mass ratio of the solvent to the reaction reference substance; in the following examples, the reaction reference substances are B1’, B2’, B5a’, B5’ and B6’ respectively.

[0124] Example 1 - Preparation Method of Intermediate B2’

[0125]

[0126] Add ethyl acetate (357.55 kg, 3.2 w / w) to the reaction flask, start stirring, add reaction raw material B1’ (111.40 kg, 1.0 w / w), heat up to 25 - 35 °C, stir until all solids are dissolved, and dropwise add 4M HCl / EA solution (421.85 kg, 3.7 w / w); after the dropwise addition, control the temperature at 25 - 35 °C, stir for 2 - 6 h and then take a sample for in-process control. After the reaction is completed, concentrate the reaction solution under reduced pressure to ≤2.5 - 3.5 v / w, add methyl tert-butyl ether (410.70 kg, 3.7 w / w), control the system temperature at 20 - 30 °C, stir and crystallize for 6 - 10 h, filter, wash the filter cake with methyl tert-butyl ether (83.45 kg, 0.75 w / w), and dry. Obtain 87.20 kg, with a yield of 99% and a purity of 98.8%.

[0127] Example 2 - Preparation method of intermediate B4’

[0128]

[0129] Add dichloromethane (915.95 kg, 10.7 w / w), acetic acid (20.65 kg, 0.9 eq), B2’ (85.26 kg, 1.0 eq), and B3’ (119.60 kg, 3.4 eq) to the reaction flask in sequence, stir evenly, control the temperature at 15 ± 5 °C, add sodium triacetoxyborohydride (185.70 kg, 2.5 eq) in batches. After the addition is completed, control the temperature at 20 ± 5 °C and stir and react for 6 h. After the reaction ends, add the reaction solution to 10% aqueous NaOH solution to quench, stir, let it stand, separate the layers, filter the organic phase (diatomaceous earth), extract the aqueous phase with dichloromethane, combine the organic phases, add anhydrous sodium sulfate (17.20 kg) in sequence, concentrate under reduced pressure, add methyl tert-butyl ether, concentrate under reduced pressure, control the temperature at 20 ± 5 °C, stir and dropwise add methyl tert-butyl ether. After the dropwise addition is completed, cool down to -5 - 5 °C, stir and crystallize for 2 - 4 h, filter, wash the filter cake with methyl tert-butyl ether, and dry to obtain 88.7 kg. The yield is 87%, the purity is 99.5%, and it is a white solid.

[0130] When the inventors started the process research, they found that in the post-treatment steps of concentration under reduced pressure and purification, when slurrying with ethyl acetate and n-heptane, the obtained product was granular and light yellow, which was not conducive to product quality control. Therefore, a recrystallization method using methyl tert-butyl ether was developed to purify B4’.

[0131] Example 3 - Preparation of intermediate B5’

[0132]

[0133] Add 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) into an autoclave; add purified water (1.90 kg, 0.029 w / w), displace with nitrogen, and then displace with hydrogen. Control the hydrogen pressure at 0.2 - 0.4 MPa and the temperature at 40 - 50 °C. After reacting for 18 - 20 h, take a sample for in - process control. After the reaction is completed, cool the system to 20 - 30 °C, filter to remove platinum - carbon, concentrate under reduced pressure to 3V remaining, control the temperature at 15 - 30 °C, add 3.8 eq of hydrogen chloride in ethyl acetate drop - wise to the system. After the drop - wise addition, stir at a controlled temperature for 8 - 10 h, control the temperature ≤50 °C, concentrate under reduced pressure to 3V remaining, add 3V of ethyl acetate to the system, control the temperature ≤50 °C, concentrate under reduced pressure to 3V remaining, continue to cool the system to - 5 - 5 °C, stir for 2 - 4 h, filter, wash the filter cake with ethyl acetate, and dry to obtain 60.20 kg. The reaction yield is 90% and the purity is 99.5%.

[0134] The inventors further studied the hydrogen pressure, the stability of the reaction system at high temperature, the types of reducing agents, and the types of solvents, as follows:

[0135] (1) The inventors further screened the hydrogen pressure, and the results are as follows:

[0136] Hydrogen pressure Reaction time Product purity 1.0 - 1.5 MPa 20h 89.84％ 0.4 - 0.6 MPa 20h 99.42％ 0.2 - 0.4 MPa 70h 99.43％ 0.05 - 0.30 MPa 24h 99.19％

[0137] As can be seen from the above table, when the hydrogen pressure is adjusted to 1.0 - 1.5 MPa and the reaction time is 20 h, it is found that the purity of the product is only 89.84%. Considering the relatively large production system, it may be necessary to extend the reaction. Reacting at a pressure of 0.2 - 0.4 MPa for 70 h is stable, and the purity of the system has no obvious change, still reaching over 99%.

