Preparation method of AZD-8421 and intermediate thereof

Abstract

The invention relates to a preparation method of AZD-8421 and an intermediate thereof, and belongs to the technical field of medicines and chemistry. The invention provides a preparation method of AZD-8421, and the reaction is as follows: # imgabs0 # comprises the following steps: step 1, in the presence of alkali, reacting a compound in a formula 1 with a compound in a formula 2 to obtain a compound in a formula 3; 2, reacting the compound shown in the formula 3 with a Boc removal reagent to obtain a compound shown in a formula 4 or a salt thereof; 3, in the presence of alkali, the compound shown in the formula 5 reacts with iodoethane at the temperature of-10 DEG C to 20 DEG C to obtain a compound shown in the formula 6; 4, the compound shown in the formula 6 and a compound shown in the formula 4 or salt thereof react at the temperature of 40-60 DEG C in the presence of organic alkali and an organic solvent to obtain a compound shown in the formula 7; 5, in the presence of alkali, the compound shown in the formula 7 reacts with a compound shown in the formula 8 in an alcohol solvent, and a compound shown in the formula 9 is obtained. The method adopts a convergent synthesis strategy, and has the advantages of simultaneous synthesis of two fragments, simple operation and high yield; the method has the advantages of being high in conversion rate, easy and convenient to operate, economical, rapid, short in consumed time, good in reproducibility and high in atom utilization rate, is suitable for industrial production, and therefore has good market value and profound practical significance.

Description

Technical Field

[0001] The invention relates to a preparation method of AZD-8421 and an intermediate thereof, belonging to the technical field of medicine and chemistry. Background Art

[0002] AZD-8421 is a selective CDK2 inhibitor developed by AstraZeneca that is selective for CDK1, CDK4, and CDK6; the structure of AZD-8421 is as follows:

[0003]

[0004] AZD8421 can inhibit cancer cell proliferation by inhibiting pRB phosphorylation, inducing cell cycle arrest and senescence. AZD8421 showed good single efficacy and synergistic effects with CDK4 / 6 inhibitors such as Palbociclib (HY-50767) in breast and ovarian in vivo models. AZD8421 also has strong single-agent inhibitory activity against drug-resistant breast cancer cells.

[0005] The preparation route of AZD-8421 disclosed in prior art WO2024127350A1 is as follows:

[0006]

[0007] This patent uses the compound of formula 5 as the starting material, first reacts with iodoethane at room temperature with a yield of 60.2%, then reacts with (S)-1-Boc-3-aminopyrrolidine and (2R, 3S)-3-aminopentan-2-ol in sequence with yields of 59.1% and 62.7%, respectively, then deprotects with a yield of 100%, and finally reacts with ethylsulfonyl chloride to obtain AZD-8421 with a yield of 52.6%.

[0008] The patented method has a total of 5 steps and a total yield of 11.7%. The yield is very low and is not suitable for industrial production. In addition, there is no other method in the prior art to prepare AZD-8421 except this method. Therefore, it is urgent to develop a new method for synthesizing AZD-8421 that is economical, fast, easy to operate, has a high yield, a simple route, a short time consumption, and a high atomic utilization rate to improve efficiency and promote industrial production.

[0009] The present invention provides a novel preparation method of AZD-8421 and its intermediates, which also uses the compound of formula 5 as a raw material, but adopts a convergent synthesis strategy to shorten the total reaction time, the yield of each step is more than 70%, and the total yield reaches more than 45%. The preparation method of AZD-8421 and its intermediates provided by the present invention has the advantages of high conversion rate, simple operation, economical and fast, short time consumption, and high atomic utilization rate, and is suitable for industrial production, so it has good market value and far-reaching practical significance. Summary of the invention

[0010] In view of the above technical background, the present invention provides a method for preparing AZD-8421 and its intermediates. The preparation method of the present invention is simple to operate, has high atom utilization rate, high conversion rate, short time consumption, reduced cost, and is conducive to industrial production.

