A method for synthesizing a chiral intermediate of casein kinase 1 epsilon inhibitor

Abstract

The application discloses a synthesis method of a casein kinase 1 epsilon inhibitor chiral intermediate, and comprises the following steps: dissolving compound 1 and a phosphine reagent L1 in a reaction solvent, adding azodicarboxylic ester, and ending the reaction; adding compound 2, and continuing the reaction until the reaction is completed; adding an acid, ending the reaction, and obtaining a compound shown in formula (I) through post-treatment of a reaction solution; and the route has the effects of no need of chiral resolution, high yield and stable process.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, and specifically relates to a method for synthesizing a chiral intermediate of a casein kinase 1ε inhibitor. Background Technology

[0002] Casein kinase 1ε is a serine / threonine protein kinase that plays a central role in key physiological processes such as cell cycle regulation and the Wnt signaling pathway. Its inhibitors have become a popular target for innovative drug development. (S)-2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-3-phenylquinazoline-4(3H)-one is a key chiral intermediate in the synthesis of the CK1ε inhibitor (S)-2-(1-(4-amino-3-(2,3-difluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-3-phenylquinazoline-4(3H)-one methanesulfonate. The stereoselectivity, yield, and cost of its synthesis process directly affect the industrialization process of downstream active pharmaceutical ingredients.

[0003] The structures of (S)-2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-3-phenylquinazoline-4(3H)-one (Formula (I)) and (S)-2-(1-(4-amino-3-(2,3-difluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-3-phenylquinazoline-4(3H)-one methanesulfonate (B) are as follows:

[0004]

[0005] Formula (I) (B)

[0006] The currently disclosed technical solutions related to intermediate type (I) mainly include the following:

[0007] Technical Route 1: Patent document CN112142745A employs a direct substitution method. 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (compound 1) reacts with compound 2-1 under alkaline conditions to generate a racemic intermediate with a yield of 83%. The reaction formula is as follows:

[0008]

[0009] R1 is selected from H.

[0010] Technical Route Two: Patent document CN 114656468 A employs the Mitsunobu (photocatalytic reaction) method. 3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound 1) reacts with compound 2 in the presence of a phosphine reagent and an azodicarboxylic acid ester via the Mitsunobu reaction to directly generate a single-configuration key intermediate, with a yield of 40%-60%. The reaction formula is as follows:

[0011]

[0012] In summary, existing technical approaches all suffer from the problem of difficulty in balancing chiral selectivity and yield. It is essential to develop a stable intermediate synthesis method that combines chiral selectivity and yield. Summary of the Invention

[0013] To address the shortcomings of existing technologies, this paper improves the existing synthetic method of (S)-2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-3-phenylquinazoline-4(3H)-one, providing a chiral intermediate synthesis method that does not require chiral resolution, has high yield, and is stable, thereby promoting the industrialization of (S)-2-(1-(4-amino-3-(2,3-difluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-3-phenylquinazoline-4(3H)-one methanesulfonate.

[0014] This invention is specifically achieved through the following technical solutions:

[0015] A method for synthesizing a chiral intermediate of a casein kinase 1ε inhibitor, comprising: compound 1 and phosphine reagent L1 (where L1 is a compound of 1, ... The compound (S) is dissolved in the reaction solvent, and the temperature is controlled below 25°C. Azodicarboxylic acid ester is added, and the reaction ends below 25°C. Compound 2 is added, and the reaction continues below 25°C until completion. Acid is added, and the reaction ends at 45~70°C. The reaction solution is post-treated to obtain the compound shown in formula (I), namely (S)-2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-3-phenylquinazoline-4(3H)-one:

[0016] The structures of compound 1, compound 2, and the compound represented by formula (I) are as follows:

[0017] .

[0018] Preferably, the reaction temperature is 0~20℃ after the addition of azodicarboxylic acid ester; the reaction temperature is 0~20℃ after the addition of compound 2; and the reaction temperature is 45~60℃ after the addition of acid.

