Preparation method of CDK9 inhibitor intermediate

Abstract

The invention relates to a preparation method of a CDK9 inhibitor intermediate. The reaction formula is as follows: # imgabs0 #, wherein R is methyl, ethyl, propyl, isopropyl, benzyl, phenyl or benzyl or phenyl of which hydrogen of a benzene ring is optionally substituted; any substituent group is selected from halogen, nitro, cyano and trifluoromethyl; the method comprises the following steps: (1) carrying out condensation reaction on a compound A and a compound B to prepare a compound C; (2) carrying out hydrolysis reaction on the compound C in the presence of inorganic alkali to obtain a compound D; the novel intermediate obtained in the synthesis process is stable in property and good in reproducibility, contributes to production of subsequent products and solves the problem of hydrolysis reaction selectivity, and the preparation method of the novel intermediate compound is simple and convenient to operate, high in yield, good in product quality and easy to realize industrial mass production.

Description

Technical Field

[0001] The invention relates to a method for synthesizing a CDK9 inhibitor intermediate, and belongs to the field of drug ligand synthesis. Background Art

[0002] PROTAC CDK9 Degrader-1 (CAS: 2118356-96-8) is a selective degrader that uses Cereblon and CDK ligands to promote the degradation of CDK9 and jointly inhibit the growth of cancer cells. It is currently known that compound D is an effective CDK9 inhibitor advanced intermediate, and CDK9 inhibitors can be used as CDK ligands for PROTAC CDK9 Degrader-1; the specific structure of compound D is shown below:

[0003]

[0004] The document Chemical Communications (Cambridge, United Kingdom) (2017), 53 (54), 7577-7580 discloses the preparation of 1,1-dimethylethyl-5-cyclobutyl-3-[[2-(4-methoxyphenyl)acetyl]amino]-1H-pyrazole-1-carboxylate. The reaction formula is shown below:

[0005]

[0006] The method prepares 1,1-dimethylethyl-5-cyclobutyl-3-[[2-(4-methoxyphenyl)acetyl]amino]-1H-pyrazole-1-carboxylate through a condensation reaction. The inventors repeated the route and found that the yield was unstable. In addition, when further preparing compound D, the tert-butyloxycarbonyl group was also removed at the same time as the methoxy group was removed, which affected the subsequent reaction and was not conducive to industrial scale-up. Summary of the invention

[0007] In view of the defects of the prior art, the present invention provides a method for preparing a CDK9 inhibitor intermediate, which is simple, efficient, and has a high yield, greatly reduces the cost, and is conducive to large-scale commercial production.

[0008] In order to achieve the above technical objectives, the present invention adopts the following technical solutions:

[0009] The first aspect of the present invention provides a method for preparing compound D, and the reaction formula is as follows:

[0010]

[0011] Wherein R is methyl, ethyl, propyl, isopropyl, benzyl, phenyl or benzyl or phenyl in which hydrogen of the benzene ring is arbitrarily substituted; and the arbitrarily substituted group is selected from halogen, nitro, cyano and trifluoromethyl.

[0012] The following steps are included:

[0013] (1) Compound A and compound B undergo condensation reaction to prepare compound C;

[0014] (2) Compound C is hydrolyzed in the presence of an inorganic base to obtain Compound D.

[0015] As a further improvement of the present invention, including but not limited to, the condensation reaction in step (1) comprises:

[0016] Method 1: Compound A is reacted with compound B in an organic solvent, a condensation agent and an organic base to obtain compound C;

[0017] Method 2: Compound A and a chlorinating agent are reacted in an organic solvent to obtain an acyl chloride intermediate, which is then condensed with compound B in the presence of an organic base to obtain compound C;

[0018] As a further improvement of the present invention, including but not limited to, the condensing agent of the method 1 in step (1) is selected from one or more of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDCI, dicyclohexylcarbodiimide DCC, N,N'-carbonyldiimidazole CDI, propanephosphoric anhydride T3P, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU, benzotriazole-N,N,N",N"-tetramethyluronium hexafluorophosphate HBTU, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate BOP, 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate PyBOP, and 1-hydroxybenzotriazole HOBt;

[0019] As a further improvement of the present invention, including but not limited to, the molar ratio of compound B in step (1) to the condensing agent in method 1 is 1:(1-5), preferably 1:(1.5-3.5);