[0011] The first aspect of the present invention provides a method for preparing AZD-8421, the reaction is as follows:

[0012]

[0013] The steps include:

[0014] Step 4: reacting the compound of formula 6 with the compound of formula 4 or a salt thereof in the presence of an organic base and an organic solvent at 40° C. to 60° C. to obtain a compound of formula 7;

[0015] Step 5: In the presence of a base, the compound of formula 7 reacts with the compound of formula 8 in an alcohol solvent to obtain a compound of formula 9;

[0016] As a further improvement of the present invention, including but not limited to, in step 4, the molar ratio of the compound of formula 6 to the compound of formula 4 or its salt is 1:(0.9-1.1), preferably 1:(1-1.1);

[0017] As a further improvement of the present invention, including but not limited to, the molar ratio of the compound of formula 6 to the organic base in step 4 is 1:(1.5-5), preferably 1:(2-5);

[0018] As a further improvement of the present invention, including but not limited to, the organic base in step 4 is one or more of triethylamine, diethylamine, pyridine, dimethylaminopyridine, diisopropylamine, N,N-diisopropylethylamine (DIPEA), and 1,8-diazabicycloundec-7-ene (DBU);

[0019] As a further improvement of the present invention, including but not limited to, the organic solvent in step 4 is one or more of tetrahydrofuran, dichloromethane, DMF, DMA, DMSO, acetonitrile, ethanol, methanol, isopropanol, propanol, n-butanol, isobutanol, tert-butanol, dioxane, and acetone, preferably one or more of DMF, DMA, DMSO, ethanol, methanol, propanol, isopropanol, n-butanol, isobutanol, and tert-butanol;

[0020] As a further improvement of the present invention, including but not limited to, the reaction time of step 4 is 5 to 18 hours, preferably 6 to 16 hours;

[0021] As a further improvement of the present invention, in certain embodiments, after the reaction of step 4 is completed, the reaction solution is dissolved in an organic solvent, extracted, separated, dried, and concentrated to obtain a crude product of the compound of formula 7;

[0022] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane;

[0023] As a further improvement of the present invention, in certain embodiments, the crude product can be further subjected to column chromatography to obtain a pure product of the compound of formula 3, and the column chromatography eluent is, for example, ethyl acetate: hexane = 5:1.

[0024] As a further improvement of the present invention, including but not limited to, the molar ratio of the compound of formula 7 to the compound of formula 8 in step 5 is 1:(1.5-10), preferably 1:(2-8);

[0025] As a further improvement of the present invention, including but not limited to, the base in step 5 is selected from one or more of triethylamine, diethylamine, pyridine, dimethylaminopyridine, diisopropylamine, N,N-diisopropylethylamine, and 1,8-diazabicycloundec-7-ene (DBU);

[0026] As a further improvement of the present invention, including but not limited to, the molar ratio of the compound of formula 7 to the base in step 5 is 1:(2-10), preferably 1:(2-8);

[0027] As a further improvement of the present invention, including but not limited to, the alcohol solvent in step 5 is one or more of propanol, isopropanol, and 3-ethyl-3-pentanol, preferably isopropanol;

[0028] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 5 is 80 to 150° C., preferably 90 to 140° C.;

[0029] As a further improvement of the present invention, including but not limited to, the reaction time of step 5 is 36 to 110 hours, preferably 48 to 100 hours;

[0030] As a further improvement of the present invention, in certain embodiments, after the reaction of step 5 is completed, the reaction solution is added to an organic solvent, extracted, separated, dried, and concentrated to obtain a crude product of the compound of formula 9;

[0031] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane;

[0032] As a further improvement of the present invention, in certain embodiments, the crude product can be further subjected to column chromatography to obtain a pure product of the compound of formula 3, and the column chromatography eluent is, for example, DCM:MeOH=10:1.

[0033] As a further improvement of the present invention, step 4 of the present invention reacts within a preferred temperature range, which not only reduces the temperature but also increases the yield by more than 23% and reduces the generation of by-products compared to the prior art which reacts at 100°C. The method of the present invention has the advantages of higher conversion rate, lower cost and better production.

[0034] As a further improvement of the present invention, when isopropanol is used as a solvent in step 5 of the present invention, the yield is increased by more than 49% compared with using N-methylpyrrolidone as a solvent, and the yield is increased by more than 24% compared with using n-butanol. The method of the present invention has the advantages of higher conversion rate, lower cost, and is conducive to production.

