Preparation method of MRGPRX2 agonist and intermediate thereof

Abstract

The invention relates to a preparation method of an MRGPRX2 agonist and an intermediate of the MRGPRX2 agonist. A reaction formula is as follows: # imgabs0 # R is selected from an amino protecting group, and the amino protecting group is selected from one of t-butyloxycarboryl, pivaloyl, acetyl, propionyl, 9-fluorenylmethoxycarbonyl, trityl, trifluoroacetyl, methoxycarbonyl and ethoxycarbonyl; the method comprises the following steps: (1) carrying out alkylation reaction on a compound 1 and methylamine at 55-65 DEG C to prepare a compound 2; (2) carrying out polymerization reaction on the compound 2 to prepare a compound 3; (3) carrying out amino protecting group reaction on the compound 3 to prepare a compound 4; and (4) performing deprotection reaction on the compound 4 to prepare a compound 5 or hydrochloride thereof. By the adoption of the temperature range, complete conversion of the compound 1 can be achieved, meanwhile, side reactions are effectively inhibited, and therefore the yield and purity of the product are effectively improved; the novel intermediate obtained in the synthesis process is stable in property and good in reproducibility, solves the problem that by-products which are difficult to remove are generated in the polymerization reaction, and is easy to realize large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing an MRGPRX2 agonist and its intermediate, belonging to the field of pharmaceutical synthesis. Background Art

[0002] The MRGPRX2 agonist (Mas-related G protein-coupled receptor X2) is a receptor mainly expressed on mast cells and is involved in physiological and pathological processes such as non-IgE-mediated allergic reactions, inflammation, and pruritus. Its agonists can activate downstream signaling pathways (such as Gq, β-arrestin), leading to the degranulation of mast cells and the release of mediators such as histamine and tryptase. Currently, it is known that the hydrochloride salt of compound 5 (CAS: 848035-21-2) mainly induces mast cell degranulation by activating the MRGPRX2 (human) or Mrgprb2 (mouse) receptor; the specific structure of the hydrochloride salt of compound 5 is shown as follows:

[0003]

[0004] The preparation of compound 5 was disclosed in the literature Chemical & Pharmaceutical Bulletin (1984), 32(10), 4185-8, and the reaction formula is shown as follows:

[0005]

[0006] This method prepares compound 5 through alkylation and polymerization. The alkylation reaction is incomplete and requires a process of recycling raw materials and reacting again multiple times. The inventor repeated this route and found that the polymerization reaction would produce by-products that are difficult to remove, and the overall yield of the two steps is only 4.38%, which is not conducive to industrial scale-up. Summary of the Invention

[0007] Aiming at the defects of the prior art, the present invention provides a method for preparing an MRGPRX2 agonist and its intermediate, which is simple, efficient, has a high yield, greatly reduces the cost, and is conducive to commercial large-scale production.

[0008] To achieve the above technical objectives, the present invention adopts the following technical solutions:

[0009] The first aspect of the present invention provides a method for preparing compound 4, and the reaction formula is shown as follows:

[0010]

[0011] It includes the following steps:

[0012] (1) Compound 1 and methylamine are subjected to an alkylation reaction at 55-65 °C to prepare compound 2;

[0013] (2) Compound 2 undergoes a polymerization reaction to prepare Compound 3;

[0014] (3) Compound 3 undergoes an amino protecting group reaction to prepare Compound 4;

[0015] R is selected from amino protecting groups, and the amino protecting group is selected from one of tert-butoxycarbonyl, pivaloyl, acetyl, propionyl, 9-fluorenylmethoxycarbonyl, trityl, trifluoroacetyl, methoxycarbonyl, and ethoxycarbonyl;

[0016] As a further improvement of the present invention, including but not limited to, the amino protecting group is selected from one of tert-butoxycarbonyl, pivaloyl, acetyl, and propionyl;

[0017] As a further improvement of the present invention, including but not limited to, the amino protecting group is selected from one of tert-butoxycarbonyl, pivaloyl, and acetyl;

[0018] As a further improvement of the present invention, including but not limited to, the amino protecting group is selected from one of tert-butoxycarbonyl and acetyl;

