A process for the preparation of alpirotenan

Abstract

The application discloses a preparation method of alpirozan. The application relates to a preparation method of a compound shown as formula I, which is method 1 or method 2. Method 1 comprises the following steps: performing substitution reaction on compound 13-1 and compound 6 in an organic solvent in the presence of an organic base to generate the compound shown as formula I; method 2 comprises the following steps: performing substitution reaction on compound 13-2 and compound 6 in an organic solvent in the presence of an organic base to generate the compound shown as formula II; and performing deprotection group reaction on the compound shown as formula II and a de-Boc protection group reagent in an alcohol solvent to generate the compound shown as formula I. The preparation method provided by the application has high yield, economical steps and low comprehensive production cost, and is more suitable for industrialized production of alpirozan.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of aprocitentan. BACKGROUND

[0002] In hypertensive patients, ET-1 can cause endothelial dysfunction, vascular hypertrophy and remodeling, sympathetic activation and aldosterone synthesis increase. Aprocitentan is a dual endothelin (ET) A / B receptor (ETA / ETB) antagonist, which can inhibit the binding of ET-1 to ETA and ETB receptors to reduce blood pressure.

[0003] The use of aprocitentan treatment can reduce the urinary albumin-creatinine ratio by about 50%, and the estimated glomerular filtration rate is slightly stable, and the N-terminal natriuretic peptide B-type pro-hormone level in the blood is moderately stable. In addition, compared with the drugs currently used to treat refractory hypertension, the outstanding advantage of aprocitentan is that it does not cause any increase in blood potassium levels, which is the main problem of spironolactone, which is currently the first choice for treating refractory hypertension.

[0004] There are currently three main synthetic routes of aprocitentan reported in the literature:

[0005] ;

[0006] Route one (WO2009024906) is the route reported by the original research, which uses compound 1 as the starting material, and a nucleophilic substitution occurs with compound 2 under the action of strong base to produce compound 3; compound 3 reacts with ethylene glycol under the action of strong base to produce compound 4, and the obtained compound 4 reacts with 2-chloro-5-bromopyrimidine under the action of strong base to obtain compound 5, and then boron tribromide is used to remove the benzyl protection to obtain the compound of formula I. This route uses strong base in multiple steps, generates more waste, and has a low yield, especially the last step has a yield of only 29%.

[0007] ;

[0008] Route two (WO2015121397) is an improved version of the original research route, which mainly adjusts the order of the ethylene glycol side chain splicing. The route is shorter and does not need to be deprotected. However, the by-products generated by the fluoride anion may affect the quality of the product aprocitentan; in the post-treatment purification process, it is necessary to overcome the adverse effects of a large amount of related fluorine-containing by-products on equipment corrosion and environment, and the post-treatment steps are more; in addition, the use of excessive non-standard fluorinated reagents such as tetra-n-butylammonium fluoride hydrate or cesium fluoride also increases the cost of raw materials, which is not conducive to industrial production.

[0009] ;

[0010] Route three (CN117736152A) reports a method for synthesizing a compound of formula I. This method is mainly to circumvent the patent, resulting in a long synthesis route and poor economic benefit.

[0011] In addition, when the compound as shown below is used as a substrate, the introduction of the amino group will passivate the aromatic ring, which is not conducive to the substitution reaction on the side containing Cl. In addition, due to the acidity of the sulfonamide, a base is often added for nucleophilic substitution, which further enhances the negative charge of the aromatic ring, further increasing the difficulty of the reaction.

[0012] . SUMMARY

[0013] The technical problem to be solved by the present application is to overcome the problems of low yield, poor process stability and high cost in the existing preparation method of alpirozan. To this end, the present application provides a preparation method of alpirozan. The preparation method provided by the present application has high yield, economical steps and low comprehensive production cost, and is more suitable for industrialized production of alpirozan.

[0014] The present application provides a preparation method of a compound as shown in formula I, which is method 1 or method 2,

[0015] Method 1 comprises the following steps:

[0016] In an organic solvent, in the presence of an organic base, compound 13-1 is subjected to substitution reaction with compound 6 to generate a compound as shown in formula I;

[0017] ;

[0018] Method 2 comprises the following steps:

[0019] In an organic solvent, in the presence of an organic base, compound 13-2 is subjected to substitution reaction with compound 6 to generate a compound as shown in formula II;

[0020] In an alcohol solvent, the compound as shown in formula II is subjected to deprotection reaction with a de-Boc protecting group reagent to generate a compound as shown in formula I;

[0021] .