[0035] The second aspect of the present invention provides a method for preparing the intermediate compound of formula 4 of AZD-8421, the reaction is as follows:

[0036]

[0037] The steps include:

[0038] Step 1: In the presence of a base, the compound of formula 1 and the compound of formula 2 react to obtain a compound of formula 3;

[0039] Step 2: reacting the compound of formula 3 with a de-Boc reagent to obtain a compound of formula 4 or a salt thereof;

[0040] As a further improvement of the present invention, including but not limited to, in step 1, the molar ratio of the compound of formula 1 to the compound of formula 2 is 1:(0.9-1.3), preferably 1:(1-1.2);

[0041] As a further improvement of the present invention, including but not limited to, the base in step 1 is selected from one or more of potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, sodium bicarbonate, potassium bicarbonate, triethylamine, diethylamine, pyridine, dimethylaminopyridine, diisopropylamine, N,N-diisopropylethylamine, and 1,8-diazabicycloundec-7-ene (DBU); preferably one or more of pyridine, potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, and potassium phosphate.

[0042] As a further improvement of the present invention, including but not limited to, the molar ratio of the compound of formula 1 to the base in step 1 is 1:(1.5-5), preferably 1:(2-5);

[0043] As a further improvement of the present invention, including but not limited to, the reaction solvent of step 1 is one or more of tetrahydrofuran, dichloromethane, DMF, DMA, DMSO, and acetonitrile, preferably one or more of dichloromethane, DMF, DMA, and DMSO.

[0044] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 1 is -5 to 40°C, preferably -5 to 35°C;

[0045] As a further improvement of the present invention, including but not limited to, the reaction time of step 1 is 1 to 5 hours, preferably 1 to 4 hours;

[0046] As a further improvement of the present invention, including but not limited to, the volume ml of the reaction solvent in step 1 is 3 to 20 times the mass g of the compound of formula 1, preferably 3 to 15 times;

[0047] As a further improvement of the present invention, in certain embodiments, after the reaction of step 1 is completed, water is added to the reaction solution to quench, an organic solvent is added, and extraction, washing, separation, drying, and concentration are performed to obtain a crude product of compound 3;

[0048] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane;

[0049] As a further improvement of the present invention, in certain embodiments, the above crude product can be further subjected to column chromatography to obtain a pure product of the compound of formula 3.

[0050] As a further improvement of the present invention, including but not limited to, the de-Boc reagent in step 2 is one or more of trifluoroacetic acid, hydrochloric acid, hydrochloric acid aqueous solution, hydrochloric acid methanol solution, hydrochloric acid ethanol solution, hydrochloric acid isopropanol solution, hydrochloric acid dioxane solution, hydrochloric acid ethyl acetate solution, preferably one or more of hydrochloric acid dioxane solution and hydrochloric acid ethyl acetate solution;

[0051] As a further improvement of the present invention, including but not limited to, in step 2, a solvent is optionally added, and the solvent is selected from one or more of water, dichloromethane, dioxane, ethyl acetate, methanol, ethanol, and acetonitrile;

[0052] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 2 is 0 to 40° C., preferably 0 to 35° C.;

[0053] As a further improvement of the present invention, including but not limited to, the reaction time of step 2 is 0.5 to 5 hours, preferably 1 to 4 hours.

[0054] As a further improvement of the present invention, the method of the present invention is used to prepare the compound of formula 3, which not only takes a short time, but also has a high yield, few impurities, and simple operation, which is conducive to industrial production.

[0055] The third aspect of the present invention provides a method for preparing the intermediate compound of formula 6 of AZD-8421, the reaction is as follows:

[0056]

[0057] The steps include:

[0058] Step 3: In the presence of a base, the compound of formula 5 reacts with iodoethane to obtain a compound of formula 6;

[0059] As a further improvement of the present invention, the compound of formula 5 is reacted with iodoethane at -10°C to 20°C to obtain the compound of formula 6;

[0060] As a further improvement of the present invention, including but not limited to, the molar ratio of the compound of formula 5 to ethyl iodide in step 3 is 1:(1-10), preferably 1:(1.5-10), more preferably 1:(2-8);

[0061] As a further improvement of the present invention, including but not limited to, the base in step 3 is selected from one or more of potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, sodium bicarbonate, potassium bicarbonate, triethylamine, diethylamine, pyridine, dimethylaminopyridine, diisopropylamine, N,N-diisopropylethylamine, 1,8-diazabicycloundec-7-ene (DBU); preferably one or more of potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, and potassium phosphate;

[0062] As a further improvement of the present invention, including but not limited to, the molar ratio of the compound of formula 5 to the base in step 3 is 1:(1.5-5), preferably 1:(2-5);

[0063] As a further improvement of the present invention, including but not limited to, the reaction solvent of step 3 is one or more of tetrahydrofuran, dichloromethane, DMF, DMA, DMSO, and acetonitrile, preferably one or more of DMF, DMA, and DMSO.

