Az191 intermediates, methods of preparation, and a method of preparing az191

Abstract

The application relates to the field of organic chemistry, in particular to AZ191 and an intermediate and a preparation method thereof. The preparation method of AZ191 is as follows: wherein X is selected from halogen, and the method comprises the following steps: A1) mixing compound 1, N, N-dimethyl methylamine dimethyl acetal and a first solvent to perform a first reaction to obtain compound 2; A2) performing a second reaction on the compound 2 obtained in the step A1), urea and a ring-closing reagent to obtain compound 3; A3) performing a third reaction on the compound 3 obtained in the step A2) and a halogenation reagent to obtain compound 4; and A4) performing a fourth reaction on the compound 4 obtained in the step A3), compound 7, an acid and a second solvent to obtain the compound. The preparation method of AZ191 in the application can obtain AZ191 in a high yield and is beneficial to industrial production because 1-(1H-pyrrolo[2,3-c]pyridin-3-yl)ethanone is used as a reaction substrate, and condensation, ring-closing, halogenation and amination reactions are sequentially performed.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, specifically to an AZ191 intermediate, its preparation method, and a method for preparing AZ191. Background Technology

[0002] Dual-specificity tyrosine phosphorylation regulated kinase 1B (Dyrk1B), also known as the Mirk gene, is located on human chromosome 19, q12–q13.11, and consists of an 8.8 kb gene fragment composed of 11 exons and 10 introns. AZ191 is a potent and selective Dyrk1B inhibitor, and its structural formula is shown in Formula 5. Chinese patent CN112516146 A discloses that AZ191 can be used to induce the proliferation of endogenous cardiomyocytes.

[0003]

[0004] In the prior art, the article "Discovery and Optimization of a Novel Series of Dyrk1B Kinase Inhibitors To Explore a MEK Resistance Hypothesis" (Journal of Medicinal Chemistry, 2015, vol. 58, #6, p. 2834-2844) reports a method for preparing AZ191, which uses 6-azaindole as a starting material and obtains AZ191 through the following route.

[0005]

[0006] The above route requires seven reaction steps from the starting materials to obtain the final target product. The long reaction route results in a low yield, with an overall yield of only 0.33% across the seven steps. Furthermore, since the above route also involves a selective coupling reaction, this reaction not only requires the use of an expensive palladium catalyst but also has strict requirements on the reaction conditions, which is not conducive to industrial production. Summary of the Invention

[0007] Given the high requirements for reaction conditions, the need for expensive palladium catalysts, and low yields of the existing technologies described above, the purpose of this invention is to provide a novel method for preparing AZ191 and its intermediates, which involves fewer reaction steps and yields relatively better results.

[0008] To achieve the above and other related objectives, the first aspect of this invention provides a method for preparing AZ191, the reaction route of which is as follows:

[0009]

[0010] Where X is selected from halogens.

[0011] Includes the following steps:

[0012] A1) Compound 1, N,N-dimethyl methyl ester dimethyl acetal and the first solvent were mixed and subjected to the first reaction to obtain compound 2.

[0013] A2) Compound 2 obtained in step A1), urea, and the cyclization reagent are subjected to a second reaction to obtain compound 3.

[0014] A3) Compound 3 obtained in step A2) is reacted with a halogenating reagent in a third reaction to obtain compound 4.

[0015] A4) Compound 4, compound 7, acid, and second solvent obtained in step A3) are subjected to a fourth reaction to obtain compound 5.

[0016] Preferably, in step A1), the first solvent is selected from one or more of N,N-dimethylformamide, toluene, or acetone.

[0017] Preferably, in step A1), the mass-to-volume ratio of compound 1 and N,N-dimethyl methyl ester dimethyl acetal is 83g:(70-500)mL, for example, it can be 83g:(70-100)mL, 83g:(100-150)mL, 83g:(150-200)mL, 83g:(200-250)mL, 83g:(250-300)mL, 83g:(300-350)mL, 83g:(350-400)mL, 83g:(400-450)mL, and 83g:(450-500)mL, etc.

[0018] Preferably, in step A1), the volume ratio of N,N-dimethyl methyl ester dimethyl acetal to the first solvent is 1:(1-6), for example, it can be 1:(1-2), 1:(2-3), 1:(3-4), 1:(4-5) and 1:(5-6), etc.

[0019] Preferably, in step A1), the temperature of the first reaction is 100-140°C, for example, it can be 100-110°C, 110-120°C, 120-130°C, and 130-140°C.