[0020] As a further improvement of the present invention, including but not limited to, the chlorination reagent in the method 2 of step (1) is selected from one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride; preferably oxalyl chloride;

[0021] As a further improvement of the present invention, including but not limited to, the molar ratio of compound B in step (1) to the chlorination reagent in method 2 is 1:(1.05-6), preferably 1:(4-5);

[0022] As a further improvement of the present invention, including but not limited to, a catalyst can be added in the method 2 of step (1), and the catalyst is selected from DMF;

[0023] As a further improvement of the present invention, including but not limited to, the molar ratio of compound B to catalyst in the method of step (1) is 1:(0.1-0.5), preferably 1:(0.15-0.25);

[0024] As a further improvement of the present invention, including but not limited to, the organic base in step (1) method 1 or method 2 is independently selected from one or more of triethylamine, diisopropylethylamine DIPEA, diisopropylamine, diethylamine, pyridine, and N-methylmorpholine; preferably diisopropylethylamine DIPEA;

[0025] As a further improvement of the present invention, including but not limited to, the molar ratio of compound B in step (1) to the organic base in method one or method two is 1:(1.05-5), preferably 1:(2.5-3.5);

[0026] As a further improvement of the present invention, including but not limited to, the molar ratio of compound B to compound A in step (1) is 1:(1-3), preferably 1:(1.2-1.6);

[0027] As a further improvement of the present invention, including but not limited to, the organic solvent in step (1) is selected from tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, N-methylpyrrolidone, toluene, acetone, acetonitrile, dimethyl sulfoxide, preferably dichloromethane, N,N-dimethylformamide;

[0028] As a further improvement of the present invention, including but not limited to, the reaction temperature of the method 1 in step (1) is 0 to 60°C;

[0029] As a further improvement of the present invention, including but not limited to, when T3P is used as the condensing agent in step (1) method 1, the reaction temperature is 35 to 60° C., preferably 45 to 55° C.;

[0030] As a further improvement of the present invention, including but not limited to, when HATU is selected as the condensing agent in step (1) method 1, the reaction temperature is 0 to 40° C., preferably 15 to 30° C.;

[0031] As a further improvement of the present invention, including but not limited to, the reaction time of the method 1 in step (1) is 3 to 24 hours;

[0032] As a further improvement of the present invention, including but not limited to, the reaction temperature of the method 2 in step (1) is 0 to 35° C.; preferably 15 to 30° C.;

[0033] As a further improvement of the present invention, including but not limited to, the reaction time of the method 2 in step (1) is 1 to 8 hours, preferably 2.5 to 5.5 hours;

[0034] As a further improvement of the present invention, the step (1) method 2 includes the following operations: dissolving compound A in dichloromethane (DCM), adding catalyst DMF, then slowly dropping oxalyl chloride, and after the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure. In order to completely remove the residual reagent, DCM is repeatedly added and evaporated twice. The resulting product is re-dissolved in DCM to obtain an acyl chloride intermediate solution of compound A. Compound B is dissolved in DCM, an organic base (such as DIPEA) is added and stirred. Under stirring conditions, the acyl chloride intermediate solution of compound A is slowly dropped into the reaction system of compound B, and the target compound C is obtained after the reaction is complete. The above-mentioned improved method improves the reaction efficiency and product purity by optimizing the reaction conditions and operating steps, and is suitable for large-scale preparation.

[0035] As a further improvement of the present invention, including but not limited to, the hydrolysis reaction in step (2) comprises: in a solvent, in the presence of an inorganic base, hydrolyzing compound C to prepare compound D;

[0036] As a further improvement of the present invention, including but not limited to, the inorganic base in step (2) is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; preferably sodium carbonate, such as sodium carbonate aqueous solution;

[0037] As a further improvement of the present invention, including but not limited to, the molar ratio of compound C to inorganic base in the hydrolysis reaction of step (2) is 1:(1-2), preferably 1:(1-1.2);

[0038] As a further improvement of the present invention, including but not limited to, the reaction solvent in step (2) is selected from one or more of tetrahydrofuran, dioxane, dichloromethane, dichloroethane, N,N-dimethylformamide, toluene, acetonitrile, methanol, ethanol, and water; preferably tetrahydrofuran, methanol or water or any combination thereof;