[0064] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 3 is -10 to 15°C, preferably -5 to 10°C;

[0065] As a further improvement of the present invention, including but not limited to, the reaction time of step 3 is 1 to 10 hours, preferably 1 to 6 hours;

[0066] As a further improvement of the present invention, in certain embodiments, after the reaction of step 3 is completed, the reaction solution is filtered, rinsed, an organic solvent is added, washed, extracted, separated, dried, and concentrated to obtain a crude product of the compound of formula 6;

[0067] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane;

[0068] As a further improvement of the present invention, in certain embodiments, the crude product can be further subjected to column chromatography to obtain a pure product of the compound of formula 3, and the column chromatography eluent is, for example, 30% ethyl acetate in hexane.

[0069] As a further improvement of the present invention, the method of step 3 of the present invention is used to prepare the compound of formula 6, and the yield is increased by more than 20% compared with the prior art method, and basically no isomeric impurities are generated, with a high conversion rate, which is conducive to promoting industrial production.

[0070] The fourth aspect of the present invention provides a method for preparing AZD-8421, the reaction is as follows:

[0071]

[0072] The steps include:

[0073] Step 1: In the presence of a base, the compound of formula 1 and the compound of formula 2 react to obtain a compound of formula 3;

[0074] Step 2: reacting the compound of formula 3 with a de-Boc reagent to obtain a compound of formula 4 or a salt thereof;

[0075] Step 3: In the presence of a base, the compound of formula 5 reacts with iodoethane at -10°C to 20°C to obtain a compound of formula 6;

[0076] Step 4: reacting the compound of formula 6 with the compound of formula 4 or a salt thereof in the presence of an organic base and an organic solvent at 40° C. to 60° C. to obtain a compound of formula 7;

[0077] Step 5: In the presence of a base, the compound of formula 7 reacts with the compound of formula 8 in an alcohol solvent to obtain a compound of formula 9;

[0078] The preferred technical solution of the present invention, step 1 can all refer to the entire technical solution of step 1 of the second aspect of the present invention specification to provide a method for preparing the intermediate compound of formula 4 of AZD-8421;

[0079] The preferred technical solution of the present invention, step 2 can all refer to the entire technical solution of step 2 of the preparation method of the intermediate compound of formula 4 of AZD-8421 provided in the second aspect of the present invention;

[0080] The preferred technical solution of the present invention, step 3 can all refer to the entire technical solution of step 3 of the present invention specification. The third aspect provides a method for preparing the intermediate compound of formula 6 of AZD-8421;

[0081] The preferred technical solution of the present invention, step 4 can all refer to the entire technical solution of step 4 of the preparation method of AZD-8421 provided in the first aspect of the present invention;

[0082] The preferred technical solution of the present invention, step 5 can all refer to the entire technical solution of step 5 of the preparation method of AZD-8421 provided in the first aspect of the present invention;

[0083] As a further improvement of the present invention, the present invention provides a new method for preparing AZD-8421, and provides the preparation of two new key intermediates. The inventors continuously adjusted the reaction reagents and conditions during the experiment, and unexpectedly found that under the conditions of the present invention, the yield of each step of preparing AZD-8421 is increased by more than 20%, and the total yield of 5 steps is as high as more than 45%, which is more than 34% higher than the prior art. The method of the present invention not only has a short reaction time and a high conversion rate, but also has the characteristics of less impurities, simple operation and high purity, which is conducive to promoting industrial production.

[0084] The fifth aspect of the present invention provides a new intermediate of AZD-8421, the structural formula of which is shown below:

[0085]

[0086] The sixth aspect of the present invention provides a method for preparing AZD-8421, which includes the first aspect mentioned above providing a method for preparing an AZD-8421 intermediate compound of formula 7 or the second aspect mentioned above providing a method for preparing an AZD-8421 intermediate compound of formula 3 or the third aspect of the present invention mentioned above providing a method for preparing an AZD-8421 intermediate compound of formula 7 or the fourth aspect mentioned above providing a method for preparing AZD-8421 or the new AZD-8421 intermediate compound of formula 3 or compound of formula 7 mentioned above.