[0019] A method for synthesizing a chiral intermediate of a casein kinase 1ε inhibitor, the method comprising the steps of:

[0020] (i) Add solvent to the reaction vessel, then add compound 1 and phosphine reagent L1, and stir until homogeneous. Control the temperature and slowly add azodicarboxylic acid ester to obtain compound 1-1;

[0021] (ii) Compound 2 was added to the reaction system in step 1, and the reaction was continued at the temperature to obtain compound 3;

[0022] (iii) In the reaction system of step 2, after adding acid solution, the temperature is raised and the reaction is completed. After the reaction is completed, the pH is adjusted to 5-7, and the compound of formula (1) is obtained by concentration and recrystallization. The temperature of step A (and step (i)) is controlled at 0~20℃; the reaction temperature is 0~20℃;

[0023] The reaction temperature in step B (and step (ii)) is 0~20℃;

[0024] The reaction temperature in step C (and step (iii)) is 45~60℃.

[0025] The reaction pathway is as follows:

[0026]

[0027] Specific operating steps: Add tetrahydrofuran, compound 1, and phosphine reagent L1 sequentially to a clean and dry reaction vessel, and stir until homogeneous. Cool the system to 0-20℃, slowly add azodicarboxylic acid ester under controlled temperature, and maintain the reaction temperature for 3 hours to obtain compound 1-1. Continue to add compound 2 to the system, maintain the reaction temperature for 3 hours, and monitor the reaction to ensure it is complete using HPLC to obtain compound 3. Add a certain concentration of acid solution to the system, raise the temperature to 45-60℃, and maintain the reaction temperature. If the temperature is within acceptable range, neutralize with sodium bicarbonate to neutral or weakly acidic pH 5-7, and concentrate under reduced pressure. Then recrystallize from methyl tert-butyl ether and acetonitrile to obtain compound (1).

[0028] The preferred scheme is as follows: 1) Methyl tert-butyl ether treatment stage: Methyl tert-butyl ether is added to the reaction vessel and stirring is started. The filter cake obtained after the system of reaction step C is concentrated under reduced pressure is added to the methyl tert-butyl ether solution in 4 portions. The temperature is raised to 52℃ (reflux) and stirred, then cooled to 20℃ and stirred again. After the end, the mixture is filtered, and the reaction vessel and filter cake are washed with methyl tert-butyl ether. The filter cake is collected.

[0029] 2) Acetonitrile treatment stage: Add acetonitrile to the reaction vessel and start stirring. Add the filter cake treated with methyl tert-butyl ether in 4 portions. Heat to 45°C and stir. Then cool to 10°C and continue stirring. Filter. Wash the reaction vessel and filter cake with acetonitrile. Collect the filter cake to obtain compound (1).

[0030] Preferably, the structure of the phosphine reagent L1 is PR1R2R3, where R1, R2, and R3 are each independently selected from C6-C10 aryl, C1-C5 alkyl, or 3-7 membered cycloalkyl groups; the aryl and alkyl groups may be further substituted by one or more C1-C2 alkoxy, C1-C5 alkyl, halogen, or phenyl substituted phosphine groups.

[0031] In a preferred embodiment, the C6-C10 aryl group is preferably phenyl;

[0032] In a preferred embodiment, the phosphine reagent L1 is selected from triphenylphosphine (PPh3), 1,2-bis(bisphenylphosphine)ethane (DPPE), triethylphosphine (PEt3), tributylphosphine (PBu3), tricyclohexylphosphine (PCy3), tris(4-methoxyphenyl)phosphine, tris(o-tolyl)phosphine (P(o-Tol)3), tris(p-tolyl)phosphine (P(p-Tol)3), di-tert-butylphenylphosphine (t-Bu2PPh), tris(3,5-dimethoxyphenyl)phosphine, and tris(4-fluorophenyl)phosphine; more preferably, the phosphine reagent L1 is preferably triphenylphosphine (PPh3) or 1,2-bis(bisphenylphosphine)ethane (DPPE).

[0033] In a preferred embodiment, the azodicarboxylic acid ester is selected from diisopropyl azodicarbonate (DIAD), dimethyl azodicarbonate (DMAD), diethyl azodicarbonate (DEAD), di-tert-butyl azodicarbonate (DBAD), dibenzyl azodicarbonate (DBzAD), and di-p-toluene azodicarbonate (DTTAD); more preferably, the azodicarboxylic acid ester is preferably diisopropyl azodicarbonate (DIAD) or diethyl azodicarbonate (DEAD).

[0034] In a preferred embodiment, the acid solution is selected from acetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, trifluoroacetic acid, and methanesulfonic acid; more preferably, the acid solution in step C is hydrochloric acid or acetic acid.

[0035] Preferably, the molar ratio of phosphine reagent L1 to compound 1 is (2~4):1; the molar ratio of azodicarboxylic acid ester to compound 1 is (2~4):1; the molar ratio of compound 1 to compound 2 is 1:(0.8~1.5); and the molar ratio of added acid to compound 1 is 0.8~10:1.