[0039] As a further improvement of the present invention, including but not limited to, the solvent in step (2) is selected from a combination of tetrahydrofuran and methanol; preferably, the volume ratio of tetrahydrofuran to methanol is 1:1;

[0040] As a further improvement of the present invention, it includes but is not limited to the following optimization: when a single solvent, methanol, is used, the substrate solubility is poor, resulting in residual raw materials and difficulty in completely carrying out the reaction; when a mixed solvent of tetrahydrofuran and methanol is used, the solubility of the substrate is significantly improved, the reaction is carried out more thoroughly, thereby effectively improving the yield and purity of the product.

[0041] As a further improvement of the present invention, the reaction temperature in step (2) is 0 to 40° C., preferably 15 to 25° C.;

[0042] As a further improvement of the present invention, the reaction time of step (2) is 1 to 5 hours, preferably 1.5 to 3 hours;

[0043] As a further improvement of the present invention, after the reaction of step (2) is complete, the following post-treatment operation can be selectively performed: slowly adding the reaction solution into water, and adjusting the pH to 5-6 with acetic acid, then extracting with an organic solvent, washing the organic phase with water to remove impurities; finally, evaporating the organic phase to dryness and purifying to obtain the target compound D. This post-treatment method is simple to operate and can effectively improve the purity and yield of the product.

[0044] As further improvements of the present invention, the following are included but not limited to: the inventors found when repeating the prior art that in the process of preparing compound D using 4-methoxyphenylacetic acid as a raw material, the removal of the methoxy group will lead to the simultaneous removal of the tert-butyloxycarbonyl group, which not only affects the smooth progress of the subsequent reaction, but also is not conducive to industrial scale-up production. The synthetic route of the present invention can effectively avoid the above problems. At the same time, the reaction conditions for preparing compound D by hydrolyzing compound C in the present invention are mild, simple to operate, and high in yield, which significantly improves the operability and scalability of the process, and provides reliable technical support for industrial production.

[0045] The second aspect of the present invention provides a novel compound C, the structure of which is shown below:

[0046]

[0047] Wherein R is methyl, ethyl, propyl, isopropyl, benzyl, phenyl or benzyl or phenyl in which hydrogen of the benzene ring is arbitrarily substituted; and the arbitrarily substituted group is selected from halogen, nitro, cyano and trifluoromethyl.

[0048] As a further improvement of the present invention, the preferred structure of the compound is as follows:

[0049]

[0050] The third aspect of the present invention also provides a method for preparing PROTAC CDK9 Degrader-1, comprising obtaining compound D by the preparation method of compound D of the first aspect of the present invention, and further preparing PROTAC CDK9Degrader-1 from compound D or using compound C of the second aspect of the present invention to prepare PROTAC CDK9 Degrader-1.

[0051] Beneficial technical effects of the present invention:

[0052] 1) When the inventors repeated the prior art and used 4-methoxyphenylacetic acid as a raw material to prepare compound D, during the demethoxylation operation, due to the limitations of the reaction conditions or the selectivity of the reaction system, the tert-butyloxycarbonyl group would inevitably be removed at the same time. This non-selective removal phenomenon would have a great negative impact on the subsequent reaction and would be unfavorable for industrial scale-up. The synthetic route provided by the present invention cleverly circumvents the above problems. By carefully designing the reaction steps and selecting appropriate reaction reagents, the stability of the tert-butyloxycarbonyl group can be ensured during the demethoxylation process, thereby allowing the entire synthetic process to proceed smoothly.

[0053] 2) The key step of preparing compound D by hydrolyzing compound C of the present invention has mild reaction conditions, simple operation, and does not require complex instruments and equipment or cumbersome operation procedures, which not only reduces the operation cost, but also reduces the errors and safety risks that may be caused by complex operations. Moreover, the yield of this step is high, which means that raw materials can be used more efficiently in industrial production, reducing the waste of raw materials, and having obvious economic advantages in the large-scale industrialization process;

[0054] 3) When the single solvent methanol is used for the hydrolysis of compound C of the present invention to prepare compound D, the substrate solubility is poor, resulting in residual raw materials and incomplete reaction; using a mixed solvent of tetrahydrofuran and methanol can significantly improve the solubility of the substrate, making the reaction more thorough, thereby improving the yield and purity of the product;