[0020] Preferably, in step A1), the time for the first reaction is 12 to 24 hours, for example, it can be 12 to 14 hours, 14 to 16 hours, 16 to 18 hours, 18 to 20 hours, 20 to 22 hours, and 22 to 24 hours.

[0021] Preferably, in step A1), step A1) of A16) the first reaction is followed by a first concentration and purification.

[0022] Preferably, in step A2), the molar ratio of compound 2 to urea is 1:(10-20), for example, it can be 1:(10-12), 1:(12-14), 1:(14-16), 1:(16-18), and 1:(18-20), etc.

[0023] Preferably, in step A2), the cyclization reagent is selected from either hydrochloric acid or sodium hydride.

[0024] Preferably, in step A2), the reaction temperature of the second reaction is 100-150°C, for example, it can be 100-110°C, 110-120°C, 120-130°C, 130-140°C, and 140-150°C.

[0025] Preferably, in step A2), the reaction time of the second reaction is 20 to 60 minutes, for example, it can be 20 to 30 minutes, 30 to 40 minutes, 40 to 50 minutes, and 50 to 60 minutes.

[0026] Preferably, in step A3), the molar ratio of compound 3 to the halogenating agent is 1:(10-30), for example, it can be 1:(10-15), 1:(15-20), 1:(20-25) and 1:(25-30), etc.

[0027] Preferably, in step A3), the halogenating agent is selected from one or more of phosphorus oxychloride, phosphorus tribromooxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, triphenylphosphine dichloride, or triphenylphosphine dibromide;

[0028] Preferably, in step A3), when carrying out the third reaction, the addition of acetonitrile, DMF, or any one or more of 1,4-dioxane, wherein the DMF is N,N-dimethylformamide, is also included.

[0029] Preferably, in step A3), the reaction temperature of the third reaction is 60–100°C, for example, it can be 60–70°C, 70–80°C, 80–90°C, and 90–100°C.

[0030] Preferably, in step A3), the reaction time of the third reaction is 12-24 hours, for example, it can be 12-14 hours, 14-16 hours, 16-18 hours, 18-20 hours, 20-22 hours, and 22-24 hours.

[0031] Preferably, in step A3), the third reaction further includes a second concentration, pH adjustment, filtration, and purification.

[0032] Preferably, in step A4), the molar ratio of compound 4 to compound 7 is (1-3):(1-3);

[0033] Preferably, in step A4), the acid is one or more of trifluoroacetic acid or p-toluenesulfonic acid;

[0034] Preferably, in step A4), the molar ratio of the acid to the compound 4 is (1-3):(1-3), for example, it can be 1:(1-3), 2:(1-3), and 3:(1-3), etc.

[0035] Preferably, in step A4), the second solvent is one or more of tert-butanol or isopropanol;

[0036] Preferably, in step A4), the volume-to-mass ratio of the second solvent to the compound 4 is (5-15) mL: 1 g, for example, it can be (5-7) mL: 1 g, (7-9) mL: 1 g, (9-11) mL: 1 g, (11-13) mL: 1 g, and (13-15) mL: 1 g, etc.

[0037] Preferably, in step A4), the reaction temperature of the fourth reaction is 80–120°C, for example, it can be 80–90°C, 90–100°C, 100–110°C, and 110–120°C.

[0038] Preferably, in step A4), the reaction time of the fourth reaction is 12-24 hours, for example, it can be 12-14 hours, 14-16 hours, 16-18 hours, 18-20 hours, 20-22 hours, and 22-24 hours.

[0039] Preferably, in step A4), after the fourth reaction, the process further includes a third concentration, pH adjustment, a fourth concentration, and purification.

[0040] Preferably, the halogen in A49) is selected from one or more of chlorine, bromine or iodine.

[0041] Preferably, in feature A22), when the cyclizing agent is sodium hydride, the molar ratio of the cyclizing agent to the urea is 1:(1.2-2.5), for example, it can be 1:(1.2-1.4), 1:(1.4-1.6), 1:(1.6-1.8), 1:(1.8-2.0), 1:(2.0-2.2), or 1:(2.2-2.5).

[0042] Preferably, in feature A222), when the cyclization reagent is hydrochloric acid, the molar ratio of the cyclization reagent to the urea is 1:(1.2:2.5), for example, it can be 1:(1.2~1.4), 1:(1.4~1.6), 1:(1.6~1.8), 1:(1.8~2.0), 1:(2.0~2.2), or 1:(2.2~2.5).