[0036] In the preferred embodiment, the molar ratio of phosphine reagent to azodicarboxylic acid ester is 1:1.

[0037] In a preferred embodiment, the molar ratio of phosphine reagent to compound 1 is (2.5~4):1; more preferably, the molar ratio is (2.5~3.5):1. Even more preferably, the molar ratio is (2.5~3.0):1. Even more preferably, the molar ratio is 2.5:1, and / or, the molar ratio is 3:1.

[0038] In a preferred embodiment, the molar ratio of azodicarboxylic acid ester to compound 1 is (2.5~4):1.0; more preferably, the molar ratio is (2.5~3.5):1; even more preferably, the molar ratio is 2.5:1; even more preferably, the molar ratio is 3.5:1; even more preferably, the molar ratio is 3:1.

[0039] In a preferred embodiment, the molar ratio of compound 1 to compound 2 is 1:(0.9~1.5); more preferably, the molar ratio is 1:(0.9~1.05); even more preferably, the molar ratio is 1:0.9; even more preferably, the molar ratio is 1:1.0; even more preferably, the molar ratio is 1:1.05.

[0040] Preferably, the molar ratio of the added acid to compound 1 is (0.8~10):1; further, the molar ratio of the added acid to compound 1 is (0.9~9):1; even further, the molar ratio of the added acid to compound 1 is (1~8):1; even further, the molar ratio of the added acid to compound 1 is (1~7):1; even further, the molar ratio of the added acid to compound 1 is (1~6):1 or (1~5):1. More specifically, when the acid is hydrochloric acid, the molar ratio of the added acid to compound 1 is (1~2):1, even further, (1~1.5):1 or (1~1.2):1; when the acid is acetic acid, the molar ratio of the added acid to compound 1 is (2~6):1, even further, (3~6):1 or (4~5):1.

[0041] Preferably, the acid is added in the form of an aqueous solution with a concentration of 0.5–10 mol / L. Further, when using strong acids such as hydrochloric acid, hydrobromic acid, or hydroiodic acid, the concentration is 0.5–5 mol / L; more preferably 1–2 mol / L; when acetic acid is selected, the concentration of the acid solution is 3–10 mol / L; more preferably 5–10 mol / L.

[0042] In a preferred embodiment, the feeding ratio of compound 1 to the acid solution is 1 g:(1~10) mL.

[0043] In a preferred embodiment, the feeding ratio of compound 1 to the acid solution is 1g:(1~4)mL. For example, the feeding ratio of compound 1 to the acid solution can be 1g:1mL, 1g:2mL, 1g:3mL, or 1g:4mL.

[0044] In a preferred embodiment, the acid solution in step C is selected from hydrochloric acid or acetic acid.

[0045] In the preferred embodiment, when the acid solution in step C is selected from hydrochloric acid, the reaction temperature is 45-55℃.

[0046] In the preferred embodiment, when the acid solution in step C is selected from acetic acid, the reaction temperature is 60°C.

[0047] In a preferred embodiment, the acid solution in step C is selected from hydrochloric acid or acetic acid; wherein the concentration of hydrochloric acid is 0.5 mol / L to 5 mol / L, preferably 1 mol / L to 2 mol / L; for example, the concentration of hydrochloric acid can be 1 mol / L and 2 mol / L.

[0048] In a preferred embodiment, the concentration of the hydrochloric acid solution in step C is selected from 1 mol / L, and the feed ratio of compound 1 to the acid solution is 1.0 g: 4 mL.

[0049] In a preferred embodiment, the concentration of the hydrochloric acid solution in step C is selected from 2 mol / L, and the feed ratio of compound 1 to the acid solution is 1.0 g: 2 mL.

[0050] In a preferred embodiment, the acid solution in step C is selected from acetic acid, and the feeding ratio of compound 1 to the acid solution is 1g:1mL; in a more preferred embodiment, the acid solution in step C is selected from acetic acid, and the feeding ratio of compound 1 to the acid solution and water is 1g:1mL:1mL.

[0051] In some specific embodiments, the reaction route is as follows:

[0052]

[0053] In some specific embodiments, the reaction route is as follows:

[0054]

[0055] In some specific embodiments, the reaction route is as follows:

[0056]

[0057] In a preferred embodiment, the phosphine reagent is triphenylphosphine or 1,2-bis(bisphenylphosphine)ethane.

