Preparation method of CDK4 / 6 inhibitor

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthetic CDK 4 / 6 inhibitor intermediate and a preparation method thereof, and the preparation method comprises the following steps: # imgabs0, in which X is selected from Cl, Br and I; r1 is selected from # imgabs 1 # or methyl; the preparation method comprises the following steps: (1) dissolving a compound A in an organic solvent, and carrying out Buchwald coupling reaction on the compound A and a compound B under the catalysis of alkali, Pd (OAc) 2 and a ligand to obtain a compound C; (2) dissolving the compound C in an organic solvent, and performing hydrolysis reaction under an acidic condition to obtain a compound D; according to the invention, through two-step reaction, a plurality of brand-new intermediates are obtained in the synthesis process, and the intermediates are stable in property and good in reproducibility; the synthesis process has the advantages of simple operation, mild reaction conditions, high repeatability, two-step yield up to 93%, stable and controllable reaction, reduction of raw material loss, and facilitation of industrial amplification production.

Description

Technical Field

[0001] The invention relates to a preparation method of a CDK 4 / 6 inhibitor, and belongs to the technical field of medicine and chemistry. Background Art

[0002] WO2017020065A1 discloses 4-thiazole-N-(pyridin-2-yl)pyrimidine-2-amine derivatives. This new compound is a highly efficient and selective CDK4 inhibitor that can inhibit cell proliferation by inhibiting the activity of CDK4 and / or CDK6, and is used to treat proliferative cell diseases and disorders in the CNS including glioblastoma.

[0003] WO2017020065A1 discloses the following representative compounds:

[0004]

[0005] WO2017020065A1 reports a method for synthesizing the compound. The last step of the route requires a microwave reaction at 180°C. The maximum yield of the three steps is only about 17%, which is not conducive to industrial scale-up. The preparation method is as follows:

[0006]

[0007] CN116693522B reports a method for synthesizing a similar compound. The two-step yield of this route is only about 15%, which is not conducive to industrial scale-up. The preparation method is as follows:

[0008]

[0009] In summary, the above-mentioned route is not suitable for industrial production. Developing a route suitable for industrial production of 4-thiazole-N-(pyridin-2-yl)pyrimidine-2-amine CDK 4 / 6 inhibitors will have very good application prospects. Summary of the invention

[0010] In view of the defects of the prior art, the present invention provides a method for preparing a CDK 4 / 6 inhibitor.

[0011] The first aspect of the present invention provides a method for preparing a CDK 4 / 6 inhibitor intermediate, the reaction is as follows:

[0012]

[0013] Wherein, X is selected from Cl, Br, I; R1 is selected from or methyl; R2 is selected from or

[0014] The following steps are included:

[0015] Compound A is dissolved in an organic solvent, and subjected to a Buchwald coupling reaction with compound B in the presence of a base, Pd(OAc)2, and a ligand for catalysis to obtain compound C.

[0016] As a further improvement of the present invention, the ligand of the coupling reaction is selected from one or more of DPBP, Ruphos, DPPP, Xantphos, Sphos, BINAP, Brettphos, preferably Xantphos;

[0017] As a further improvement of the present invention, the molar ratio of compound A to ligand in the coupling reaction is 1:(0.1-0.5), preferably 1:(0.15-0.25);

[0018] As a further improvement of the present invention, the molar ratio of compound A to compound B in the coupling reaction is 1:(1-1.5), preferably 1:(1-1.1);

[0019] As a further improvement of the present invention, the molar ratio of compound A to Pd(OAc)2 in the coupling reaction is 1:(0.05-0.5), preferably 1:(0.08-0.12);

[0020] As a further improvement of the present invention, the base of the coupling reaction is selected from one or more of triethylamine, diisopropylethylamine, pyridine, sodium ethoxide, sodium tert-butoxide organic bases; or one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide inorganic bases, preferably cesium carbonate;

[0021] As a further improvement of the present invention, the molar ratio of compound A to base in the coupling reaction is 1:(1-5), preferably 1:(2.5-3.5);

[0022] As a further improvement of the present invention, the organic solvent for the coupling reaction is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, diethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and dimethyl sulfoxide, preferably dioxane;

[0023] As a further improvement of the present invention, the volume of the organic solvent in the coupling reaction is 5 to 20 times, preferably 10 to 15 times, the mass of the compound A in mL.