[0043] More preferably, the hydrochloric acid has a mass fraction of 30-37.5%.

[0044] Preferably, in feature A331), the mass-to-volume ratio of compound 3 to acetonitrile is 1g:(2-5)mL, for example, it can be 1g:(2-3)mL, 1g:(3-4)mL, 1g:(4-5)mL, etc.

[0045] Preferably, in feature A36), the reagent for adjusting pH is an aqueous solution of sodium hydroxide or an aqueous solution of sodium carbonate.

[0046] Preferably, in feature A36), the pH is 9-10.

[0047] Preferably, in feature A48), the reagent for adjusting pH is an aqueous solution of sodium carbonate or an aqueous solution of sodium hydroxide.

[0048] Preferably, in feature A48), the pH is 8-9.

[0049] A second aspect of this invention provides an AZ191 intermediate with the following structural formula:

[0050] The third aspect of the present invention provides a method for preparing an AZ191 intermediate, comprising mixing compound 1, N,N-dimethyl methyl ester dimethyl acetal and a third solvent, and carrying out a fifth reaction to obtain compound 2.

[0051] The reaction route is

[0052]

[0053] Preferably, the third solvent in B1) is one or more of N,N-dimethylformamide, toluene, or acetone.

[0054] Preferably, the mass-to-volume ratio of compound 1 and N,N-dimethyl methyl ester dimethyl acetal in B2) is 83 g:(70-500 mL), for example, it can be 83 g:(70-100) mL, 83 g:(100-150) mL, 83 g:(150-200) mL, 83 g:(200-250) mL, 83 g:(250-300) mL, 83 g:(300-350) mL, 83 g:(350-400) mL, 83 g:(400-450) mL, and 83 g:(450-500) mL, etc.

[0055] Preferably, the volume ratio of N,N-dimethyl methyl ester dimethyl acetal to the third solvent in B3) is 1:(1-6), for example, it can be 1:(1-2), 1:(2-3), 1:(3-4), 1:(4-5) and 1:(5-6), etc.

[0056] Preferably, the temperature of the fifth reaction in B4) is 100-140°C, for example, it can be 100-110°C, 110-120°C, 120-130°C and 130-140°C.

[0057] Preferably, the time for the fifth reaction (B5) is 12 to 24 hours, for example, it can be 12 to 14 hours, 14 to 16 hours, 16 to 18 hours, 18 to 20 hours, 20 to 22 hours, and 22 to 24 hours.

[0058] Preferably, the fifth reaction described in B6) includes concentration and column chromatography purification.

[0059] The fourth aspect of this invention provides an AZ191 intermediate with the following structural formula:

[0060] Preferably, the preparation method includes a sixth reaction of compound 2, urea and a cyclization reagent to obtain compound 3;

[0061] The reaction route is as follows:

[0062]

[0063] Preferably, the molar ratio of compound 2 to urea in C1) is 1:(10-20), for example, it can be 1:(10-12), 1:(12-14), 1:(14-16), 1:(16-18) and 1:(18-20), etc.

[0064] Preferably, the cyclization reagent in C2) is selected from either hydrochloric acid or sodium hydride;

[0065] Preferably, the reaction temperature of the sixth reaction in C3) is 100-150°C, for example, it can be 100-110°C, 110-120°C, 120-130°C, 130-140°C and 140-150°C, etc.

[0066] Preferably, the reaction time of the sixth reaction in C4) is 20 to 60 minutes, for example, it can be 20 to 30 minutes, 30 to 40 minutes, 40 to 50 minutes, and 50 to 60 minutes.

[0067] Preferably, in feature C2), when the cyclizing agent is sodium hydride, the molar ratio of the cyclizing agent to the urea is 1:(1.2-2.5), for example, it can be 1:(1.2-1.4), 1:(1.4-1.6), 1:(1.6-1.8), 1:(1.8-2.0), 1:(2.0-2.2), or 1:(2.2-1.5).

[0068] The above technical solution has at least one of the following beneficial effects:

[0069] 1) The preparation of AZ191 and its intermediates in this invention does not require the use of transition metal catalysts, which reduces the requirements for production conditions and saves production costs.

[0070] 2) The preparation method of AZ191 in this invention uses 1-(1H-pyrrolo[2,3-c]pyridin-3-yl)ethyl ketone as the reaction substrate and carries out condensation, cyclization, halogenation and amination reactions in sequence. Therefore, the whole route can obtain AZ191 in a high yield, which is conducive to industrial production. Attached Figure Description

[0071] Figure 1 It is compound 2 in Example 2 of the present invention. 1 HNMR image.