[0019] As a further improvement of the present invention, including but not limited to, the methylamine in step (1) is selected from an alcohol solution of methylamine or an aqueous solution of methylamine, preferably an alcohol solution of methylamine; more preferably a methanol solution of methylamine;

[0020] As a further improvement of the present invention, including but not limited to, the molar ratio of Compound 1 to methylamine in step (1) is 1:(1 - 6), preferably 1:(4 - 6);

[0021] As a further improvement of the present invention, including but not limited to, an organic solvent can be selectively added in step (1);

[0022] As a further improvement of the present invention, including but not limited to, the organic solvent in step (1) is selected from one or a combination of methanol, ethanol, isopropanol, tetrahydrofuran, ether, or dioxane;

[0023] As a further improvement of the present invention, including but not limited to, the volume dosage mL of the organic solvent in step (1) is 1 - 16 times the mass dosage g of Compound 1;

[0024] As a further improvement of the present invention, including but not limited to, the reaction time in step (1) is 3 - 24 hours, preferably 4 - 10 hours;

[0025] As a further improvement of the present invention, it includes but is not limited to the following optimizations: When the reaction temperature is lower than 55 °C, it is difficult for Compound 1 to react completely; when the reaction temperature is higher than 65 °C, by-products will be generated. While using the temperature range of the present invention, Compound 1 can react completely and no by-products will be generated, thereby effectively improving the yield and purity of the product.

[0026] As a further improvement of the present invention, including but not limited to, the polymerization reaction in step (2) includes: in the presence of an acid catalyst and an aldehyde, Compound 2 undergoes a polymerization reaction to prepare Compound 3;

[0027] As a further improvement of the present invention, including but not limited to, the acid catalyst in step (2) is selected from one of perchloric acid and sulfuric acid, preferably perchloric acid; for example, perchloric acid with a mass concentration of 20%;

[0028] As a further improvement of the present invention, including but not limited to, the volume dosage mL of the acid catalyst in step (2) is 5 to 15 times the mass dosage g of Compound 2, preferably 8 to 12 times;

[0029] As a further improvement of the present invention, including but not limited to, the aldehyde in step (2) is selected from at least one or any combination of formaldehyde, paraformaldehyde, and furfural;

[0030] As a further improvement of the present invention, including but not limited to, the aldehyde in step (2) is selected from formaldehyde, preferably a formaldehyde solution with a mass concentration of 37 to 40%;

[0031] As a further improvement of the present invention, including but not limited to, the molar ratio of Compound 2 to the aldehyde in step (2) is 1:(1 to 2), preferably 1:(1 to 1.2);

[0032] As a further improvement of the present invention, including but not limited to, the reaction time in step (2) is 8 to 24 hours, preferably 10 to 16 hours;

[0033] As a further improvement of the present invention, including but not limited to, the reaction temperature in step (2) is 60 to 120 °C, preferably 80 to 105 °C;

[0034] As a further improvement of the present invention, including but not limited to, the amino-protecting group reaction in step (3) includes: in an organic solvent, in the presence of a base catalyst and an amino-protecting group reagent, Compound 3 undergoes an amino-protecting group reaction to prepare Compound 4;

[0035] As a further improvement of the present invention, including but not limited to, the base catalyst in step (3) is selected from one of 4-dimethylaminopyridine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, N,N-diisopropylethylamine, preferably 4-dimethylaminopyridine;

[0036] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 3 to the base catalyst in step (3) is 1:(0.01 - 0.5), preferably 1:(0.05 - 0.15);

[0037] As a further improvement of the present invention, including but not limited to, the amino protecting group reagent in step (3) is selected from one of di-tert-butyl dicarbonate, acetic anhydride, acetyl chloride, pivalic anhydride, pivaloyl chloride, propionic anhydride, 9-fluorenylmethyl chloroformate, triphenylmethyl chloride, ethyl chloroformate, diethyl carbonate, trifluoroacetic anhydride, trifluoroacetyl chloride, preferably di-tert-butyl dicarbonate;

[0038] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 3 to the amino protecting group reagent in step (3) is 1:(1.5 - 8), preferably 1:(2.5 - 6.5);

[0039] As a further improvement of the present invention, including but not limited to, the organic solvent in step (3) is selected from one or a combination of methanol, ethanol, propanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform, acetone, acetonitrile, ethyl acetate, ethyl formate, isopropyl acetate, preferably acetonitrile;

[0040] As a further improvement of the present invention, including but not limited to, the volume dosage mL of the organic solvent in step (3) is 6 - 25 times the mass dosage g of compound 3;

[0041] As a further improvement of the present invention, including but not limited to, the reaction time of step (3) is 10 - 24 hours, preferably 12 - 18 hours;

[0042] As a further improvement of the present invention, including but not limited to, the reaction temperature of step (3) is 10 - 40 °C, preferably 15 - 35 °C.