[0022] The reagents, operations and conditions used in the substitution reaction in the method 1 and method 2 can be conventional in the art, and the present application preferably comprises the following.

[0023] In method 1 and method 2, the organic solvent is an aromatic hydrocarbon solvent, such as toluene.

[0024] In the method 1, the molar volume ratio of the compound 13-1 to the organic solvent is (0.05-1) mol / L; preferably 0.1-0.5 mol / L; for example 0.2 mol / L.

[0025] In the method 2, the molar volume ratio of the compound 13-2 to the organic solvent is (0.05-1) mol / L; preferably 0.1-0.5 mol / L; for example 0.34 mol / L.

[0026] In the method 1 and the method 2, the organic base is an alkali metal alcoholate, preferably an alkali metal tertiary alcoholate; for example potassium tert-butoxide.

[0027] In the method 1, the molar ratio of the compound 13-1 to the organic base is 1:(0.8-6), preferably 1:(1.5-4), for example 1:3.5.

[0028] In the method 2, the molar ratio of the compound 13-2 to the organic base is 1:(0.8-6), preferably 1:(1.5-4), for example 1:2.

[0029] In the method 1, the molar ratio of the compound 13-1 to the compound 6 is 1:(0.5-4), preferably 1:(0.9-2), for example 1:1.1.

[0030] In the method 2, the molar ratio of the compound 13-2 to the compound 6 is 1:(0.5-4), preferably 1:(0.9-2), for example 1:1.2.

[0031] In the method 1 and the method 2, the temperature of the substitution reaction is 50-100℃, for example 70-80℃.

[0032] In the method 1 and the method 2, the progress of the substitution reaction can be detected by using the conventional monitoring methods in the art (for example TLC, HPLC or NMR), and the reaction is generally ended when the compound 13-1 or compound 13-2 disappears or its content no longer changes. The time of the substitution reaction is preferably 2-6h, for example 4h.

[0033] In the method 1 and the method 2, the raw materials of the substitution reaction are the compound 13-1 or compound 13-2, the organic base, the compound 6 and the organic solvent.

[0034] In the method 1 and the method 2, the substitution reaction comprises the following steps: under nitrogen protection, the compound 13-1 or compound 13-2 is mixed with the organic base in the organic solvent at room temperature, the compound 6 is added, and the reaction is carried out at 70-80℃; the addition is preferably dropwise.

[0035] The reagents, operations and conditions used in the deprotection reaction in the method 2 can be conventional in the art, and the present application preferably uses the following.

[0036] In the method 2, the alcohol solvent is methanol.

[0037] In the method 2, the deprotection reagent is an acidic reagent, such as trifluoroacetic acid, hydrochloric acid or sulfuric acid; preferably, the acidic reagent can be used in the form of an acidic alcohol solution with the alcohol solvent;

[0038] In the method 2, the acidic alcohol solution is preferably a methanol solution of hydrochloric acid; for example, a 2-8 mol / L methanol solution of hydrochloric acid; for another example, a 4 mol / L methanol solution of hydrochloric acid.

[0039] In the method 2, the temperature of the deprotection reaction is 10-40°C, for example, 25°C.

[0040] In the method 2, the progress of the deprotection reaction can be detected by using conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction is generally considered to be completed when the compound II disappears or its content no longer changes. The time of the deprotection reaction is preferably 2-6 h, for example, 3 h.

[0041] In the method 2, the deprotection reaction includes the following steps: after the completion of the substitution reaction, the mixture containing the compound II is cooled to 20-30°C; the obtained organic phase is extracted with water, washed (for example, using a saturated sodium chloride solution), concentrated and dried, dissolved in methanol, and then a 4 mol / L methanol solution of hydrochloric acid is added for the deprotection reaction; the addition is preferably dropwise.