[0055] 4) After creative work, the inventors found that when ester-based substances are used as the protecting groups of phenolic hydroxyl groups, they show significant advantages in the deprotection process compared with alkyl or silyl protecting groups. In comparison, the yield can be increased by more than 50% when ester-based protecting groups are used; further research found that among the many ester-based protecting groups, the ethyl ester protecting group performs better than the aromatic ester protecting group in the phenolic hydroxyl protection-deprotection system. Experimental data show that the yield can be increased by about 9% when the ethyl ester protecting group is used compared with the aromatic ester protecting group;

[0056] 5) The new intermediate obtained in the synthesis process of the present invention has stable properties and good reproducibility, and contributes to the production of subsequent products, solving the problem of hydrolysis reaction selectivity. The preparation method of the new intermediate compound 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

[0057] Figure 1 The product obtained by Example 6 of the present invention 1 H-NMR spectrum. DETAILED DESCRIPTION

[0058] 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.

[0059] 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.

[0060] Example 1: Preparation of Compound A1

[0061]

[0062] Compound M (1.5 g, 9.86 mmol) was dissolved in DCM (33 mL), cooled to 0°C, then DIPEA (3.82 g, 29.58 mmol, 3 eq) was added, and propionyl chloride (2.28 g, 24.65 mmol, 2.5 eq, dissolved in 25 mL of DCM) solution was slowly added dropwise, and the mixture was returned to room temperature for 1.5 h. TLC detected that the reaction of the raw materials was complete. The reaction solution was added to water and washed twice. Evaporated and concentrated, and purified to obtain compound A1 (1.8 g, 87.7%).

[0063] Example 2: Preparation of Compound A2

[0064]

[0065] Compound M (1.5 g, 9.86 mmol) was dissolved in DCM (33 mL), cooled to 0°C, then DIPEA (3.82 g, 29.58 mmol, 3 eq) was added, and benzoyl chloride (3.46 g, 24.65 mmol, 2.5 eq, dissolved in 25 mL of DCM) solution was slowly added dropwise, and the mixture was returned to room temperature for 1.5 h. TLC detected that the reaction of the raw material was complete. The reaction solution was added to water and washed twice. Evaporated and concentrated, and purified to obtain compound A2 (2.18 g, 86.3%).

[0066] Example 3: Preparation of Compound A3

[0067]

[0068] Compound M (5 g, 32.9 mmol, 1 eq) was added to acetic anhydride (20 mL, 212 mmol, 6.45 eq), the product was insoluble, then concentrated sulfuric acid (0.10 mL) was added, the product dissolved, the temperature was raised to 65°C and stirred for 4 h, TLC detected that the raw material had reacted completely. The reaction solution was added to water and stirred for 0.5 h, extracted and evaporated to dryness and concentrated to obtain compound A3 (5.0 g, 78.4%).

[0069] Example 4: Preparation of Compound C1

[0070]

[0071] Compound A1 (395 mg, 1.89 mmol, 1.5 eq) was dissolved in DCM (18 mL), cooled to 0 ° C, DMF (0.02 mL, 0.27 mmol, 0.21 eq) was added, and then oxalyl chloride (722 mg, 5.67 mmol, 4.5 eq) was added dropwise, and the reaction was allowed to react at room temperature for 2 h. The reaction was completed by spot plate detection. The reaction solution was suspended at 20 ° C, and DCM (18 mL) was added and evaporated twice. After evaporation, the reactant was dissolved in DCM (10 mL) to obtain an intermediate solution of the acyl chloride of compound A1, and compound B (300 mg, 1.26 mmol, 1 eq) was dissolved in DCM (12 mL), cooled to 0 ° C, and DIPEA (490 mg, 3.78 mmol, 3 eq) was added and stirred. The intermediate solution of the acyl chloride of compound A1 was added dropwise to the reaction system of compound B, and the reaction was allowed to react at room temperature for 2 h. The reaction was completed by TLC detection. The reaction solution was added to water, extracted with DCM, evaporated to dryness, washed with water, concentrated, and purified by column to obtain compound C1 (240 mg, 44.4%).