[0043] As a further improvement of the present invention, including but not limited to the following: The present invention first discovers and confirms that the by-products generated by the polymerization reaction of compound 2 are highly similar to the target product compound 3 in terms of polarity, molecular weight, and chromatographic behavior. By nuclear magnetic resonance hydrogen spectrum ( 1It was confirmed by 1H-NMR analysis that the retention times of this by-product and Compound 3 in liquid chromatography-mass spectrometry (LCMS) detection were almost exactly the same, resulting in severe overlap of chromatographic peaks. Traditional purification methods (such as column chromatography, preparative liquid chromatography, etc.) could not achieve effective separation. Through the innovative method of converting Compound 3 into the new intermediate Compound 4, the present invention successfully removed this by-product, and when preparing Compound 5 subsequently, a high-purity product could be obtained only by simple concentration, and the yield was increased by 15% compared with the prior art, providing a key technical guarantee for large-scale production.

[0044] The second aspect of the present invention provides a preparation method of Compound 2, and the reaction formula is as follows:

[0045]

[0046] It includes the following steps:

[0047] (1) Compound 1 and methylamine are subjected to an alkylation reaction at 55-65 °C to prepare Compound 2;

[0048] In this scheme, the preparation method of step (1) is as described in the first aspect of the present invention above.

[0049] The third aspect of the present invention provides a novel Compound 4, and the structure is as follows:

[0050]

[0051] Among them, R is as described in the first aspect;

[0052] As a further improvement of the present invention, the preferred structure of Compound 4 is as follows:

[0053]

[0054] The fourth aspect of the present invention provides a preparation method of Compound 5 or its hydrochloride salt, including using Compound 4 of the third aspect to further prepare Compound 5 or its hydrochloride salt, and the reaction formula is as follows:

[0055]

[0056] (4) Compound 4 undergoes a deprotection reaction to prepare Compound 5 or its hydrochloride salt.

[0057] Among them, R is as described in the first aspect;

[0058] As a further improvement of the present invention, including but not limited to, the deprotection reaction in step (4) includes: Compound 4 undergoes a deprotection reaction in a solvent in the presence of a deprotection reagent to prepare Compound 5 or its hydrochloride salt;

[0059] As a further improvement of the present invention, including but not limited to, the deprotection reagent in step (4) is selected from hydrochloric acid reagents and basic reagents; the hydrochloric acid reagents are selected from one or a combination of concentrated hydrochloric acid, dilute hydrochloric acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / ethanol solution, and hydrochloric acid / methanol solution, preferably hydrochloric acid / dioxane solution; the basic reagents are selected from one or a combination of piperidine, triethylamine, N,N-diisopropylethylamine, triisopropylamine, pyridine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, and sodium carbonate;

[0060] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 4 to the deprotection reagent in step (4) is 1:(5-20);

[0061] As a further improvement of the present invention, including but not limited to, the solvent in step (4) is selected from one or a combination of methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform, acetone, acetonitrile, ethyl acetate, ethyl formate, isopropyl acetate, and water, preferably dichloromethane;

[0062] As a further improvement of the present invention, including but not limited to, the volume dosage mL of the solvent in step (4) is 5-16 times the mass dosage g of compound 4, preferably 6-12 times;

[0063] As a further improvement of the present invention, including but not limited to, the reaction time of step (4) is 10-24 hours, preferably 12-18 hours;

[0064] As a further improvement of the present invention, including but not limited to, the reaction temperature of step (4) is 10-40 °C, preferably 15-35 °C.