[0058] In a preferred embodiment, the azodicarboxylic acid ester is diisopropyl azodicarboxylate or diethyl azodicarboxylate.

[0059] In the preferred embodiment, the acid solution in step C is a 1 mol / L hydrochloric acid solution or an 8.75 mol / L acetic acid solution.

[0060] Table 1. Advantages of the present invention's approach compared to existing technologies.

[0061]

[0062] Compared with the prior art, the present invention has the following advantages:

[0063] (1) This invention provides a method for synthesizing (S)-2-(1-(4-amino-3-(2,3-difluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-3-phenylquinazoline-4(3H)-one methanesulfonate intermediate, using Mitsunobu reaction and hydrolysis reaction to construct a chiral synthetic strategy;

[0064] (2) The present invention provides a synthesis method in which an acid reagent is added in step C to further react the phosphine-containing imine intermediate to generate the product, thereby improving the conversion rate and the yield of the product;

[0065] (3) This invention provides a synthesis method with high reaction yield, which can reduce costs and is conducive to the industrial production of active pharmaceutical ingredients, and has good industrial application prospects.

[0066] In summary, the synthesis method of the present invention has the following advantages: 1) It constructs a chiral synthesis method to obtain a single-chiral intermediate product; 2) By innovatively adding an acid solution, the conversion rate and product yield are improved; 3) The synthesis route of the present invention is mild and has good prospects for industrial application. Detailed Implementation

[0067] The beneficial effects of the present invention are further described below through embodiments. It should be understood that the embodiments of the present invention are merely illustrative and not intended to limit the invention. Therefore, any simple modifications to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0068] In the following examples, unless otherwise specified, all temperatures are in Celsius; unless otherwise specified, all starting materials and reagents are commercially available and used directly without further purification; unless otherwise specified, all solvents are industrial grade solvents and used directly without further treatment.

[0069] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0070] The following embodiments further illustrate the present invention. However, it should be noted that the following embodiments are only used to describe the content of the invention and do not constitute a limitation on the scope of protection of the present invention. The scope of protection of the present invention shall be determined by the claims.

[0071] Comparative Example 1:

[0072] Synthesis Step 1:

[0073] Following the chiral synthesis method described in patent (CN112142745A), compound 1 (2 g, 7.66 mmol, 1.0 equivalent), compound 2 (4.6 g, 15.3 mmol, 2.0 equivalent), triphenylphosphine (4.1 g, 15.3 mmol, 2.0 equivalent), and tetrahydrofuran (30 mL) were added to a reaction flask. The mixture was cooled to 0°C, and diisopropyl azodicarbonate (3.1 g, 15.3 mmol, 2.0 equivalent) was added dropwise. After the addition was complete, the mixture was heated to room temperature and reacted for approximately 6 h. After the reaction was confirmed to be complete by TLC, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.66 g of a white solid product (formula (I)), with a yield of 40% and an ee value of 95.0%.

[0074]

[0075] Example 1:

[0076] Synthesis Step 1:

[0077] In a clean, dry reaction flask, tetrahydrofuran (650 mL), compound 1 (65.00 g, 249 mmol, 1.0 equivalent), and triphenylphosphine (163.28 g, 623 mmol, 2.5 equivalent) were added sequentially and stirred until dissolved. The system was cooled to 0–20 °C, and diisopropyl azodicarbonate (125.89 g, 623 mmol, 2.5 equivalent) was slowly added under controlled temperature. The reaction was maintained at 0–20 °C for 3 hours.

[0078] Synthesis Step 2:

[0079] Compound 2 (78.63 g, 261 mmol, 1.05 equivalents) was added to the system and the reaction was carried out at 0-20°C for 3 hours.

[0080] Synthesis Step 3:

[0081] 260 mL of 1 mol / L dilute hydrochloric acid solution was added to the system, and the reaction was maintained at 45–55 °C. After the reaction was complete (monitored by HPLC), the pH was neutralized to 6–7 with sodium bicarbonate, and the mixture was concentrated under reduced pressure. The product was then purified by recrystallization from methyl tert-butyl ether and acetonitrile to obtain 110 g of an off-white product, with a yield of 81%.