[0138] (2) React the reaction system at 60 - 70 °C for 72 hours, and the reaction purity has no obvious change, indicating that the reaction system is stable within 72 h under this condition. (3) The inventors further optimized and adjusted the types of reducing agents, and the results are as follows.

[0139]

[0140]

[0141] (4) The inventors further screened the types of solvents, and the results are as follows:

[0142] Reaction solvent Reaction temperature Reaction time Product purity Methanol 40～50℃ 19h 98.14％ Isopropanol 40～50℃ 25h 97.64％ Ethyl acetate 40～50℃ 24h 98.98％

[0143] Example 4 - Preparation method of intermediate B6’

[0144]

[0145] Add isopropyl alcohol (653.0 kg, 11.9 w / w), water (55.10 kg, 1.0 w / w), and potassium phosphate (149.10 kg, 3.0 eq) into the reaction flask. Start stirring and control the temperature at 15 - 30 °C. Add B4' (73.30 kg, 1.10 eq) and B5' (55.10 kg, 1.00 eq) sequentially. Replace the air in the system with nitrogen. Keep the temperature of the system at 15 - 30 °C. Add palladium acetate (0.525 kg, 0.01 eq) and RuPhos (2.10 kg, 0.02 eq). Replace the air in the system with nitrogen again. Heat up to 80 ± 5 °C and react for 4 - 8 h. Take samples for in - process control. After the reaction is completed, cool down to ≤50 °C. Add purified water and control the temperature at 20 - 30 °C. Stir for 0.5 - 1 h. Separate the liquid layers and retain the organic phase. Concentrate the solution. Add ethyl acetate and concentrate again. Then add ethyl acetate and water, let it stand, and separate the liquid layers. At the same time, add N - acetyl - L - cysteine (0.1 eq) and activated carbon (10% w / w). Stir at 50 °C for 1 - 3 h. Filter the solution. Wash the filter cake with sodium carbonate aqueous solution and saturated brine successively. Concentrate the solution. Stir and dropwise add methyl tert - butyl ether and n - heptane at 20 - 30 °C. Keep stirring for 1 - 2 h. Concentrate again. Add n - heptane and concentrate again. Cool down to - 5 - 5 °C and stir for 4 h to crystallize. Filter the crystals. Wash the filter cake with n - heptane and dry it to obtain 67.7 kg. The reaction yield is 87% and the purity is 99.4%.

[0146] Referring to the above preparation method, the types of ligands were optimized and adjusted, and the following results were obtained.

[0147]

[0148]

[0149] Furthermore, the inventors optimized the palladium - removing process in the post - treatment step, and the results are as follows.

[0150]

[0151] When using N - acetyl - L - cysteine to remove palladium, impurities in the system will increase. Therefore, the number of times of removing palladium with N - acetyl - L - cysteine needs to be reduced. Combining the operation of removing palladium with activated carbon and the operation of removing palladium with N - acetyl - L - cysteine can reduce the operation time and the possibility of liquid - liquid separation emulsification. At the same time, the Pd residue can be controlled below 200 ppm.

[0152] Preparation method of intermediate B8' in Example 5

[0153]

[0154] Under nitrogen protection, add B6’ (30.1 kg, 1.0 eq), B7’ (37.85 kg, 1.05 eq) and isopropyl alcohol (192.64 kg, 6.4 w / w) into a three-necked flask. Under nitrogen protection, add concentrated hydrochloric acid (1.2 eq) dropwise to the system. Stir and heat up to 75 - 85 °C, and stir for reaction for 24 h. After the reaction is completed, cool down to 60 - 70 °C, add ethyl acetate (240 L, 8V) dropwise, cool the temperature of the system to room temperature, stir at room temperature for 12 - 16 h, filter, wash the filter cake with ethyl acetate, and collect the filter cake.

[0155] Add dichloromethane (180 L, 6V) to the filter cake, stir for 30 min, add 10% sodium carbonate solution under stirring, stir for 30 - 60 min to ensure that the system is clear, let it stand for liquid separation, collect the organic phase, and wash the organic phase with 10% sodium carbonate solution again, stir for 30 min to ensure that the pH of the aqueous layer > 8, let it stand for liquid separation, collect the organic phase, wash the organic phase, let it stand, separate the layers, collect the organic phase, concentrate the organic phase under reduced pressure, add acetonitrile to the concentrated residue, stir overnight at room temperature, filter, wash the filter cake with acetonitrile, and collect the filter cake.