[0065] Advantageous technical effects of the present invention:

[0066] 1) Aiming at the problem of difficult-to-remove by-products generated during the polymerization of compound 2 to prepare compound 3 in the prior art, the present invention creatively adopts a protection-deprotection route (compound 3 → compound 4 → compound 5), successfully solving the technical problem of difficult removal of this by-product. The synthesis route of the present invention not only has mild reaction conditions and simple operation, but also significantly improves the product yield, greatly enhancing the operability and scalability of the process, providing a reliable technical solution for industrial production;

[0067] 2) The present invention discovers and confirms for the first time that the by-products generated by the polymerization reaction of compound 2 are highly similar to the target product compound 3 in terms of polarity, molecular weight, and chromatographic behavior. Only through nuclear magnetic resonance hydrogen spectrum ( 1It was confirmed by 1H-NMR analysis that the retention times of this by-product and compound 3 in liquid chromatography-mass spectrometry (LCMS) detection were almost exactly the same, resulting in severe overlap of chromatographic peaks, and effective separation could not be achieved by traditional purification methods (such as column chromatography, preparative liquid chromatography, etc.). Through the innovative method of converting compound 3 into a new intermediate compound 4, the present invention successfully removed this by-product, and when preparing compound 5 or its hydrochloride salt subsequently, a high-purity product could be obtained only by simple concentration, and the yield was increased by 15% compared with the prior art, providing a key technical guarantee for large-scale production;

[0068] 3) Through creative work, the inventors of the present invention found that there is a key temperature window in the process of preparing compound 2 from compound 1: when the temperature is lower than 55 °C, the reaction is incomplete, and when it is higher than 65 °C, by-products will be generated. By controlling the reaction temperature, the present invention achieved the complete conversion of compound 1 and effectively inhibited the occurrence of side reactions. Compared with the prior art, the yield was increased by 16%, and there was no need to recycle raw materials repeatedly, significantly improving the utilization rate of raw materials and showing outstanding economic benefits in industrialized scale-up production;

[0069] 4) The newly designed intermediate compound 4 of the present invention has excellent stability and reproducibility, fundamentally solving the problem that it is difficult to remove the by-products of the polymerization reaction. The preparation method of this intermediate is simple and efficient, with high product yield and good quality, fully meeting the requirements of industrialized large-scale production, and providing a new technical route for the large-scale preparation of related products. Description of the Drawings

[0070] Figure 1 1H-NMR spectrum of the product obtained in Example 2 of the present invention; 1 1H-NMR spectrum;

[0071] Figure 2 LCMS spectrum of the product obtained in Example 2 of the present invention;

[0072] Figure 3 HPLC spectrum of the product obtained in Example 3 of the present invention;

[0073] Figure 4 1H-NMR spectrum of the product obtained in Example 4 of the present invention; 1 1H-NMR spectrum. Detailed Description of the Invention

[0074] The preparation method of the present invention will be further described in detail below with reference to specific examples. It should be understood that the following examples are only for illustrative and explanatory purposes of the present invention and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection of the present invention.

[0075] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples can all be obtained from commercial sources unless otherwise specified.

[0076] Example 1: Preparation of Compound 2

[0077]

[0078] Compound 1 (157.1 g, 0.92 mol) was added to a reaction flask, and 28% methylamine methanol solution (510 g, 4.6 mol) was added. After stirring at room temperature for 1 h, the temperature was raised to 60 °C and reacted for 4 h. After concentration and purification, yellow solid Compound 2 (135.8 g, yield 89.3%) was obtained.

[0079] Example 2: Preparation of Compound 3

[0080]

[0081] Compound 2 (67 g, 0.405 mol) was added to 20% perchloric acid (740 mL), and then 37% formaldehyde solution (30.8 mL) was added. The reaction system was transferred to 100 °C and reacted for 12 h. The reaction system was placed in an ice bath for 12 h to allow it to separate into layers. The supernatant was poured off, and the remaining part was dissolved in an appropriate amount of 4M hydrogen chloride methanol solution. After adjusting the pH to 10 with 2M potassium hydroxide solution, it was extracted with ethyl acetate until there was no product in the aqueous phase. After washing, drying, and concentration, it was purified by column chromatography with dichloromethane:methanol:28% ammonia water = 20 - 10:1:0.25 to obtain pale yellow oily Compound 3 (49 g, yield 21%, NMR purity 90%). 1 The H-NMR spectrum is as Figure 1 shown, and the LCMS spectrum is as Figure 2 shown.