[0024] As a further improvement of the present invention, the reaction temperature of the coupling reaction is 80 to 120° C., preferably 90 to 110° C.;

[0025] As a further improvement of the present invention, the reaction time of the coupling reaction is 8 to 18 hours, preferably 10 to 16 hours.

[0026] The second aspect of the present invention provides a method for preparing compound D CDK 4 / 6 inhibitor, the reaction is as follows:

[0027]

[0028] Wherein R1, R2, and X are the same as described in the first aspect above;

[0029] The steps include:

[0030] (1) Compound A is dissolved in an organic solvent, and subjected to a Buchwald coupling reaction with compound B in the presence of a base, Pd(OAc)2, and a ligand to obtain compound C;

[0031] (2) dissolving compound C in an organic solvent and performing a hydrolysis reaction under acidic conditions to obtain compound D;

[0032] Includes the following methods:

[0033] The preparation method of step (1) refers to all the technical solutions of the first aspect mentioned above.

[0034] As a further improvement of the present invention, the acid for the hydrolysis reaction is selected from one or more of hydrochloric acid, trifluoroacetic acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / ethanol solution, and hydrochloric acid / methanol solution, preferably hydrochloric acid and trifluoroacetic acid;

[0035] As a further improvement of the present invention, the volume amount mL of the acid in the hydrolysis reaction of step (2) is 1 to 8 times the mass amount g of compound C, preferably 1 to 3.5 times;

[0036] As a further improvement of the present invention, the organic solvent for the hydrolysis reaction in step (2) is one or more of ethyl acetate, ether, dichloromethane, tetrahydrofuran, toluene, and dioxane, preferably dichloromethane;

[0037] As a further improvement of the present invention, the volume of the organic solvent in the hydrolysis reaction of step (2) is 5 to 20 times, preferably 10 to 15 times, the mass of the compound C.

[0038] As a further improvement of the present invention, the reaction temperature of the hydrolysis reaction in step (2) is 10 to 40° C., preferably 20 to 30° C.;

[0039] As a further improvement of the present invention, the reaction time of the hydrolysis reaction in step (2) is 0.5 to 3 hours.

[0040] The second aspect of the present invention uses Pd(OAc)2 for Buchwald coupling and then deamination protection. The two-step synthesis route has a yield that is 18-68% higher than the prior art report of using Pd2(dba)3 to synthesize 4-thiazole-N-(pyridin-2-yl)pyrimidine-2-amine derivatives in one step. The method of the present invention is more conducive to industrial scale-up production.

[0041] The third aspect of the present invention provides a method for preparing compound A, and the reaction formula is as follows:

[0042]

[0043] Wherein R1 is the same as described in the first aspect above;

[0044] The steps include:

[0045] (1) Compound E is subjected to a protection reaction with Boc2O to obtain compound F;

[0046] (2) Compound F is coupled with B2Pin2 in the presence of an alkaline reagent to obtain compound G;

[0047] (3) Compound G undergoes a coupling reaction with compound H to obtain compound A;

[0048] As a further improvement of the present invention, the upper protection reaction in step (1) comprises: in an organic solvent, compound E and Boc2O are subjected to an upper protection reaction in the presence of DMAP to obtain compound F;

[0049] As a further improvement of the present invention, in the protection reaction in step (1), the molar ratio of the compound E to Boc2O is 1:(1-5), preferably 1:(1.5-2.5);

[0050] As a further improvement of the present invention, in the protection reaction in step (1), the molar ratio of the compound E to DMAP is 1:(0.1-1), preferably 1:(0.1-0.6);

[0051] As a further improvement of the present invention, the organic solvent in step (1) is selected from one or more of ethyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, methanol, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably tetrahydrofuran;

[0052] As a further improvement of the present invention, in the protection reaction in step (1), the volume of the organic solvent used in mL is 5 to 15 times the mass of compound E used in g, preferably 8 to 15 times;

[0053] As a further improvement of the present invention, the reaction time of the protection reaction in step (1) is 5 to 20 hours, preferably 10 to 16 hours;