[0082] The specific steps of recrystallization are as follows: Methyl tert-butyl ether is added to the reaction vessel and stirring is started. The filter cake obtained after vacuum concentration is added to the methyl tert-butyl ether solution in four portions. The temperature is raised to 52°C (reflux) and stirred, then cooled to 20°C and stirred again. After the reaction is completed, the mixture is filtered, and the reaction vessel and filter cake are washed with methyl tert-butyl ether. The filter cake is then collected. Acetonitrile is then added to the reaction vessel and stirring is started. The filter cake treated with methyl tert-butyl ether is added in four portions, and the temperature is raised to 45°C and stirred, then cooled to 10°C and stirred again. The mixture is filtered, and the reaction vessel and filter cake are washed with acetonitrile. The filter cake is then collected to obtain the product.

[0083] HPLC analysis showed a purity of 99.51% and an ee value of 100%.

[0084] Example 2:

[0085] Synthesis Step 1:

[0086] In a clean, dry reaction flask, add tetrahydrofuran (20 mL), compound 1 (2.0 g, 7.66 mmol, 1.0 equivalent), and triphenylphosphine (4.02 g, 15.3 mmol, 2.0 equivalent) sequentially. Stir until homogeneous, cool to 0–20 °C, and add diisopropyl azodicarbonate (3.10 g, 15.3 mmol, 2.0 equivalent) dropwise under controlled temperature. After the addition is complete, maintain the reaction temperature at 0–20 °C for 3 hours.

[0087] Synthesis Step 2:

[0088] Compound 2 (2.42 g, 8.0 mmol, 1.05 equivalents) was added to the system and the reaction was carried out at 0-20°C for 3 hours.

[0089] Synthesis Step 3:

[0090] Add 8 mL of 1 mol / L dilute hydrochloric acid solution to the system and maintain the temperature at 45–55 °C. After the reaction is complete, neutralize the pH to 6–7 with sodium bicarbonate and concentrate under reduced pressure. Then, recrystallize sequentially with methyl tert-butyl ether and acetonitrile to obtain 2.12 g of an off-white product, with a yield of 51%. HPLC analysis showed a purity of 99.47% and an ee value of 99.4%.

[0091] Example 3:

[0092] Synthesis Step 1:

[0093] In a clean, dry reaction flask, add tetrahydrofuran (20 mL), compound 1 (2.0 g, 7.66 mmol, 1.0 equivalent), and triphenylphosphine (7.03 g, 26.8 mmol, 3.5 equivalent) sequentially. Stir to dissolve, cool to 0–20 °C, and add diisopropyl azodicarbonate (5.42 g, 26.8 mmol, 3.5 equivalent) dropwise under controlled temperature. After the addition is complete, maintain the reaction temperature at 0–20 °C for 3 hours.

[0094] Synthesis Step 2:

[0095] Compound 2 (2.43 g, 8.0 mmol, 1.05 equivalents) was added to the system and the reaction was maintained at 0-20°C for 3 hours.

[0096] Synthesis Step 3:

[0097] Add 8 mL of 1 mol / L dilute hydrochloric acid solution to the system and maintain the reaction temperature at 45–55 °C. After the reaction is complete, neutralize the pH to 6–7 with sodium bicarbonate and concentrate under reduced pressure. Then, recrystallize sequentially from methyl tert-butyl ether and acetonitrile to obtain 3.58 g of an off-white product, with a yield of 86%. HPLC analysis showed a purity of 99.60% and an ee value of 99.2%.

[0098] Example 4:

[0099] Synthesis Step 1:

[0100] In a clean, dry reaction flask, add tetrahydrofuran (20 mL), compound 1 (2.0 g, 7.66 mmol, 1.0 equivalent), and triphenylphosphine (5.0 g, 19.2 mmol, 2.5 equivalent) sequentially. Stir until homogeneous, cool to 0–20 °C, and add diisopropyl azodicarbonate (3.87 g, 19.1 mmol, 2.5 equivalent) dropwise under controlled temperature. After the addition is complete, maintain the reaction temperature at 0–20 °C for 3 hours.

[0101] Synthesis Step 2:

[0102] Compound 2 (2.07 g, 6.9 mmol, 0.9 equivalent) was added to the system and the reaction was maintained at 0-20°C for 3 hours.

[0103] Synthesis Step 3:

[0104] Add 8 mL of 1 mol / L dilute hydrochloric acid solution to the system and maintain the temperature at 45–55 °C until the reaction is complete. Neutralize the pH to 6–7 with sodium bicarbonate and concentrate under reduced pressure. Then, recrystallize successively with methyl tert-butyl ether and acetonitrile to obtain 3.42 g of off-white product, yield 82%. HPLC analysis showed a purity of 99.67% and an ee value of 100%.