[0087] Beneficial technical effects of the present invention:

[0088] 1. The inventors conducted the reaction within the preferred temperature range. Compared with the prior art which conducted the reaction at 100° C., the temperature was lowered, the energy consumption was reduced, the yield was increased by more than 23%, the selectivity was improved, the generation of by-products was reduced, and the purification was facilitated. The method has the advantages of high atomic utilization, simple operation, and high conversion rate, and is suitable for industrial production.

[0089] 2. Through continuous attempts by the inventors, it was unexpectedly discovered that the lower the reaction temperature in step 3, the more favorable it is to obtain the target product. When the temperature is higher than 20°C, isomer impurities are easily generated. If the temperature is not controlled, only 17% of the target product can be obtained. The yield of the present invention can reach more than 80% by controlling the reaction temperature, which is 63% higher than the yield without temperature control and more than 20% higher than the prior art. Step 3 of the present invention has the advantages of high conversion rate and few impurities, and is suitable for industrial production.

[0090] 3. The present invention adopts a convergent synthesis strategy, which shortens the total reaction time. The yield of each step is above 70%, and the yield of each step is increased by more than 20% compared with the prior art. The total yield of 5 steps is as high as more than 45%, which is more than 34% higher than the total yield of the prior art. The method of the present invention not only has a short reaction time and a high conversion rate, but also has the characteristics of less impurities, simple operation and high purity, which is conducive to promoting industrial production.

[0091] 4. The use of isopropanol as solvent in step 5 of the present invention increases the yield by 20% to 50% compared with the use of NMP or n-butanol as solvent.

[0092] 5. The present invention also provides two new AZD-8421 intermediates, provides a new method for the synthesis of AZD-8421, and is beneficial to the commercial production of AZD-8421. At the same time, the present invention also provides a method for preparing compound 4. There is no method for preparing compound 4 in the prior art. The method of the present invention has the advantages of high conversion rate, simple operation, economical and fast, short time consumption, good reproducibility, and high atomic utilization rate. It is suitable for industrial production and therefore has good market value and far-reaching practical significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0093] Figure 1 The HNMR spectrum of the product obtained in Example 1 of the present invention;

[0094] Figure 2 This is the HNMR spectrum of the product obtained in Example 3 of the present invention;

[0095] Figure 3 The HNMR spectrum of the product obtained in Example 4 of the present invention;

[0096] Figure 4 This is the HNMR spectrum of the product obtained in Example 6 of the present invention;

[0097] Figure 5 The LCMS spectrum of the product obtained in Comparative Example 2 of the present invention;

[0098] Figure 6 The LCMS spectrum of the product obtained in Comparative Example 3 of the present invention. DETAILED DESCRIPTION

[0099] The present invention will be further described below in conjunction with specific examples. It should be understood that the following detailed description of the technical solution of the present invention with examples will help to further understand the advantages and effects of the technical solution of the present invention, and the examples do not limit the protection scope of the present invention, which is determined by the claims.

[0100] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or conditions recommended by the manufacturers.

[0101] Unless otherwise specified, the raw materials and reagents used in the examples are commercially available.

[0102] Unless otherwise specified, the reagents were used directly without purification. All solvents were purchased from commercial suppliers, such as Aldrich, and used directly without further treatment.

[0103] Embodiment 1:

[0104]

[0105] Compound 1 (930 mg, 5 mmol) was dissolved in DMF (5 mL), potassium carbonate (2.42 g, 17.5 mmol, 3.5 eq) was added, argon was replaced, compound 2 (790 mg, 5.5 mmol, 1.1 eq) was added at 0 ° C, and stirred at room temperature for 2 h. Water was added to quench, extracted with DCM, washed, dried, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (hexane-ethyl acetate = 20:1) to obtain a white solid compound of formula 3 (1.27 g, 4.3 mmol, yield 87.0%), 1 H-NMR spectrum Figure 1 shown.

[0106] Embodiment 2:

[0107]

[0108] 4N hydrochloric acid-dioxane solution (2 mL) was added to compound 3 (150 mg, 511.3 umol), stirred at room temperature for 1 hour, and concentrated in vacuo to obtain the hydrochloride of compound 4 (100 mg).

[0109] Embodiment 3:

[0110]

[0111] Compound 5 (1 g, 5.8 mmol) was dissolved in DMF (15 mL), potassium carbonate (2 g, 14.5 mmol) was added, iodoethane (3 ml, 37.5 mmol, 6.5 eq) was added dropwise at 0-5 ° C., the mixture was reacted at 0-5 ° C. for 3 hours, filtered on diatomaceous earth, washed with DMF, DMF was removed, the crude product was dissolved in ethyl acetate, washed with saturated brine, dried and concentrated, and purified by silica gel column chromatography (30% ethyl acetate in hexane) to obtain white solid compound 6 (960 mg, yield 82.6%). 1 H-NMR spectrum Figure 2 shown.