[0054] As a further improvement of the present invention, the coupling reaction in step (2) comprises: dissolving compound F in an organic solvent, and performing a coupling reaction with B2Pin2 in an alkaline reagent at low temperature to obtain compound G;

[0055] As a further improvement of the present invention, the alkaline reagent in step (2) can be one or more of lithium diisopropylamide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, n-butyllithium, tert-butyllithium, preferably n-butyllithium;

[0056] As a further improvement of the present invention, in the coupling reaction of step (2), the molar ratio of the compound F to the alkaline reagent is 1:(1-5), preferably 1:(1.5-2.5);

[0057] As a further improvement of the present invention, in the coupling reaction of step (2), the molar ratio of compound F to B2Pin2 is 1:(1.1-5), preferably 1:(1.2-3.5);

[0058] As a further improvement of the present invention, the organic solvent in step (2) is one or more of toluene, 2-methyltetrahydrofuran, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and water, preferably tetrahydrofuran;

[0059] As a further improvement of the present invention, in the coupling reaction of step (2), the volume of the organic solvent used in mL is 3 to 25 times, preferably 6 to 21 times, the mass of compound F used in g;

[0060] As a further improvement of the present invention, the reaction temperature of the coupling reaction in step (2) is -80 to -40°C, preferably -80 to -60°C;

[0061] As a further improvement of the present invention, the reaction time of the coupling reaction in step (2) is 0.5 to 5 h, preferably 1.5 to 2.5 h;

[0062] As a further improvement of the present invention, the coupling reaction in step (3) comprises: dissolving compound G in an organic solvent, and carrying out a coupling reaction with compound H in the presence of a base and a palladium catalyst to obtain compound A;

[0063] As a further improvement of the present invention, the molar ratio of compound H to compound G in the coupling reaction of step (3) is 1:(1-2), preferably 1:(1-1.5);

[0064] As a further improvement of the present invention, the palladium catalyst for the coupling reaction in step (3) is selected from one or more of Pd(dppf)Cl2, Pd(PPh3)4, Pd(dppp)Cl2, Pd(OAc)2, Pd(PPh3)2Cl2, Pd2(dba)3, preferably Pd(dppf)Cl2;

[0065] As a further improvement of the present invention, the molar ratio of compound H to palladium catalyst in the coupling reaction of step (3) is 1:(0.01-0.5), preferably 1:(0.01-0.15);

[0066] As a further improvement of the present invention, the base for the coupling reaction in step (3) is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, and potassium hydroxide, preferably potassium carbonate;

[0067] As a further improvement of the present invention, the molar ratio of compound H to base in the coupling reaction of step (3) is 1:(1-5), preferably 1:(2.5-3.5);

[0068] As a further improvement of the present invention, the organic solvent for the coupling reaction in step (3) is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and dimethyl sulfoxide, preferably dioxane;

[0069] As a further improvement of the present invention, the volume of the organic solvent in the coupling reaction of step (3) is 5 to 20 times, preferably 8 to 15 times, the mass of the compound G.

[0070] As a further improvement of the present invention, the reaction temperature of the coupling reaction in step (3) is 80 to 120° C., preferably 90 to 110° C.;

[0071] As a further improvement of the present invention, the reaction time of the coupling reaction in step (3) is 8 to 18 hours, preferably 10 to 16 hours.

[0072] The fourth aspect of the present invention provides a new key intermediate compound A and compound C, the structures of which are as follows:

[0073]

[0074] Wherein R1 and R2 are the same as described in the first aspect above;

[0075] As a further improvement of the present invention, the compound structure is as follows:

[0076]

[0077] The present invention also provides a new intermediate compound F1, the structure of which is as follows:

[0078]

[0079] Beneficial technical effects of the present invention:

[0080] (1) The two-step reaction of the present invention is simple to operate, has mild reaction conditions, and is highly repeatable. The two-step yield can reach up to 93%, which is about 75% higher than the synthesis method reported in the prior art WO2017020065A1. The reaction is stable and controllable, which reduces the loss of raw materials and is conducive to industrial scale-up production.