[0105] Example 5:

[0106] Synthesis Step 1:

[0107] In a clean, dry reaction flask, add tetrahydrofuran (20 mL), compound 1 (2.0 g, 7.66 mmol, 1.0 equivalent), and triphenylphosphine (5.03 g, 19.1 mmol, 2.5 equivalent) sequentially. Stir to dissolve, cool to 0°C, and add diisopropyl azodicarbonate (3.87 g, 19.2 mmol, 2.5 equivalent) dropwise under controlled temperature. After the addition is complete, maintain the reaction temperature at 0°C for 3 hours.

[0108] Synthesis Step 2:

[0109] Compound 2 (2.43 g, 8.0 mmol, 1.05 equivalents) was added to the system and the reaction was maintained at 0°C for 3 hours.

[0110] Synthesis Step 2:

[0111] Add 8 mL of 1 mol / L dilute hydrochloric acid solution to the system, maintain the temperature at 45-55℃ until the reaction is complete, neutralize the pH to 6-7 with sodium bicarbonate, and concentrate under reduced pressure. Then, recrystallize successively with methyl tert-butyl ether and acetonitrile to obtain 3.59 g of off-white product, yield 85%. HPLC analysis showed a purity of 99.80% and an ee value of 99.80%.

[0112] Example 6:

[0113] Synthesis Step 1:

[0114] In a clean, dry reaction flask, add tetrahydrofuran (20 mL), compound 1 (2.0 g, 7.66 mmol, 1.0 equivalent), and triphenylphosphine (5.02 g, 19.1 mmol, 2.5 equivalent) sequentially. Stir until homogeneous, cool to 20°C, and add diisopropyl azodicarbonate (3.87 g, 19.1 mmol, 2.5 equivalent) dropwise under controlled temperature. After the addition is complete, maintain the reaction temperature at 20°C for 3 hours.

[0115] Synthesis Step 2:

[0116] Compound 2 (2.43 g, 8.0 mmol, 1.05 equivalents) was added to the system and the reaction was maintained at 20°C for 3 hours.

[0117] Synthesis Step 3:

[0118] Add 8 mL of 1 mol / L dilute hydrochloric acid solution to the system, maintain the temperature at 45-55℃ until the reaction is complete, neutralize the pH to 6-7 with sodium bicarbonate, and concentrate under reduced pressure. Then, recrystallize successively with methyl tert-butyl ether and acetonitrile to obtain 3.28 g of off-white product, yield 79%. HPLC analysis showed a purity of 99.56% and an ee value of 99.5%.

[0119] Example 7:

[0120] Synthesis Step 1:

[0121] In a clean, dry reaction flask, add tetrahydrofuran (20 mL), compound 1 (2.0 g, 7.66 mmol, 1.0 equivalent), and triphenylphosphine (5.03 g, 19.1 mmol, 2.5 equivalent) sequentially. Stir to dissolve, cool to 0–20 °C, and add diisopropyl azodicarbonate (3.84 g, 19.1 mmol, 2.5 equivalent) dropwise under controlled temperature. After the addition is complete, maintain the reaction temperature at 0–20 °C for 3 hours.

[0122] Synthesis Step 2:

[0123] Compound 2 (2.45 g, 8.0 mmol, 1.05 equivalents) was added to the system and the reaction was maintained at 0-20°C for 3 hours.

[0124] Synthesis Step 3:

[0125] An aqueous solution of acetic acid (4 mL, 1:1) was added to the system, and the temperature was controlled at 60 °C until the reaction was complete. The pH was neutralized to 6-7 with sodium bicarbonate, and the solution was concentrated under reduced pressure. The product was then purified by recrystallization from methyl tert-butyl ether and acetonitrile to obtain 3.67 g of an off-white product, with a yield of 87%. HPLC analysis showed a purity of 99.20% and an ee value of 99.40%.

[0126] Example 8:

[0127]

[0128] Synthesis Step 1:

[0129] In a clean, dry reaction flask, tetrahydrofuran (650 mL), compound 1 (65.00 g, 249 mmol, 1.0 equivalent), and 1,2-bis(bisphenylphosphine)ethane (248.21 g, 623 mmol, 2.5 equivalent) were added sequentially and stirred until dissolved. The system was cooled to 0–20 °C, and diisopropyl azodicarbonate (125.91 g, 623 mmol, 2.5 equivalent) was slowly added while maintaining the temperature. The reaction was carried out at 0–20 °C for 3 hours.