[0072] Figure 2 It is compound 3 in Example 3 of the present invention. 1 HNMR image. Detailed Implementation

[0073] The technical solution of the present invention is illustrated below through specific examples. It should be understood that the one or more method steps mentioned in the present invention do not preclude the existence of other method steps before or after the combined steps, or the insertion of other method steps between these explicitly mentioned steps; it should also be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, unless otherwise stated, the numbering of each method step is merely a convenient tool for identifying each method step, and not for limiting the order of the method steps or defining the scope of the present invention. Changes or adjustments to their relative relationships, without substantially altering the technical content, should also be considered within the scope of the present invention.

[0074] In the following examples, unless otherwise stated, all reactants are commercially available products.

[0075] NR indicates no response.

[0076] <Example 1>

[0077] Preparation of Compound 1

[0078] This embodiment provides a method for preparing compound 1, and the reaction formula is as follows:

[0079]

[0080] Includes the following steps:

[0081] 200 g of compound 6 (1.69 mol, 1.0 eq), 1127 g of aluminum trichloride (8.45 mol, 5.0 eq), 663 g of acetyl chloride (8.45 mol, 5.0 eq), and 2 L of dichloromethane were added to a reaction vessel and reacted at 25 °C for 16 h. Water was added, and the pH was adjusted to 10 with a saturated sodium hydroxide aqueous solution. Water was removed under reduced pressure, and the mixture was slurried with acetonitrile, filtered, concentrated, and dried to obtain 207.4 g of compound 1, a pale yellow solid, with a yield of 76.5%.

[0082] <Example 2>

[0083] Preparation of compound 2

[0084] This embodiment provides a method for preparing compound 2, and the reaction formula is as follows:

[0085]

[0086] Includes the following steps:

[0087] 83 g of compound 1 (518.2 mmol, 1.0 eq), 0.4 L of N,N-dimethylformamide dimethyl acetal, and 0.4 L of N,N-dimethylformamide were added to a reaction vessel and reacted at 140 °C for 16 h. The reaction solution was concentrated and purified by column chromatography to give 63.8 g of compound 2, a brown solid, with a yield of 53.7%.

[0088] Products 1 HNMR spectrum as follows Figure 1 As shown.

[0089] <Example 3>

[0090] Screening of reaction temperature

[0091] This embodiment is based on Example 2, and the reaction temperature has been screened. Except for the parameters listed in the table below, the other steps are the same as those described in Example 2.

[0092] Table 1 Screening of reaction temperatures

[0093] 1 100 41.3 2 110 42.5 3 130 52.3

[0094] As shown in the table above, the higher the temperature, the higher the yield of the reaction. This reaction can achieve good yields at temperatures ranging from 100℃ to 140℃.

[0095] <Example 4>

[0096] Preparation of compound 3

[0097] This embodiment provides a method for preparing compound 3, and the reaction formula is as follows:

[0098]

[0099] Includes the following steps:

[0100] 35 g of compound 2 (152.7 mmol, 1.0 eq), 48 g of 60% sodium hydride (1.2 mol, 8.0 eq), and 138 g of urea (2.3 mol, 15.0 eq) were added to a reaction vessel and reacted at 140 °C for 30 min. Methanol was added, and the mixture was purified by dichloromethane column chromatography to obtain 70 g of compound 3, with a purity of 40%. The main impurity was dichloromethane, and the solid was yellow. The yield of compound 3 was 81%. No further drying was required before proceeding to the next step.

[0101] Products 1 HNMR spectrum as follows Figure 2 As shown.

[0102] <Example 5>

[0103] Screening of reaction reagents

[0104] This embodiment is based on Example 4, and the reaction reagents were screened. Except for the parameters listed in the table below, the other steps are the same as those described in Example 4.

[0105] Table 2 Screening of Reaction Reagents

[0106] 1 37% hydrochloric acid 35.3 2 potassium hydroxide NR 3 Sodium methoxide NR 4 mesylate NR 5 Triethylamine NR

[0107] As shown in the table above, not all acids or bases can complete this reaction. When the reagent is hydrochloric acid, although the target product can be obtained, the yield is low. Therefore, sodium hydride is chosen as the reagent for this reaction.