[0081] (2) The present invention uses Pd(OAc)2 for Buchwald coupling and then removes the amino protection to synthesize 4-thiazole-N-(pyridin-2-yl)pyrimidine-2-amine derivatives in two steps. Compared with the synthesis method of 4-thiazole-N-(pyridin-2-yl)pyrimidine-2-amine derivatives synthesized in one step using Pd2(dba)3 reported in the prior art, the yield is increased by 18-68%. The method of the present invention is more conducive to industrial scale-up production.

[0082] (3) The yield of the synthetic route using the Boc amino protecting group in the present invention is increased by about 66% compared with the synthetic route using the PMB amino protecting group to synthesize similar compounds reported in CN116693522B. The Boc amino protecting substrate has higher reaction activity and higher product yield under the reaction conditions of the present invention, which is conducive to industrial scale-up production.

[0083] (4) The preparation method of the present invention has a high yield; multiple new intermediates are obtained in the synthesis process, and the intermediates are stable in nature and have good reproducibility. The intermediate compounds of the present invention are judged based on the method for producing subsequent API products or the resulting products: the new intermediate compounds of the present invention contribute to the creative method for producing subsequent API products, and the preparation method of the new intermediate compounds of the present invention is simple to operate, has a high yield, and has good product quality, and is easy to realize large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0084] Figure 1 is the compound C1 of Example 4 of the present invention 1 H-NMR spectrum;

[0085] Figure 2 This is the HPLC spectrum of compound D1 of Example 5 of the present invention;

[0086] Figure 3 is the compound D1 of Example 5 of the present invention 1 H-NMR spectrum. DETAILED DESCRIPTION

[0087] The preparation method of the present invention will be described in further detail below in conjunction with specific examples. It should be understood that the following examples are only exemplary illustrations and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0088] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels. Specific embodiment:

[0090] Example 1

[0091]

[0092] Compound E1 (83.2 g, 401.8 mmol) was dissolved in 1000 mL of tetrahydrofuran, and Boc2O (176.24 g, 807.5 mmol) and DMAP (24.54 g, 200.9 mmol) were added at 25°C, and then reacted at 25°C for 12 hours. After the reaction, the reaction solution was slowly poured into water, and EtOAc was added for extraction, filtered, and the organic phase was concentrated and purified to obtain 117.38 g of white solid compound F1 with a yield of 95%.

[0093] Example 2

[0094]

[0095] Compound F1 (38.8 g, 126.3 mmol) was dissolved in 400 mL of tetrahydrofuran, B2Pin2 (41.7 g, 164.2 mmol) was added, and the temperature was lowered to -78°C. Then, 2.5 M n-BuLi (81.3 mL, 203.3 mmol) was added dropwise at low temperature, and the mixture was stirred at -78°C for 2 hours. After the reaction, the reaction solution was slowly poured into water, and EtOAc was added for extraction. The mixture was filtered, and the organic phase was concentrated and purified to obtain 29.17 g of white solid compound G1 with a yield of 65.2%.

[0096] Example 3

[0097]

[0098] Compound G1 (18.0 g, 500.8 mmol) was dissolved in 200 mL of dioxane, and compound H1 (5.0 g, 33.9 mmol), K2CO3 (14.1 g, 102.0 mmol), Pd(dppf)Cl2 (167.1 mg, 3.9 mmol) and H2O (40 mL) were added in sequence. The temperature was raised to 100°C and the reaction was carried out for 12 h. After the reaction was completed, the mixture was purified to obtain 10.58 g of yellow solid compound A1 with a yield of 92%.

[0099] Example 4

[0100]

[0101] Compound A1 (4.7 g, 13.9 mmol) was dissolved in 60 mL of dioxane, and compound B1 (3.9 g, 13.9 mmol), Cs2CO3 (13.5 g, 41.6 mmol), Pd(OAc)2 (0.31 g, 1.4 mmol), and Xantphos (1.6 g, 2.8 mmol) were added in sequence, and the temperature was raised to 100°C for reaction for 12 h. After the reaction, the reaction solution was slowly poured into water, and EtOAc was added for extraction, filtered, and the organic phase was concentrated, and then the crude product was purified by chromatographic column ( 80g Silica Flash), the eluent was 0-10% MeOH / DCM ether, the gradient was 80 mL / min), and 6.4 g of yellow solid compound C1 was obtained with a yield of 85%. 1 H-NMR spectrum Figure 1 As shown. LCMS: m / z (ES + )[M+H] + =543.2.