[0072] Example 5: Preparation of Compound C2

[0073]

[0074] Compound A2 (486 mg, 1.89 mmol, 1.5 eq) was dissolved in DCM (18 mL), cooled to 0 ° C, DMF (0.02 mL, 0.27 mmol, 0.21 eq) was added, and then oxalyl chloride (722 mg, 5.67 mmol, 4.5 eq) was added dropwise, and the reaction was allowed to react at room temperature for 2 h. The reaction was completed by spot plate detection. The reaction solution was suspended at 20 ° C, and DCM (18 mL) was added and evaporated twice. After evaporation, the reactant was dissolved in DCM (10 mL) to obtain an acyl chloride intermediate solution of compound A2, and compound B (300 mg, 1.26 mmol, 1 eq) was dissolved in DCM (12 mL), cooled to 0 ° C, and DIPEA (490 mg, 3.78 mmol, 3 eq) was added and stirred. The acyl chloride intermediate solution of compound A2 was added dropwise to the reaction system of compound B, and the reaction was allowed to react at room temperature for 2 h. The reaction was completed by TLC detection. The reaction solution was added into water, extracted with DCM, evaporated to dryness, washed with water, concentrated, and purified by column to obtain compound C2 (220 mg, 37%).

[0075] Example 6: Preparation of Compound C3

[0076]

[0077] Compound A3 (368 mg, 1.89 mmol, 1.5 eq) was dissolved in DCM (18 mL), cooled to 0 ° C, DMF (0.02 ml, 0.27 mmol, 0.21 eq) was added, and then oxalyl chloride (722 mg, 5.67 mmol, 4.5 eq) was added dropwise, and the reaction was allowed to react at room temperature for 2 h. The reaction was completed by spot plate detection. The reaction solution was suspended at 20 ° C, and DCM (18 mL) was added and evaporated twice. After evaporation, the reactant was dissolved in DCM (10 mL) to obtain an acyl chloride intermediate solution of compound A3. Compound B (300 mg, 1.26 mmol, 1 eq) was dissolved in DCM (12 mL), cooled to 0 ° C, and DIPEA (490 mg, 3.79 mmol, 3 eq) was added and stirred. The acyl chloride intermediate solution of compound A3 was added dropwise to the reaction system of compound B, and the reaction was allowed to react at room temperature for 2 h. The reaction was completed by TLC detection. The reaction solution was added into water, extracted with DCM, evaporated to dryness, washed with water, concentrated, and purified by column to obtain compound C3 (250 mg, 48%). 1 H-NMR spectrum Figure 1 shown.

[0078] Example 7: Preparation of Compound C3

[0079]

[0080] Compound A3 (368 mg, 1.89 mmol, 1.5 eq) was dissolved in DMF (18 mL), DIPEA (490 mg, 3.79 mmol, 3 eq) was added and stirred at room temperature for 5 min, a DMF solution of 50% T3P (2.41 g, 3.79 mmol, 3 eq) was added and stirred for 10 min, compound B (300 mg, 1.26 mmol, 1 eq) was added, and then the temperature was raised to 50°C, and the reaction was carried out for 3-4 h. The reaction was completed by TLC detection. The reaction solution was added to water, extracted with ethyl acetate, evaporated to dryness, washed with water, concentrated, and purified by column to obtain compound 4 (230 mg, 44%).

[0081] Example 8: Preparation of Compound C3

[0082]

[0083] Compound A3 (368 mg, 1.89 mmol, 1.5 eq) was dissolved in DMF (18 mL), DIPEA (490 mg, 3.79 mmol, 3 eq) was added, and the mixture was stirred at room temperature for 5 min. HATU (961.4 mg, 2.52 mmol, 2 eq) was added, and compound B (300 mg, 1.26 mmol, 1 eq) was added, and the mixture was reacted at 25° C. overnight. The reaction was completed after TLC detection. The reaction solution was added to water, extracted with ethyl acetate, evaporated to dryness, washed with water, concentrated, and purified by column to obtain compound 4 (220 mg, 42%).

[0084] Example 9: Preparation of Compound D

[0085]

[0086] Compound C1 (630 mg, 1.45 mmol, 1 eq) was dissolved in a mixed solution of methanol (15 mL) and tetrahydrofuran (15 mL), cooled to 0°C, and then sodium carbonate (156.2 mg, 1.45 mL aqueous solution, 1 eq) was added, stirred at room temperature for 2 h, and the reaction was completed by TLC detection. The reaction solution was added to water, the pH was adjusted to 5-6 with acetic acid, extracted with ethyl acetate, and washed with water. Evaporated and purified by column to obtain compound D (400 mg, 73.1%).