[0042] In the method 1, after the completion of the substitution reaction, the following post-treatment steps are included: cooling the reaction liquid (for example, the temperature is 10-45°C; for another example, 20-30°C), extracting with water, washing the organic phase (for example, using a saturated sodium chloride solution), treating the obtained organic phase with activated carbon (for example, stirring at a temperature of 60-100°C; for another example, 80°C), filtering (for example, using a silica gel pad at a temperature of 15-40°C), concentrating the filtrate, and recrystallizing the obtained oily liquid.

[0043] In the method 2, after the completion of the deprotection reaction, the following post-treatment steps are included: concentrating the reaction liquid, redissolving in an aromatic hydrocarbon solvent (for example, toluene), and then treating the obtained organic phase with activated carbon (for example, stirring at a temperature of 60-100°C; for another example, 80°C), filtering (for example, using a silica gel pad at a temperature of 15-40°C), concentrating the filtrate, and recrystallizing the obtained oily liquid.

[0044] In the method 1 and the method 2, the recrystallization preferably comprises the following steps: dissolving the oily liquid in an alcohol solvent, adding a basic solution, mixing at a temperature of 60-100℃, then cooling to 0-20℃, stirring, precipitating a solid, filtering, and vacuum drying.

[0045] In an embodiment, the temperature of the mixing is, for example, 80℃.

[0046] In an embodiment, the temperature of the cooling is, for example, 5℃.

[0047] In an embodiment, the alcohol solvent is preferably ethanol.

[0048] In an embodiment, the basic solution is preferably a sodium hydroxide solution with a mass concentration of 2-10%, for example, a sodium hydroxide solution with a mass concentration of 5%.

[0049] In an embodiment, the volume ratio of the alcohol solvent to the basic solution is preferably 1: (1-4); for example, 1:2.

[0050] In an embodiment, the method for preparing the compound of formula I further comprises the following step: performing a substitution reaction between compound 1 and compound 2 in an organic solvent in the presence of an organic base to obtain compound 13.

[0051]

[0052] R is H or Boc (tert-butyloxycarbonyl).

[0053] The reagents, operations and conditions used in the substitution reaction can be conventional in the art, and the present application preferably comprises the following.

[0054] In an embodiment, the organic base is an alkali metal alcoholate, preferably an alkali metal tertiary alcoholate; for example, potassium tert-butoxide.

[0055] In an embodiment, the molar ratio of compound 1 to the organic base is 1: (1-6); preferably 1: (1.5-3.5); for example, 1:2.

[0056] In an embodiment, the molar ratio of compound 1 to compound 2 is 1: (1-4); preferably 1: (1.5-3); for example, 1:2.

[0057] In an embodiment, the organic solvent is a sulfone solvent or a pyrrolidone solvent; for example, DMSO, NMP or sulfolane.

[0058] In an embodiment, the molar volume ratio of compound 1 to the organic solvent is (0.2-2) mol / L; preferably (0.4-0.8) mol / L; for example, 0.66 mol / L.​

[0059] In a certain solution, the temperature of the substitution reaction is 10-40℃; for example, 25℃.

[0060] The progress of the substitution reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction is generally considered to be complete when the compound 1 disappears or its content no longer changes. The time of the substitution reaction is preferably 12-20 hours.

[0061] In a certain solution, the substitution reaction preferably comprises the following steps: under nitrogen protection, the compound 2 and the organic base are mixed in an organic solvent, the compound 1 is added, and the reaction is carried out at 10-40℃.

[0062] In a certain solution, the substitution reaction is carried out by the compound 2, the organic base, the compound 1 and the organic solvent.

[0063] In a certain solution, after the substitution reaction is completed, the following post-treatment steps are included: water is added to the reaction solution to precipitate solids, filtration, washing of the filter cake, and drying.

[0064] The present application provides a preparation method of a compound as shown in formula II, which comprises the following steps: in an organic solvent, in the presence of an organic base, compound 13-2 is subjected to a substitution reaction with compound 6 to generate a compound as shown in formula II;

[0065] .

[0066] In a certain solution, the reagents, operations and conditions of the substitution reaction are as described in the reagents, operations and conditions of the substitution reaction in method 2.

[0067] The present application also provides a compound, the structure of which is as shown below:

[0068] .

[0069] The "room temperature" is 10-40℃, for example, 25℃.

[0070] On the basis of common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the present application.

[0071] The reagents and raw materials used in the present application are commercially available.