[0082] Example 3: Preparation of Compound 4-1

[0083]

[0084] Compound 3 (5 g, 9.63 mmol) was added to a single-necked flask containing 100 ml of acetonitrile. Boc anhydride (12.6 g, 57.8 mmol) and 4-dimethylaminopyridine (117 mg, 0.96 mmol) were added respectively. The reaction was carried out overnight at room temperature. After concentration and purification, pale yellow oily Compound 4-1 (7 g, yield 89%) was obtained. The HPLC spectrum is as Figure 3 shown.

[0085] Example 4: Preparation of Compound 5-1

[0086]

[0087] Compound 4-1 (5 g, 9.63 mmol) was added to 40 mL of 4 M hydrogen chloride dioxane solution and 40 mL of dichloromethane. After stirring at room temperature for 2 h, the mixture was concentrated to obtain pure compound 5-1 (3.5 g, yield 92%). 1 The 1H-NMR spectrum is as Figure 4 shown.

[0088] Example 5: Preparation of Compound 2

[0089]

[0090] Compound 1 (1 g, 5.86 mmol) was added to a reaction flask, and 3.25 g of 28% methylamine methanol solution was added. The reaction was carried out at 30 °C for 4 h. TLC detection showed that the raw materials were not completely reacted. The reaction was continued at 30 °C for 4 h. TLC detection still showed that the raw materials were not completely reacted. The mixture was concentrated and purified by column chromatography to obtain yellow solid compound 2 (0.56 g, yield 58%).

[0091] Example 6: Preparation of Compound 2

[0092] Compound 1 (1.5 g, 8.79 mmol) was added to a reaction flask, and 3.25 g of 28% methylamine methanol solution was added. The reaction was carried out at 75 °C for 4 h. TLC detection showed that the raw materials had reacted completely, and the number of impurity spots increased. The mixture was concentrated and purified to obtain yellow solid compound 2 (0.49 g, yield 51%).

[0093] Example 7: Preparation of Compound 2

[0094] Compound 1 (1 g, 5.86 mmol) was added to a reaction flask, and 2.3 g of 40% methylamine methanol solution was added. The reaction was carried out at room temperature for 4 h. TLC detection showed that the raw materials were not completely reacted. The mixture was concentrated and purified to obtain yellow solid compound 2 (0.62 g, yield 65%).

Claims

1. A compound 4 has the structure shown below: Among them, R is selected from amino protecting groups, and the amino protecting groups are selected from one of tert-butoxycarbonyl, pivaloyl, acetyl, propionyl, 9-fluorenylmethoxycarbonyl, trityl, trifluoroacetyl, methoxycarbonyl, and ethoxycarbonyl.

2. A method for preparing a compound 4, and the reaction formula is shown below: Among them, R is the same as that described in claim 1; It includes the following steps: (1) Compound 1 and methylamine are subjected to an alkylation reaction at 55 - 65 °C to prepare compound 2; (2) Compound 2 is subjected to a polymerization reaction to prepare compound 3; (3) Compound 3 is subjected to an amino protecting group reaction to prepare compound 4.

3. A method for preparing the compound 2 as described in claim 2, and the reaction formula is shown below: It includes the following steps: (1) Compound 1 and methylamine are subjected to an alkylation reaction at 55 - 65 °C to prepare compound 2.

4. The preparation method according to claim 2 or 3, characterized in that, The alkylation reaction in step (1) satisfies one or more of the following conditions: 1) The methylamine is selected from an alcohol solution of methylamine or an aqueous solution of methylamine, preferably an alcohol solution of methylamine; more preferably a methanol solution of methylamine; 2) The molar ratio of compound 1 to methylamine is 1:(1 - 6), preferably 1:(4 - 6); 3) An organic solvent can be selectively added, and the organic solvent is selected from one or a combination of methanol, ethanol, isopropanol, tetrahydrofuran, ether, or dioxane; preferably, the volume dosage mL of the organic solvent is 1 - 16 times the mass dosage g of compound 1; 4) The reaction time is 3 - 24 hours, preferably 4 - 10 hours.