[0087] Example 10: Preparation of Compound D

[0088]

[0089] Compound C2 (756 mg, 1.45 mmol, 1 eq) was dissolved in a mixed solution of methanol (15 mL) and tetrahydrofuran (15 mL), cooled to 0°C, and then sodium carbonate (168.5 mg, 1.45 mL aqueous solution, 1 eq) was added, stirred at room temperature for 2 h, and the reaction was completed by TLC detection. The reaction solution was added to water, the pH was adjusted to 5-6 with acetic acid, extracted with ethyl acetate, and washed with water. Evaporated and purified by column to obtain compound D (380 mg, 64.3%).

[0090] Example 11: Preparation of Compound D

[0091]

[0092] Compound C3 (600 mg, 1.45 mmol, 1 eq) was dissolved in a mixed solution of methanol (15 mL) and tetrahydrofuran (15 mL), cooled to 0°C, and then sodium carbonate (154 mg, 1.45 mL aqueous solution, 1 eq) was added, stirred at room temperature for 2 h, and the reaction was completed by TLC detection. The reaction solution was added to water, the pH was adjusted to 5-6 with acetic acid, extracted with ethyl acetate, and washed with water. Evaporated and purified by column to obtain compound D (450 mg, 83.5%).

[0093] Comparative Example 1:

[0094]

[0095] Compound C4 (290 mg, 0.75 mmol, 1 eq) was dissolved in DCM (7.5 mL), cooled to -40°C, and boron tribromide (226 mg, 0.9 mmol, 1.2 eq) was added dropwise. The reaction was continued for 1 h. TLC detection showed that no compound D was produced and the main product was compound N.

[0096] Comparative Example 2:

[0097]

[0098] Compound C5 (271 mg, 0.61 mmol, 1 eq) was dissolved in THF (6 mL), and a tetrahydrofuran solution of TBAF (1 mol / L, 1.2 mL, 2 eq) was added dropwise. The reaction was allowed to react at room temperature for 40 min. TLC detection showed that the reaction was complete and two main points (product points) were shown. The reaction solution was added to water, extracted with ethyl acetate, and purified by column to obtain compound D (70 mg, 27%).

Claims

1. A compound C, the structure of which is shown below: Wherein R is methyl, ethyl, propyl, isopropyl, benzyl, phenyl or benzyl or phenyl in which hydrogen of the benzene ring is arbitrarily substituted, and the arbitrarily substituted group is selected from halogen, nitro, cyano and trifluoromethyl.

2. A compound C3, the structure of which is shown below:

3. A method for preparing compound D, the reaction formula is as follows: wherein R is methyl, ethyl, propyl, isopropyl, benzyl, phenyl or benzyl or phenyl in which hydrogen atoms of the benzene ring are arbitrarily substituted, Any substituent group is selected from halogen, nitro, cyano, trifluoromethyl; The steps include: (1) Compound A and compound B undergo condensation reaction to prepare compound C; (2) Compound C is hydrolyzed in the presence of an inorganic base to obtain Compound D.

4. The preparation method according to claim 3, characterized in that: The condensation reaction in step (1) comprises: Method 1: Compound A is reacted with compound B in an organic solvent, a condensation agent and an organic base to obtain compound C; Method 2: Compound A is reacted with a chlorinating agent in an organic solvent to undergo an acyl chloride reaction to obtain an acyl chloride intermediate, which is then subjected to a condensation reaction with compound B in the presence of an organic base to obtain compound C.