[0072] The positive progress effect of the present application is that, by taking compound 1 as a starting raw material, a compound as shown in formula I is obtained through two-step nucleophilic substitution, without the need for fluorination through a fluorine reagent, which has the advantages of easy availability of raw materials, economical steps, environmental friendliness, and lower comprehensive production cost, etc., and is more suitable for industrialized production of aloglitantan. Detailed Implementation

[0073] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0074] DMSO: Dimethyl sulfoxide

[0075] NMP: N-methylpyrrolidone

[0076]

[0077] Example 1: Synthesis of Compound 6

[0078] Under nitrogen protection, 100 g of compound 5-bromo-2-chloropyrimidine and 500 mL of ethylene glycol were added sequentially to a jacketed flask and stirred. Then, 116.0 g (2.6 eq) of potassium tert-butoxide was added, and the temperature was raised to 80-85 °C and stirred for 6 hours. After the reaction was completed as detected by LC-MS, the reaction system was cooled to room temperature. 1000 mL of water and 10 mL of methyl tert-butyl ether were added to the reaction system, and the mixture was stirred and separated. The aqueous phase was extracted twice with 500 mL of methyl tert-butyl ether, and the organic phases were combined. The organic phase was concentrated to dryness to obtain crude compound 6.

[0079] Add 300 mL of a mixed solvent (n-heptane / methyl tert-butyl ether = 5 / 1) to the crude product, stir at room temperature for 2 hours, filter, and dry to obtain 109.5 g of white solid compound 6, with a yield of 96.47%.

[0080] Example 2: Synthesis of Compound 13-1

[0081]

[0082] Under nitrogen protection, 63.2 g of compound 2 (R=H) and 500 mL of DMSO were added sequentially to a jacketed flask, followed by 73.8 g of potassium tert-butoxide. After stirring for 0.5 hours, 100 g of compound 1 was added in portions. The mixture was stirred at room temperature for 16 hours. After the reaction was completed as detected by LC-MS, 1 L of purified water was added dropwise to the system. A solid precipitated during the process. The mixture was filtered, washed with purified water, and dried to obtain 93.3 g of off-white solid, with a yield of 78.6%.

[0083] Example 3: Synthesis of Compound I

[0084] Under nitrogen protection, 35 g of compound 13-1 was added into 350 mL of toluene, 37.7 g of potassium tert-butoxide was added, and stirring was carried out at room temperature for 0.5 h; 23.2 g of compound 6 was dissolved in 100 mL of toluene, and the mixture was added dropwise into the compound 13-1 solution, and the temperature was slowly increased to 70-80 °C, and reaction was carried out for 4 h, and LC-MS detection showed that the reaction was complete; the temperature was decreased to 20-30 °C, 175 mL of water was added dropwise into the reaction solution, and stirring was carried out for 0.5 h, and the aqueous phase was separated, and the organic phase was washed once with 175 mL of saturated sodium chloride; 3.5 g of activated carbon was added into the organic phase, the temperature was increased to 80 °C, and stirring was carried out for 2 h, and the temperature was decreased to room temperature, and the mixture was filtered through a silica gel pad, and the filtrate was concentrated to dryness to obtain an oily liquid; the oily liquid was dissolved in 70 mL of ethanol, 140 mL of 5% sodium hydroxide solution was added dropwise, the temperature was increased to 80 °C, and stirring was carried out for 0.5 h, and the temperature was decreased to 5 °C, and stirring was carried out, and solid was precipitated, and the solid was filtered, and vacuum drying was carried out to obtain 40.0 g of the compound of formula I, and the yield was 76.1%, and MS = 544.9 (M+1).

[0085] Example 4: Synthesis of compound 13-2

[0086]

[0087] Under nitrogen protection, 129.6 g of compound 2 (R = boc) and 500 mL of NMP were sequentially added into a jacketed bottle, and then 110.74 g of potassium tert-butoxide was added, and stirring was carried out for 0.5 h, and then 100 g of compound 1 was added in batches; stirring was carried out at room temperature for 16 h, and LC-MS detection showed that the reaction was complete, and then 1 L of 1N hydrochloric acid aqueous solution was slowly added dropwise into the system to adjust the pH to 4-5, and solid was precipitated during the process; the solid was filtered, and the filtrate was purified by water elution, and then drying was carried out to obtain 125.7 g of light brown solid, and the yield was 82.4%, and MS = 463.0 (M+1), 363.0 (M+1-100).