[0102] Example 5

[0103]

[0104] Compound C1 (2.5 g, 4.6 mmol) was dissolved in 30 mL of dichloromethane, HCl (3 mL) was added, and the mixture was reacted at 25°C for 1 h. After the reaction, the reaction solution was directly dried by rotary evaporation and purified by HPLC column to obtain 1.95 g of yellow solid compound D1 with a yield of 96%, HPLC purity of 99.25%, and retention time RT = 2.017 min. The HPLC spectrum is shown in FIG. Figure 2 shown. 1 H-NMR spectrum Figure 3 As shown. LCMS: m / z (ES + )[M+H] + =443.4,Rt=0.886min.

[0105] 1 H NMR (400MHz, DMSO) δ11.65(s,1H),11.15(d,J=4.4Hz,1H),9.10(s,1H),8.63(d,J=3.6 Hz,1H),8.22(dd,J=9.6,2.8Hz,1H),7.94(d,J=2.8Hz,1H),7.72(d,J=9.6Hz,1H),3.85 (d,J=12.8Hz,2H),3.37–3.27(m,1H),2.96(s,3H),2.80(t,J=11.6Hz,2H),2.72(d,J=4 .0Hz, 6H), 2.61 (d, J = 2.0Hz, 3H), 2.17 (d, J = 12.0Hz, 2H), 1.78 (td, J = 12.0, 8.4Hz, 2H).

[0106] Example 6

[0107]

[0108] Compound E2 (20 g, 76.6 mmol) was dissolved in 200 mL of tetrahydrofuran, and Boc2O (33.4 g, 153.2 mmol) and DMAP (1.22 g, 10.0 mmol) were added at 25°C, and then reacted at 25°C for 12 hours. After the reaction, the reaction solution was slowly poured into water, and EtOAc was added for extraction. The mixture was filtered, and the organic phase was concentrated and purified to obtain 26.6 g of white solid compound F2 with a yield of 96.2%.

[0109] Example 7

[0110]

[0111] Compound F2 (20.0 g, 55.4 mmol) was dissolved in 400 mL of tetrahydrofuran, B2Pin2 (42.2 g, 166.1 mmol) was added, the temperature was lowered to -78°C, and then 2.5 M n-butyllithium (44.3 mL, 110.7 mmol) was added dropwise at low temperature, and the mixture was stirred at -78°C for 2 hours; after the reaction, the reaction solution was slowly poured into water, EtOAc was added for extraction, filtered, the organic phase was concentrated, and purified to obtain 20 g of white solid compound G2 with a yield of 88.5%.

[0112] Example 8

[0113]

[0114] Compound G2 (5.0 g, 12.2 mmol) was dissolved in 50 mL of dioxane, and compound H2 (1.8 g, 12.2 mmol), K2CO3 (5.1 g, 36.6 mmol), Pd(dppf)Cl2 (601.6 mg, 1.2 mmol) and H2O (10 mL) were added in sequence. The temperature was raised to 100°C and the reaction was carried out for 12 h. After the reaction, the reaction solution was slowly poured into water, and EtOAc was added for extraction. The mixture was filtered, and the organic phase was concentrated and purified to obtain 4.58 g of yellow solid compound A2 with a yield of 95.4%.

[0115] Example 9

[0116]

[0117] Compound A2 (2.0 g, 5.1 mmol) was dissolved in 20 mL of dioxane, and compound B2 (1.4 g, 5.1 mmol), Cs2CO3 (5.0 g, 15.25 mmol), Pd(OAc)2 (114.1 mg, 0.5 mmol), and Xantphos (294.1 mg, 0.5 mmol) were added in sequence, and the temperature was raised to 100°C for reaction for 12 h. After the reaction, the reaction solution was slowly poured into water, and EtOAc was added for extraction, filtered, and the organic phase was concentrated. Then, the crude product was purified by chromatographic column to obtain 2.88 g of yellow solid compound C2 with a yield of 95%.

[0118] Example 10

[0119]

[0120] Compound C2 (2.0 g, 3.4 mmol) was dissolved in 30 mL of dichloromethane, TFA (6 mL) was added, and the mixture was reacted at 25° C. for 1 h. After the reaction, the reaction solution was directly spin-dried and purified to obtain 1.58 g of yellow solid compound D2 with a yield of 98%.