5. The preparation method according to claim 4, characterized in that: The condensation reaction in step (1) satisfies one or more of the following conditions: The condensing agent of the method 1 is selected from one or more of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDCI, dicyclohexylcarbodiimide DCC, N,N'-carbonyldiimidazole CDI, propanephosphoric anhydride T3P, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU, benzotriazole-N,N,N",N"-tetramethyluronium hexafluorophosphate HBTU, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate BOP, 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate PyBOP, and 1-hydroxybenzotriazole HOBt; And / or, preferably, the molar ratio of the compound B to the condensing agent of method one is 1:(1-5), preferably 1:(1.5-3.5); and / or, preferably, the chlorinating agent of method two is selected from one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride; preferably oxalyl chloride; And / or, preferably, the molar ratio of the compound B to the chlorination agent of method 2 is 1:(1.05-6), preferably 1:(4-5); and / or, preferably, a catalyst may be added in method 2, and the molar ratio of the compound B to the catalyst is 1:(0.1-0.5), Preferably it is 1:(0.15-0.25); the catalyst is preferably DMF; And / or, preferably, the organic base of method 1 or method 2 is independently selected from triethylamine, diisopropylethylamine DIPEA, One or more of diisopropylamine, diethylamine, pyridine, and N-methylmorpholine; preferably diisopropylethylamine DIPEA; And / or, preferably, the molar ratio of compound B to the organic base of method one or method two is 1:(1.05-5), preferably 1: (2.5～3.5)； And / or, preferably, the molar ratio of compound B to compound A is 1:(1-3), preferably 1:(1.2-1.6); And / or, preferably, the organic solvent in step (1) is selected from tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, N-methylpyrrolidone, toluene, acetone, acetonitrile, dimethyl sulfoxide, preferably dichloromethane and N,N-dimethylformamide; And / or, preferably, the reaction temperature of the method 2 of step (1) is 0 to 35°C, preferably 15 to 30°C; And / or, preferably, the reaction time of the method 1 in step (1) is 3 to 24 hours; And / or, preferably, the reaction time of the method 2 in step (1) is 1 to 8 hours, preferably 2.5 to 5.5 hours.

6. The preparation method according to claim 4, characterized in that: The second method of step (1) comprises the following operations: dissolving compound A in dichloromethane (DCM), adding catalyst DMF, and then slowly dropping oxalyl chloride. After the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure; In order to completely remove the residual reagent, DCM was repeatedly added and evaporated twice; the obtained product was redissolved in DCM to obtain an acyl chloride intermediate solution of compound A; compound B was dissolved in DCM, DIPEA was added and stirred; under stirring conditions, the acyl chloride intermediate solution of compound A was slowly added dropwise to the reaction system of compound B, and the target compound C was obtained after the reaction was complete.

7. The preparation method according to claim 3, characterized in that: The hydrolysis reaction in step (2) comprises: in a solvent and in the presence of an inorganic base, compound C is subjected to a hydrolysis reaction to prepare compound D.

8. The preparation method according to claim 7, characterized in that: The hydrolysis reaction in step (2) satisfies one or more of the following conditions: And / or, preferably, the inorganic base in step (2) is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; preferably sodium carbonate, such as sodium carbonate aqueous solution; And / or, preferably, the molar ratio of compound C to inorganic base in the hydrolysis reaction of step (2) is 1:(1-2), preferably 1:(1-1.2); And / or, preferably, the reaction solvent in step (2) is selected from one or more of tetrahydrofuran, dioxane, dichloromethane, dichloroethane, N,N-dimethylformamide, toluene, acetonitrile, methanol, ethanol, and water; preferably tetrahydrofuran, methanol or water or any combination thereof; And / or, preferably, the solvent in step (2) is selected from a combination of tetrahydrofuran and methanol; preferably, the volume ratio of tetrahydrofuran to methanol is 1:1; And / or, preferably, the reaction temperature in step (2) is 0 to 40°C, preferably 15 to 25°C; And / or, preferably, the reaction time of step (2) is 1 to 5 hours, preferably 1.5 to 3 hours.

9. The preparation method according to claim 3 or 7, characterized in that: After the reaction of step (2) is complete, the following post-treatment operation can be selectively performed: the reaction solution is slowly added into water, and the pH is adjusted to 5-6 with acetic acid, followed by extraction with an organic solvent, and the organic phase is washed with water to remove impurities; finally, the organic phase is evaporated to dryness and purified to obtain the target compound D.

10. A method for preparing PROTAC CDK9 Degrader-1, characterized in that: Using compound C as claimed in claim 1 or compound C3 as claimed in claim 2 to prepare PROTAC CDK9 Degrader-1, or comprising obtaining compound D by the preparation method of compound D according to any one of claims 3 to 9, and compound D is further prepared to obtain PROTAC CDK9 Degrader-1.

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