[0130] Synthesis Step 2:

[0131] Compound 2 (78.62 g, 261 mmol, 1.05 equivalents) was then added to the system, and the reaction was maintained at 0-20°C for 3 hours.

[0132] Synthesis Step 3:

[0133] 260 mL of 1 mol / L dilute hydrochloric acid solution was added to the system, and the reaction was maintained at 45–55 °C. After the temperature control was satisfactory, the pH was neutralized to 6–7 with sodium bicarbonate, and the mixture was concentrated under reduced pressure. The product was then purified by recrystallization from methyl tert-butyl ether and acetonitrile sequentially to obtain 108 g of an off-white product, with a yield of 80%. HPLC analysis showed a purity of 99.37% and an ee value of 99.60%.

[0134] Example 9:

[0135] Synthesis Step 1:

[0136] In a clean, dry reaction flask, add tetrahydrofuran (20 mL), compound 1 (2.0 g, 7.66 mmol, 1.0 equivalent), and triphenylphosphine (5.02 g, 19.1 mmol, 2.5 equivalent) sequentially. Stir to dissolve, cool to 0–20 °C, and add diethyl azodicarbonate (3.34 g, 19.2 mmol, 2.5 equivalent) dropwise under controlled temperature. After the addition is complete, maintain the reaction temperature at 0–20 °C for 3 hours.

[0137] Synthesis Step 2:

[0138] Compound 2 (2.44 g, 8.0 mmol, 1.05 equivalents) was added to the system and the reaction was maintained at 0-20°C for 3 hours.

[0139] Synthesis Step 3:

[0140] Add 8 mL of 1 mol / L dilute hydrochloric acid solution to the system and maintain the reaction temperature at 45–55 °C. Once the temperature is within acceptable limits, neutralize the pH to 6–7 with sodium bicarbonate and concentrate under reduced pressure. Then, recrystallize sequentially from methyl tert-butyl ether and acetonitrile to obtain 3.63 g of an off-white product, with a yield of 87%. HPLC analysis showed a purity of 99.67% and an ee value of 99.26%.

[0141] Example 10:

[0142] Synthesis Step 1:

[0143] In a clean, dry reaction flask, add tetrahydrofuran (20 mL), compound 1 (2.0 g, 7.66 mmol, 1.0 equivalent), and triphenylphosphine (5.01 g, 19.1 mmol, 2.5 equivalent) sequentially. Stir to dissolve, cool to 0–20 °C, and add diisopropyl azodicarbonate (3.86 g, 19.2 mmol, 2.5 equivalent) dropwise under controlled temperature. After the addition is complete, maintain the reaction temperature at 0–20 °C for 3 hours.

[0144] Synthesis Step 2:

[0145] Compound 2 (2.43 g, 8.0 mmol, 1.05 equivalents) was added to the system and the reaction was maintained at 0-20°C for 3 hours.

[0146] Synthesis Step 3:

[0147] Add 4 mL of 2 mol / L dilute hydrochloric acid solution to the system and maintain the reaction temperature at 45–55 °C. Once the temperature is within acceptable limits, neutralize the pH to 6–7 with sodium bicarbonate and concentrate under reduced pressure. Then, recrystallize sequentially from methyl tert-butyl ether and acetonitrile to obtain 3.54 g of an off-white product, with a yield of 85%. HPLC analysis showed a purity of 99.37% and an ee value of 99.72%.

Claims

1. A method for synthesizing a chiral intermediate of a casein kinase 1ε inhibitor, characterized in that, include: Compound 1 and phosphine reagent L1 were dissolved in the reaction solvent, and azodicarboxylic acid ester was added to complete the reaction. Compound 2 was added, and the reaction continued until completion. An acid was added to complete the reaction, and the reaction solution was post-treated to obtain the compound shown in formula (I): The structures of compound 1, compound 2, and the compound represented by formula (I) are as follows: ； The structure of the phosphine reagent L1 is PR1R2R3, where R1, R2, and R3 are each independently selected from C6-C10 aryl, C1-C5 alkyl, and 3-7 membered cycloalkyl groups; the aryl and alkyl groups may be further substituted by one or more C1-C2 alkoxy, C1-C5 alkyl, halogen, or phenyl substituted phosphine groups.