Claims

1. A method for preparing compound C, the reaction formula is as follows: in, X is selected from Cl, Br, I; R1 is selected from or methyl; R2 is selected from or The steps include: Compound A is dissolved in an organic solvent, and subjected to a Buchwald coupling reaction with compound B in the presence of a base, Pd(OAc)2, and a ligand for catalysis to obtain compound C.

2. A method for preparing a compound D CDK 4 / 6 inhibitor, the reaction formula is as follows: Wherein X, R1, and R2 substituents are as defined in claim 1; The steps include: (1) Compound A is dissolved in an organic solvent, and subjected to a Buchwald coupling reaction with compound B in the presence of a base, Pd(OAc)2, and a ligand to obtain compound C; (2) Compound C is dissolved in an organic solvent and subjected to a hydrolysis reaction under acidic conditions to obtain Compound D.

3. The preparation method according to claim 1 or 2, characterized in that: The ligand for the coupling reaction in step (1) is selected from one or more of DPBP, Ruphos, DPPP, Xantphos, Sphos, BINAP, and Brettphos, preferably Xantphos.

4. The preparation method according to claim 1 or 2, characterized in that: The coupling reaction of step (1) of claim 1 or step (1) of claim 2 satisfies one or more of the following conditions: And / or, preferably, the molar ratio of compound A to ligand in the coupling reaction is 1:(0.1-0.5), preferably 1:(0.15-0.25); And / or, preferably, the molar ratio of compound A to compound B in the coupling reaction is 1:(1-1.5), preferably 1:(1-1.1); And / or, preferably, the molar ratio of compound A to Pd(OAc)2 in the coupling reaction is 1:(0.05-0.5), preferably 1:(0.08-0.12); And / or, preferably, the base of the coupling reaction is selected from one or more of triethylamine, diisopropylethylamine, pyridine, sodium ethoxide, sodium tert-butoxide organic bases; or one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide inorganic bases, preferably cesium carbonate; And / or, preferably, the molar ratio of compound A to base in the coupling reaction is 1:(1-5), preferably 1:(2.5-3.5); And / or, preferably, the organic solvent for the coupling reaction is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, diethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, preferably dioxane; And / or, preferably, the volume amount of the organic solvent in the coupling reaction is 5 to 20 times, preferably 10 to 15 times, the mass amount of compound A in mL; And / or, preferably, the reaction temperature of the coupling reaction is 80 to 120°C, preferably 90 to 110°C; And / or, preferably, the reaction time of the coupling reaction is 8 to 18 hours, preferably 10 to 16 hours.

5. The preparation method according to claim 2, characterized in that: The hydrolysis reaction in step (2) satisfies one or more of the following conditions: The acid used in the hydrolysis reaction in step (2) is selected from one or more of hydrochloric acid, trifluoroacetic acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / ethanol solution, and hydrochloric acid / methanol solution, preferably hydrochloric acid or trifluoroacetic acid; And / or, preferably, the volume amount mL of the acid in the hydrolysis reaction of step (2) is 1 to 8 times the mass amount g of compound C, preferably 1 to 3.5 times; And / or, preferably, the organic solvent for the hydrolysis reaction in step (2) is one or more of ethyl acetate, ether, dichloromethane, tetrahydrofuran, toluene, and dioxane, preferably dichloromethane; And / or, preferably, the volume amount of the organic solvent in the hydrolysis reaction of step (2) mL is 5 to 20 times the mass amount of compound C g, preferably 10 to 15 times; And / or, preferably, the reaction temperature of the hydrolysis reaction in step (2) is 10 to 40°C, preferably 20 to 30°C; And / or, preferably, the reaction time of the hydrolysis reaction in step (2) is 0.5 to 3 hours.

6. The preparation method according to claim 1 or 2, characterized in that: The preparation method of compound A is as follows: Wherein the R1 substituent is defined as in claim 1; The steps include: (1) Compound E is subjected to a protection reaction with Boc2O to obtain compound F; (2) Compound F is coupled with B2Pin2 in the presence of an alkaline reagent to obtain compound G; (3) Compound G is coupled with compound H to obtain compound A.