[0112] Embodiment 4:

[0113]

[0114] Compound 6 (200 mg, 1 mmol, 1 eq), the hydrochloride of compound 4 (230 mg, 1 mmol, 1 eq) and DIPEA (450 mg, 3.5 mmol, 3.5 eq) were dissolved in n-butanol (5 mL), and reacted at 50° C. overnight. The reaction solution was dissolved in ethyl acetate, extracted, separated, dried and concentrated, and purified by silica gel column chromatography (ethyl acetate: hexane = 3:2) to obtain compound 7 (290 mg, 81.4%, purity 100%). 1 H-NMR spectrum Figure 3 shown.

[0115] Embodiment 5:

[0116]

[0117] Compound 6 (13.00 g, 64.8 mmol, 1 eq), hydrochloride of compound 4 (14.9 g, 64.9 mmol, 1 eq) and DIPEA (34 g, 263.1 mmol, 4 eq) were dissolved in n-butanol (375 mL), and reacted at 50°C overnight. The reaction solution was dissolved in ethyl acetate, extracted, separated, dried and concentrated, and purified by silica gel column chromatography (ethyl acetate: hexane = 3:2) to obtain compound 7 (19 g, 82%).

[0118] Embodiment 6:

[0119]

[0120] Compound 7 (12 g, 33.6 mmol) was dissolved in isopropanol (180 ml), DIEA (21.6 g, 168 mmol, 5 eq) and compound 8 (12.1 g, 117 mmol, 3.5 eq) were added, and the mixture was stirred at 100° C. for 96 h. The reaction solution was cooled to room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with water, dried, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (DCM: MeOH=10:1) to obtain a white solid compound of formula 9 (11.8 g, yield 80%). 1 H-NMR spectrum Figure 4 shown.

[0121] Comparative Example 1:

[0122]

[0123] Compound 5 (1 g, 5.8 mmol) was dissolved in DMF (15 mL), potassium carbonate (2 g, 14.5 mmol) was added, iodoethane (3 ml, 30 mmol) was added dropwise at room temperature, and the mixture was reacted for 3 hours. The mixture was filtered through celite and rinsed with DMF to remove DMF. The crude product was dissolved in ethyl acetate, washed with saturated brine, dried and concentrated, and purified by silica gel column chromatography (30% ethyl acetate in hexane) to give white solid compound 6 (200 mg, yield 17%).

[0124] The inventors combined TLC, LCMS, and HNMR data analysis to conclude that the reaction preferentially produces isomeric impurities at room temperature, and the structures are as follows:

[0125]

[0126] Through continuous attempts, the inventors unexpectedly discovered that adding iodoethane at low temperature has better effect than adding it at room temperature, the yield is increased by 46% to 66%, the isomer impurities are less, and it is beneficial to the purification of compound 6.

[0127] Comparative Example 2:

[0128]

[0129] Compound 6 (200 mg, 1 mmol, 1 eq), the hydrochloride of compound 4 (230 mg, 1 mmol, 1 eq) and DIPEA (450 mg, 3.5 mmol) were dissolved in n-butanol (5 mL), and reacted at 110° C. overnight. The reaction solution was dissolved in ethyl acetate, extracted, separated, dried and concentrated, and purified by silica gel column chromatography (ethyl acetate: hexane = 3:2) to obtain compound 7 (125 mg, 35%). The LCMS spectrum is shown as follows: Figure 5 shown.

[0130] Comparative Example 3:

[0131]

[0132] Compound 6 (2.00 g, 10 mmol, 1 eq), the hydrochloride of compound 4 (2.3 g, 10 mmol, 1 eq) and DIPEA (4.5 g, 35 mmol, 3.5 eq) were dissolved in n-butanol (50 mL), and the mixture was reacted at 90° C. overnight. The reaction solution was dissolved in ethyl acetate, extracted, separated, dried and concentrated, and purified by silica gel column chromatography (ethyl acetate: hexane = 3:2) to obtain compound 7 (2 g, 56%). The LCMS spectrum is shown as follows: Figure 6 shown.