2. The method for synthesizing the chiral intermediate of the casein kinase 1ε inhibitor according to claim 1, characterized in that, After the addition of azodicarboxylic acid ester, the reaction temperature was 0~20℃; after the addition of compound 2, the reaction temperature was 0~20℃; after the addition of acid, the reaction temperature was 45~60℃.

3. The method for synthesizing the chiral intermediate of the casein kinase 1ε inhibitor according to claim 1, characterized in that, The phosphine reagent L1 is selected from one or more of triphenylphosphine, 1,2-bis(bisphenylphosphine)ethane, triethylphosphine, tributylphosphine, tricyclohexylphosphine, tris(4-methoxyphenyl)phosphine, tris(o-tolyl)phosphine, tris(p-tolyl)phosphine, di-tert-butylphenylphosphine, tris(3,5-dimethoxyphenyl)phosphine, and tris(4-fluorophenyl)phosphine.

4. The method for synthesizing the chiral intermediate of the casein kinase 1ε inhibitor according to claim 1, characterized in that, The azodicarboxylic acid ester is selected from one or more of diisopropyl azodicarbonate, dimethyl azodicarbonate, diethyl azodicarbonate, di-tert-butyl azodicarbonate, dibenzyl azodicarbonate, and di-p-toluene azodicarbonate. The acid solution is selected from one or more of acetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, trifluoroacetic acid, and methanesulfonic acid.

5. The method for synthesizing the chiral intermediate of the casein kinase 1ε inhibitor according to claim 1, characterized in that, The method for synthesizing the chiral intermediate of the casein kinase 1ε inhibitor according to claim 1 is characterized in that the molar ratio of phosphine reagent L1 to compound 1 is (2~4):1; the molar ratio of azodicarboxylic acid ester to compound 1 is (2~4):1; the molar ratio of compound 1 to compound 2 is 1:(0.8~1.5); and the molar ratio of added acid to compound 1 is 0.8~10:

1.

6. The method for synthesizing the chiral intermediate of the casein kinase 1ε inhibitor according to claim 1, characterized in that, The molar ratio of phosphine reagent L1 to compound 1 is (2.5~4):1; the molar ratio of azodicarboxylic acid ester to compound 1 is (2.5~4):1; the molar ratio of compound 1 to compound 2 is 1:(0.8~1.5); the molar ratio of compound 1 to compound 2 is 1:(0.9~1.5); and the molar ratio of added acid to compound 1 is 1~5:

1.

7. The method for synthesizing the chiral intermediate of the casein kinase 1ε inhibitor according to claim 1, characterized in that, The phosphine reagent L1 is selected from triphenylphosphine or 1,2-bis(bisphenylphosphine)ethane; the azodicarboxylic acid ester is selected from diisopropyl azodicarboxylate or diethyl azodicarboxylate; the acid is selected from hydrochloric acid or acetic acid; and the solvent is selected from tetrahydrofuran.

8. The method for synthesizing the chiral intermediate of the casein kinase 1ε inhibitor according to claim 1, characterized in that, The acid is added in the form of an aqueous solution with a concentration of 0.5~10 mol / L.

9. The method for synthesizing the chiral intermediate of the casein kinase 1ε inhibitor according to any one of claims 1 to 8, characterized in that, Includes the following steps: (i) Add solvent to the reaction vessel, add compound 1 and phosphine reagent L1, stir until homogeneous; control the temperature and slowly add azodicarboxylic acid ester to obtain compound 1-1; (ii) Compound 2 is added to the reaction system of step (i), and the reaction is continued at a constant temperature to obtain compound 3; (iii) In the reaction system of step (ii), after adding acid solution, the temperature is raised and the reaction is completed. After the reaction is completed, the pH is adjusted to 5-7 and then the compound of formula (1) is obtained by concentration and recrystallization. The structures of compounds 1-1 and 3 are as follows: 、 ； In step (i), the temperature is controlled at 0~20℃; the reaction temperature is 0~20℃. The reaction temperature in step (ii) is 0~20℃; The reaction temperature in step (iii) is 45~60℃; The structure of the phosphine reagent L1 is PR1R2R3, where R1, R2, and R3 are each independently selected from C6-C10 aryl, C1-C5 alkyl, and 3-7 membered cycloalkyl groups; the aryl and alkyl groups may be further substituted by one or more C1-C2 alkoxy, C1-C5 alkyl, halogen, or phenyl substituted phosphine groups.

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