7. The preparation method according to claim 6, characterized in that: The step (1) of the upper protection reaction comprises: in an organic solvent, compound E and Boc2O are subjected to an upper protection reaction in the presence of DMAP to obtain compound F; Step (1) satisfies one or more of the following conditions: In the protection reaction of step (1), the molar ratio of compound E to Boc2O is 1:(1-5), preferably 1: (1.5～2.5)； And / or, preferably, in the protection reaction in step (1), the molar ratio of compound E to DMAP is 1:(0.1-1), preferably 1:(0.1-0.6); And / or, preferably, the organic solvent in step (1) is selected from one or more of ethyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, methanol, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably tetrahydrofuran; And / or, preferably, in the protection reaction in step (1), the volume of the organic solvent used in mL is 5 to 15 times the mass of compound E used in g, preferably 8 to 15 times; And / or, preferably, the reaction time of the protection reaction in step (1) is 5 to 20 hours, preferably 10 to 16 hours.

8. The preparation method according to claim 6, characterized in that: The coupling reaction in step (2) comprises: dissolving compound F in an organic solvent, and performing a coupling reaction with B2Pin2 in an alkaline reagent at low temperature to obtain compound G; Step (2) satisfies one or more of the following conditions: The alkaline reagent in step (2) can be one or more of lithium diisopropylamide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, n-butyllithium, tert-butyllithium, preferably n-butyllithium; And / or, preferably, in the coupling reaction of step (2), the molar ratio of compound F to alkaline reagent is 1:(1-5), preferably 1:(1.5-2.5); And / or, preferably, in the coupling reaction of step (2), the molar ratio of compound F to B2Pin2 is 1:(1.1-5), preferably 1:(1.2-3.5); And / or, preferably, the organic solvent in step (2) is selected from one or more of toluene, 2-methyltetrahydrofuran, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, water, preferably tetrahydrofuran; And / or, preferably, in the coupling reaction of step (2), the volume of the organic solvent used in mL is 3 to 25 times, preferably 6 to 21 times, the mass of compound F used in g; And / or, preferably, the reaction temperature of the coupling reaction in step (2) is -80 to -40°C, preferably -80 to -60°C; And / or, preferably, the reaction time of the coupling reaction in step (2) is 0.5 to 5 h, preferably 1.5 to 2.5 h.

9. The preparation method according to claim 6, characterized in that: The coupling reaction in step (3) comprises: dissolving compound G in an organic solvent, and carrying out a coupling reaction with compound H in the presence of a base and a palladium catalyst to obtain compound A; Step (3) satisfies one or more of the following conditions: The molar ratio of compound H to compound G in the coupling reaction of step (3) is 1:(1-2), preferably 1:(1-1.5); And / or, preferably, the palladium catalyst for the coupling reaction in step (3) is selected from one or more of Pd(dppf)Cl2, Pd(PPh3)4, Pd(dppp)Cl2, Pd(OAc)2, Pd(PPh3)2Cl2, Pd2(dba)3, preferably Pd(dppf)Cl2; And / or, preferably, the molar ratio of compound H to palladium catalyst in the coupling reaction of step (3) is 1:(0.01-0.5), preferably 1:(0.01-0.15); And / or, preferably, the base for the coupling reaction in step (3) is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably potassium carbonate; And / or, preferably, the molar ratio of compound H to base in the coupling reaction of step (3) is 1:(1-5), preferably 1:(2.5-3.5); And / or, preferably, the organic solvent for the coupling reaction in step (3) is one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, preferably dioxane; And / or, preferably, the volume of the organic solvent in the coupling reaction of step (3) is 5 to 20 times, preferably 8 to 15 times, the mass of the compound G in mL; And / or, preferably, the reaction temperature of the coupling reaction in step (3) is 80 to 120° C., preferably 90 to 110° C.; And / or, preferably, the reaction time of the coupling reaction in step (3) is 8 to 18 hours, preferably 10 to 16 hours.

10. A compound A, a compound C and a compound F1, each having the following structure: Wherein the R1 substituent in compound A and the R1 substituent and R2 substituent in compound C are defined as in claim 1, and compound A and compound C are further preferably the following compounds:

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