5. The preparation method according to claim 2, characterized in that, The polymerization reaction in step (2) includes: compound 2 is subjected to a polymerization reaction in the presence of an acid catalyst and an aldehyde to prepare compound 3.

6. The preparation method according to claim 5, characterized in that, The polymerization reaction in step (2) satisfies one or more of the following conditions: 1) The acid catalyst is selected from one of perchloric acid and sulfuric acid, preferably perchloric acid; for example, perchloric acid with a mass concentration of 20%; 2) The volume dosage mL of the acid catalyst is 5 - 15 times the mass dosage g of compound 2, preferably 8 - 12 times; 3) The aldehyde is selected from at least one of formaldehyde, paraformaldehyde, or furfural or any combination thereof; preferably a formaldehyde solution with a mass concentration of 37 - 40%; 4) The molar ratio of compound 2 to the aldehyde is 1:(1 - 2), preferably 1:(1 - 1.2); 5) The reaction time is 8 - 24 hours, preferably 10 - 16 hours; 6) The reaction temperature is 60 - 120 °C, preferably 80 - 105 °C.

7. The preparation method according to claim 2, wherein The amino protecting group reaction in step (3) includes: compound 3 is subjected to an amino protecting group reaction in an organic solvent in the presence of a base catalyst and an amino protecting group reagent to prepare compound 4.

8. The preparation method according to claim 7, characterized in that, The amino protecting group reaction in step (3) satisfies one or more of the following conditions: 1) The base catalyst is selected from one of 4-dimethylaminopyridine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, and N,N-diisopropylethylamine; 2) The molar ratio of compound 3 to the base catalyst is 1:(0.01 - 0.5), preferably 1:(0.05 - 0.15); 3) The amino protecting group reagent is selected from one of di-tert-butyl dicarbonate, acetic anhydride, acetyl chloride, pivalic anhydride, pivaloyl chloride, propionic anhydride, 9-fluorenylmethyl chloroformate, triphenylmethyl chloride, ethyl chloroformate, diethyl carbonate, trifluoroacetic anhydride, trifluoroacetyl chloride; 4) The molar ratio of the compound 3 to the amino protecting group reagent is 1:(1.5 - 8), preferably 1:(2.5 - 6.5); 5) The organic solvent is selected from one or a combination of methanol, ethanol, propanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform, acetone, acetonitrile, ethyl acetate, ethyl formate, isopropyl acetate; 6) The volume dosage mL of the organic solvent is 6 - 25 times the mass dosage g of the compound 3; 7) The reaction time is 10 - 24 hours, preferably 12 - 18 hours; 8) The reaction temperature is 10 - 40 °C, preferably 15 - 35 °C.

9. A method for preparing compound 5 or its hydrochloride salt, characterized in that, The compound 5 or its hydrochloride salt is further prepared using the compound 4 as claimed in claim 1, and the reaction formula is as follows: wherein, R is the same as that described in claim 1; It comprises the following steps: (4) The compound 4 undergoes a deprotection reaction to prepare the compound 5 or its hydrochloride salt.

10. The preparation method according to claim 9, characterized in that, The deprotection reaction in the step (4) includes: the compound 4 undergoes a deprotection reaction in a solvent in the presence of a deprotection reagent to prepare the compound 5 or its hydrochloride salt; The deprotection reaction in the step (4) satisfies one or more of the following conditions: 1) The deprotection reagent is selected from a hydrochloric acid reagent or a basic reagent; the hydrochloric acid reagent is selected from one or a combination of concentrated hydrochloric acid, dilute hydrochloric acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / ethanol solution, hydrochloric acid / methanol solution; the basic reagent is selected from one or a combination of piperidine, triethylamine, N,N-diisopropylethylamine, triisopropylamine, pyridine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate; 2) The molar ratio of the compound 4 to the deprotection reagent is 1:(5 - 20); 3) The solvent is selected from one or a combination of methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform, acetone, acetonitrile, ethyl acetate, ethyl formate, isopropyl acetate, water; 4) The volume dosage mL of the solvent is 5 - 16 times the mass dosage g of the compound 4, preferably 6 - 12 times; 5) The reaction time is 10 - 24 hours, preferably 12 - 18 hours; 6) The reaction temperature is 10 - 40 °C, preferably 15 - 35 °C.

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