[0133] The inventors have improved the temperature through creative work and found that when the temperature is too high, a by-product of formula 7A will be produced. The higher the temperature, the more by-products there are. It can be seen from the LCMS spectrum that compound 7 and by-product 7A are contained in one peak, which is difficult to purify. Through continuous attempts, the inventors have found that within the reaction temperature of the present invention, no by-product 7A is produced, thereby improving the yield, simplifying purification, saving energy consumption, and facilitating industrial production.

[0134] Comparative Example 4:

[0135]

[0136] Compound 7 (119 mg, 333 umol) was dissolved in N-methylpyrrolidone (3 ml), DIEA (215 mg, 1.66 mmol, 5 eq) and compound 8 (171 mg, 1.66 mmol, 5 eq) were added, and the mixture was stirred at 140°C for 24 h. The reaction solution was cooled to room temperature, excess water was added, and the mixture was filtered. The organic phase was extracted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (DCM: MeOH = 10: 1) to obtain compound 9 as a white solid (45 mg, yield 30.7%).

[0137] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for preparing AZD-8421, characterized in that: The reaction is as follows: The steps include: Step 4: reacting the compound of formula 6 with the compound of formula 4 or a salt thereof in the presence of an organic base and an organic solvent at 40° C. to 60° C. to obtain a compound of formula 7; Step 5: In the presence of a base, the compound of formula 7 reacts with the compound of formula 8 in an alcohol solvent to obtain a compound of formula 9.

2. The method according to claim 1, characterized in that The compound of formula 4 is prepared by the following method, and the reaction is as follows: The steps include: Step 1: In the presence of a base, the compound of formula 1 and the compound of formula 2 react to obtain a compound of formula 3; Step 2: The compound of formula 3 reacts with a de-Boc reagent to obtain a compound of formula 4 or a salt thereof.

3. The method according to claim 1, characterized in that The compound of formula 6 is prepared by the following method, and the reaction is as follows: Step 3: In the presence of a base, the compound of formula 5 is reacted with iodoethane to obtain a compound of formula 6.

4. The preparation method according to claim 2, characterized in that: The preparation method satisfies one or more of the following conditions: (1) In step 1, the molar ratio of the compound of formula 1 to the compound of formula 2 is 1:(0.9-1.3), preferably 1:(1-1.2); (2) the base in step 1 is selected from one or more of potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, sodium bicarbonate, potassium bicarbonate, triethylamine, diethylamine, pyridine, dimethylaminopyridine, diisopropylamine, N,N-diisopropylethylamine, and 1,8-diazabicycloundec-7-ene; preferably one or more of pyridine, potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, and potassium phosphate; (3) In step 1, the molar ratio of the compound of formula 1 to the base is 1:(1.5-5), preferably 1:(2-5); (4) The reaction solvent of step 1 is one or more of tetrahydrofuran, dichloromethane, DMF, DMA, DMSO, and acetonitrile, preferably one or more of dichloromethane, DMF, DMA, and DMSO; (5) The reaction temperature of step 1 is -5 to 40°C, preferably -5 to 35°C; (6) The reaction time of step 1 is 1 to 5 hours, preferably 1 to 4 hours; (7) The volume of the reaction solvent in step 1 is 3 to 20 times, preferably 3 to 15 times, the mass of the compound of formula 1; (8) After the reaction of step 1 is completed, water is added to the reaction solution to quench it, and an organic solvent is added, followed by extraction, washing, separation, drying, and concentration to obtain a crude product of the compound of formula 3; the crude product of the compound of formula 3 can optionally be further subjected to column chromatography to obtain a pure product of the compound of formula 3.

5. The preparation method according to claim 2, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The de-Boc reagent in step 2 is one or more of trifluoroacetic acid, hydrochloric acid, hydrochloric acid aqueous solution, hydrochloric acid methanol solution, hydrochloric acid ethanol solution, hydrochloric acid isopropanol solution, hydrochloric acid dioxane solution, and hydrochloric acid ethyl acetate solution, preferably one or more of hydrochloric acid dioxane solution and hydrochloric acid ethyl acetate solution; (2) In step 2, a solvent may be optionally added, wherein the solvent is selected from one or more of water, dichloromethane, dioxane, ethyl acetate, methanol, ethanol, and acetonitrile; (3) The reaction temperature of step 2 is 0 to 40° C., preferably 0 to 35° C.; (4) The reaction time of step 2 is 0.5 to 5 h, preferably 1 to 4 h.