[0156] Add acetonitrile to the filter cake, displace with nitrogen under stirring, and protect with nitrogen (Note: avoid light)

[0157] , stir and heat up to 75 - 85 °C, stir for 0.5 - 1.5 h, cool down to room temperature, stir overnight, filter, wash the filter cake with acetonitrile, collect the filter cake, and dry it under vacuum to obtain 51.78 kg, with a yield of about 89% and a purity of 99.84%.

[0158] Repeat the above Example 5, replace concentrated hydrochloric acid with p-toluenesulfonic acid, and the product yield is 74%. Since p-toluenesulfonic acid and alcohol solvents are prone to form genotoxic impurities during heating, which is not conducive to subsequent process development, a process using concentrated hydrochloric acid as an acid catalyst has been developed.

Claims

1. 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, 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, coupling compound A4 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, wherein 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 be (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 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; (9) In step (1), the molar ratio of compound B3 to compound A2 is (1 - 1.1):1, for example 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, for example 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, for example 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 the protection of an inert gas; (16) In step (1), the coupling reaction further includes a palladium removal step, for example, using one or more of N-acetyl-L-cysteine, activated carbon, and L-cysteine, and preferably using N-acetyl-L-cysteine and activated carbon simultaneously for palladium removal; (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" and "compound B3" undergo a coupling reaction to obtain compound A4.

3. The preparation method according to claim 2, characterized in that, It satisfies one or more of the following conditions: (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 - 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 further includes a step of simultaneously using N-acetyl-L-cysteine and activated carbon for palladium removal; 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, It satisfies one or more of the following conditions: (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 compound A8 to compound A4 is (1 - 1.5):1; (4) In step (2), the molar ratio of the acid to compound A4 is (1 - 1.5):1; (5) In step (2), the molar volume ratio of 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, wherein 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 isopropyl alcohol hydrogen chloride, ethyl acetate hydrogen chloride, methanol hydrogen chloride, ethanol hydrogen chloride or dioxane hydrogen chloride solution; (2) In step (2), the molar ratio of compound A8 to compound A4 is 1.05:1; (3) In step (2), the molar ratio of the acid to compound A4 is 1.2:1; (4) In step (2), the molar volume ratio of 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, characterized in that, The preparation method of compound A9 further includes 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 the 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 in the form of the hydrochloride salt of the compound A2; (10) The temperature of the reduction reaction is 40 - 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 the 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 salt 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 - 50 °C; (9) The reaction time of the reduction reaction is 20 h; (10) When obtaining the hydrochloride salt form of the compound A2, the post-treatment step further includes adding an acid, such as adding ethyl acetate hydrogen chloride, and the molar ratio of the ethyl acetate hydrogen chloride to the compound A1 is preferably 3:1 - 5:1, more preferably 4:

1.

9. The preparation method according to claim 1, characterized in that, The preparation method of the compound A9 further includes 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 salt 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 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 molar volume ratio of the compound B2 to the solvent is 1:(5 - 20) mol / L; (9)The post-treatment steps in the reductive amination reaction further include: 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 salt 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 the compound B2 is 2.5:1; (6)In the reductive amination reaction, the molar volume ratio of the compound B2 to the solvent is 1:10 mol / L; (7)In the post-treatment steps of the reductive amination reaction, 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 post-treatment steps of the reductive amination reaction, 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 preparation method of the compound A9 further includes the following steps: in a solvent, under acidic conditions, the compound B1 undergoes a deprotection reaction to obtain the compound B2 or its salt; 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 the compound B2 is in the form of the hydrochloride salt of the 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 the 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, wherein It satisfies 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 salt of the compound B2, the molar ratio of the 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 the compound B1 is (3 - 10):1, such as 3.7:1; (4) In the deprotection reaction, the mass ratio of the 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 a compound A4, which comprises the following reaction steps: in a solvent, in the presence of a metal catalyst, a ligand and a base, coupling a "compound A2 or its salt" with a "compound B3 or its salt" to obtain a 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-; Each step and reaction condition in the method for preparing the compound A4 is 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, the compound A1 undergoes a reduction reaction to obtain a 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; Each step and reaction condition in the method for preparing the compound A2 is as described in any one of claims 6 - 8.

Images