[0108] <Example 6>

[0109] Preparation of compound 4a

[0110] This embodiment provides a method for preparing compound 4a, and the reaction formula is as follows:

[0111]

[0112] Includes the following steps:

[0113] 140 g of compound 3 (40% purity, 247.5 mmol, 1.0 eq), 500 mL of phosphorus oxychloride, and 500 mL of acetonitrile were added to a reaction vessel and reacted at 80 °C for 16 h. The reaction solution was concentrated, the pH was adjusted to 10 with saturated sodium hydroxide aqueous solution, filtered, and the filter cake was purified by column chromatography. Column chromatography purification yielded 38.5 g of compound 4a, an off-white solid, with a yield of 63.6%.

[0114] <Example 7>

[0115] Preparation of compound 5

[0116] This embodiment provides a method for preparing compound 5, and the reaction formula is as follows:

[0117]

[0118] Includes the following steps:

[0119] 32 g of compound 4a (130.8 mmol, 1.0 eq), 29 g of compound 7 (130.8 mmol, 1.0 eq), 15 g of trifluoroacetic acid (130.8 mmol, 1.0 eq), and 320 mL of tert-butanol were added to a reaction vessel and reacted at 100 °C for 16 h. The reaction solution was concentrated, the pH was adjusted to 8 with saturated sodium carbonate aqueous solution, concentrated, and purified by column chromatography to give 33.4 g of compound 5 as a gray solid, with a yield of 59.4%.

[0120] <Comparative Example 1>

[0121] Preparation of compound 4a

[0122] This comparative example provides a method for preparing compound 4a, and the reaction formula is as follows:

[0123]

[0124] Includes the following steps:

[0125] 100 mg of compound 3 (0.44 mmol, 1.0 eq), 56.9 mg of N,N-diisopropylethylamine (0.44 mmol, 1 eq), and 1 mL of toluene were added to a reaction vessel. 81.3 mg of phosphorus oxychloride (0.53 mmol, 1.2 eq) was added dropwise. The reaction was carried out at 100 °C for 4 h. The reaction solution was concentrated, and the pH was adjusted to 10 with saturated sodium hydroxide aqueous solution. The solution was concentrated again and purified by preparative plate to give 10 mg of compound 4a, an off-white solid, with a yield of 9.3%.

[0126] <Comparative Example 2>

[0127] A method for preparing compound 5

[0128] This comparative example provides a method for preparing compound 5, and the reaction formula is as follows:

[0129]

[0130] Includes the following steps:

[0131] 73 mg of compound 4a (0.3 mmol, 1.0 eq), 132 mg of compound 7 (0.6 mmol, 2.0 eq), 170 mg of 4-methylbenzenesulfonic acid hydrate (0.9 mmol, 3.0 eq), and 3 mL of N-methylpyrrolidone were added to a reaction vessel. The reaction mixture was heated at 200 °C for 2 h and then cooled. The reaction mixture was diluted with water and saturated sodium bicarbonate was added. The mixture was extracted with ethyl acetate and washed with water and saturated brine. The combined organic layers were dried, filtered, and evaporated to give the crude product, which was purified by column chromatography to give 30 mg of compound 5 as a solid, in a yield of 23.3%.

[0132] <Comparative Example 3>

[0133] A method for preparing compound 5

[0134] This comparative example provides a method for preparing compound 5, and the reaction formula is as follows:

[0135]

[0136] Includes the following steps:

[0137] 10 mg of compound 4a (0.04 mmol, 1.0 eq), 17.7 mg of compound 7 (0.08 mmol, 2.0 eq), 0.1 mL of acetic acid, and 0.1 mL of dioxane were added to a microwave tube (microwave power 40 W). The reaction was heated at 110 °C for 0.5 h. No product was found to be formed by LC-MS.

[0138] The role and effect of the embodiments

[0139] According to the preparation method of AZ191 involved in the above embodiments, in step A1 of this application, 1-(1H-pyrrolo[2,3-c]pyridin-3-yl)acetone is used as the reaction substrate and reacted with N,N-dimethylformamide dimethyl acetal in N,N-dimethylformamide to obtain the target product in a yield of 53.7%.

[0140] According to the preparation method of AZ191 involved in the above embodiments, the base used in step A2 of this application is sodium hydride, and the target product can be obtained in step b with a yield of 81%.

[0141] According to the preparation method of AZ191 involved in the above embodiments, in step A3 of this application, phosphorus oxychloride is used as a halogenating agent and reacted in acetonitrile solution to obtain the target product in a yield of 63.6%.