6. The preparation method according to claim 3, characterized in that: The preparation method satisfies one or more of the following conditions: (1) the compound of formula 5 in step 3 is reacted with iodoethane at -10°C to 20°C to obtain a compound of formula 6; (2) In step 3, the molar ratio of the compound of formula 5 to ethyl iodide is 1:(1-10), preferably 1:(1.5-10), more preferably 1:(2-8); (3) In step 3, the base is selected from one or more of potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, sodium bicarbonate, potassium bicarbonate, triethylamine, diethylamine, pyridine, dimethylaminopyridine, diisopropylamine, N,N-diisopropylethylamine, and 1,8-diazabicycloundec-7-ene; preferably one or more of potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, and potassium phosphate; (4) In step 3, the molar ratio of the compound of formula 5 to the base is 1:(1.5-5), preferably 1:(2-5); (5) The reaction solvent of step 3 is one or more of tetrahydrofuran, dichloromethane, DMF, DMA, DMSO, and acetonitrile, preferably one or more of DMF, DMA, and DMSO; (6) The reaction temperature of step 3 is -10 to 15°C, preferably -5 to 10°C; (7) The reaction time of step 3 is 1 to 10 hours, preferably 1 to 6 hours; (8) After the reaction of step 3 is completed, the reaction solution is filtered, rinsed, an organic solvent is added, washed, extracted, separated, dried, and concentrated to obtain a crude product of the compound of formula 6; the crude product of the compound of formula 6 can be further subjected to column chromatography to obtain a pure product of the compound of formula 6.

7. The preparation method according to any one of claims 1 to 3, characterized in that: The preparation method satisfies one or more of the following conditions: (1) In step 4, the molar ratio of the compound of formula 6 to the compound of formula 4 or its salt is 1:(0.9-1.1), preferably 1:(1-1.1); (2) In step 4, the molar ratio of the compound of formula 6 to the organic base is 1:(1.5-5), preferably 1:(2-5); (3) the organic base in step 4 is one or more of triethylamine, diethylamine, pyridine, dimethylaminopyridine, diisopropylamine, N,N-diisopropylethylamine, and 1,8-diazabicycloundec-7-ene; (4) The organic solvent in step 4 is one or more of tetrahydrofuran, dichloromethane, DMF, DMA, DMSO, acetonitrile, ethanol, methanol, isopropanol, propanol, dioxane, acetone, n-butanol, isobutanol, and tert-butanol, preferably one or more of DMF, DMA, DMSO, ethanol, methanol, propanol, isopropanol, n-butanol, isobutanol, and tert-butanol; (5) The reaction time of step 4 is 5 to 18 hours, preferably 6 to 16 hours; (6) After the reaction in step 4 is completed, the reaction solution is dissolved in an organic solvent, extracted, separated, dried, and concentrated to obtain a crude product of the compound of formula 7; the crude product of the compound of formula 7 can be further subjected to column chromatography to obtain a pure product of the compound of formula 7.

8. The preparation method according to any one of claims 1 to 3, characterized in that: The preparation method satisfies one or more of the following conditions: (1) In step 5, the molar ratio of the compound of formula 7 to the compound of formula 8 is 1:(1.5-10), preferably 1:(2-8); (2) in step 5, the base is selected from one or more of triethylamine, diethylamine, pyridine, dimethylaminopyridine, diisopropylamine, N,N-diisopropylethylamine, and 1,8-diazabicycloundec-7-ene; (3) In step 5, the molar ratio of the compound of formula 7 to the base is 1:(2-10), preferably 1:(2-8); (4) The alcohol solvent in step 5 is one or more of propanol, isopropanol, and 3-ethyl-3-pentanol, preferably isopropanol; (5) The reaction temperature of step 5 is 80 to 150° C., preferably 90 to 140° C.; (6) The reaction time of step 5 is 36 to 110 hours, preferably 48 to 100 hours; (7) After the reaction in step 4 is completed, the reaction solution is added to an organic solvent, extracted, separated, dried, and concentrated to obtain a crude product of the compound of formula 9; the crude product of the compound of formula 9 can be further subjected to column chromatography to obtain a pure product of the compound of formula 7.

9. An intermediate compound of AZD-8421, having the following structure:

10. A method for preparing AZD-8421, characterized in that: The compound is prepared by the method of claim 1, 2 or 3, or by the intermediate of claim 9.

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