[0142] According to the preparation method of AZ191 involved in the above embodiments, in step A4 of this application, trifluoroacetic acid is used as the reaction reagent and reacted in tert-butanol to obtain the target product in a yield of 61.6%.

[0143] According to the preparation method of AZ191 involved in the above embodiments, compared with the prior art, the route of this application only requires five steps to obtain AZ191, with a total yield of 13%, which is much higher than the prior art.

Claims

1. A method for preparing AZ191, characterized in that, The reaction route is as follows: ； Where X is selected from halogens. Includes the following steps: A1) Compound 1, N,N-dimethylmethyl esteramine dimethyl acetal and the first solvent are mixed and subjected to the first reaction to obtain compound 2; A2) The compound 2 obtained in step A1), urea, and the cyclizing reagent are subjected to a second reaction to obtain compound 3; A3) The compound 3 obtained in step A2) is subjected to a third reaction with the halogenating reagent to obtain compound 4; A4) Compound 4 and compound 7 obtained in step A3) are subjected to a fourth reaction with the acid and the second solvent to obtain compound 5; In step A4), the acid is trifluoroacetic acid; the halogen is chlorine; and the second solvent is one or more of tert-butanol or isopropanol.

2. The method for preparing AZ191 as described in claim 1, characterized in that, Includes at least one of the following technical features: A11) In step A1), the first solvent is selected from one or more of N,N-dimethylformamide, toluene, or acetone; A12) In step A1), the mass-to-volume ratio of compound 1 and N,N-dimethyl methyl ester dimethyl acetal is 83 g: (70~500) mL; A13) In step A1), the volume ratio of N,N-dimethyl methyl ester dimethyl acetal to the first solvent is 1:(1~6). In step A1), the temperature of the first reaction is 100~140℃; In step A1), the first reaction takes 12-24 hours. In step A1), the first reaction is followed by a first concentration and purification. In step A2), the molar ratio of compound 2 to urea is 1:(10~20). A22) In step A2), the cyclization reagent is selected from either hydrochloric acid or sodium hydride; In step A2), the reaction temperature of the second reaction is 100~150℃; In step A2), the reaction time of the second reaction is 20-60 min; In step A3), the molar ratio of compound 3 to the halogenating agent is 1:(10~30). A32) In step A3), the halogenating agent is selected from one or more of phosphorus oxychloride, phosphorus tribromooxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, triphenylphosphine dichloride, or triphenylphosphine dibromide; In step A3), the third reaction further includes the addition of acetonitrile, DMF, or any one or more of 1,4-dioxane. In step A3), the reaction temperature of the third reaction is 60~100℃; In step A3), the reaction time of the third reaction is 12-24 hours. In step A3), the third reaction further includes a second concentration, pH adjustment, filtration, and purification. In step A4), the molar ratio of compound 4 to compound 7 is (1~3):(1~3). In step A4), the molar ratio of the acid to the compound 4 is (1~3):(1~3). In step A4), the volume-to-mass ratio of the second solvent to compound 4 is (5~15) mL: 1 g; In step A4), the reaction temperature of the fourth reaction is 80~120℃; In step A4), the reaction time of the fourth reaction is 12-24 hours. In step A4), after the fourth reaction, the process further includes a third concentration, pH adjustment, a fourth concentration, and purification.

3. The method for preparing AZ191 as described in claim 2, characterized in that, In feature A22), when the cyclization reagent is sodium hydride, the molar ratio of the cyclization reagent to the urea is 1:(1.2~2.5).

4. The method for preparing AZ191 as described in claim 2, characterized in that, In feature A22), when the cyclization reagent is hydrochloric acid, the molar ratio of the cyclization reagent to the urea is 1:(1.2~2.5), and the mass fraction of the hydrochloric acid is 30-37.5%.

5. The method for preparing AZ191 as described in claim 2, characterized in that, In feature A33), the mass-to-volume ratio of compound 3 to acetonitrile is 1 g: (2~5) mL.

6. The method for preparing AZ191 as described in claim 2, characterized in that, In feature A36), the pH is 9-10.

7. The method for preparing AZ191 as described in claim 2, characterized in that, In feature A36), the reagent for adjusting pH is an aqueous solution of sodium hydroxide or an aqueous solution of sodium carbonate.

8. The method for preparing AZ191 as described in claim 2, characterized in that, In feature A48), the reagent for adjusting pH is an aqueous solution of sodium carbonate or an aqueous solution of sodium hydroxide.

9. The method for preparing AZ191 as described in claim 2, characterized in that, In feature A48), the pH is 8-9.

Images