[0088] Example 5: Synthesis of compound of formula I

[0089] Under nitrogen protection, 70 g of compound 13-2 (R = boc) was added into 350 mL of toluene, and 33.8 g of potassium tert-butoxide was added, and stirring was carried out at room temperature for 0.5 h; 39.2 g of compound 6 was dissolved in 100 mL of toluene, and the mixture was added dropwise into the compound 13-2 solution, and the temperature was slowly increased to 70-80 °C, and reaction was carried out for 4 h, and LC-MS detection showed that the reaction was complete, and the content of the product in the reaction solution was 85%; the temperature was decreased to 20-30 °C, 175 mL of water was added dropwise into the reaction solution, and stirring was carried out for 0.5 h, and the aqueous phase was separated, and the organic phase was washed once with 175 mL of saturated sodium chloride; the mixture was concentrated to dryness, and then redissolved in 350 mL of methanol;

[0090] To the above methanol solution, 100 mL of 4M hydrochloric acid methanol solution was added dropwise, stirred at room temperature for 3 hours, and LC-MS detection showed that the reaction was complete. After drying and concentrating, it was redissolved in 350 mL of toluene. 3.5 g of activated carbon was added, and the temperature was raised to 80°C and stirred for 2 hours. After cooling to room temperature, it was filtered through a silica gel pad. The filtrate was concentrated to dryness to obtain an oily liquid. It was redissolved in 70 mL of ethanol, and 140 mL of 5% sodium hydroxide solution was added dropwise. The temperature was raised to 80°C and stirred for 0.5 hours. After cooling to 5°C, the solid was separated by filtration and dried under vacuum to obtain 45.8 g of the compound of formula I with a yield of 55.6%.

[0091] Comparative Example 1:

[0092]

[0093] Under nitrogen protection, 122.5 g of compound 2 (R=Bn) and 500 mL of cyclobutane sulfone were sequentially added to a jacketed bottle, followed by the addition of 110.74 g of potassium tert-butoxide. After stirring for 0.5 hours, 100 g of compound 1 was added in batches. After stirring at room temperature for 16 hours, LC-MS detection showed that the reaction was complete. Then 1 L of 1N hydrochloric acid aqueous solution was added dropwise to the system, and solid was precipitated during the process. After filtration and purification by water elution, 125.7 g of light brown solid was obtained with a yield of 84.2%.

[0094] Under nitrogen protection, 70 g of compound 13-3 (R=Bn) was added to 350 mL of toluene, and 34.6 g of potassium tert-butoxide was added. After stirring at room temperature for 0.5 hours, 40.5 g of compound 6 was dissolved in 100 mL of toluene and added dropwise to the compound 13 mixture. The temperature was slowly raised to 70-80°C, and the reaction was maintained for 4 hours. LC-MS detection showed that the reaction was complete. After cooling to 20-30°C, 175 mL of water was added dropwise to the reaction liquid, and stirred for 0.5 hours. The aqueous phase was separated, and the organic phase was washed once with 175 mL of saturated sodium chloride. After drying and concentrating, it was redissolved in 350 mL of methanol.

[0095] To the above methanol solution, 100 mL of 4M hydrochloric acid methanol solution was added dropwise, stirred at room temperature for 3 hours, and LC-MS detection showed that the reaction was complete. After drying and concentrating, it was redissolved in 350 mL of toluene. 3.5 g of activated carbon was added, and the temperature was raised to 80°C and stirred for 2 hours. After cooling to room temperature, it was filtered through a silica gel pad. The filtrate was concentrated to dryness to obtain an oily liquid. It was redissolved in 70 mL of ethanol, and 140 mL of 5% sodium hydroxide solution was added dropwise. The temperature was raised to 80°C and stirred for 0.5 hours. After cooling to 5°C, the solid was separated by filtration and dried under vacuum to obtain 45.8 g of the compound of formula I with a yield of 55.6%.

Claims

1. A method for preparing a compound as shown in Formula I, wherein method 1 or method 2, Method 1 includes the following steps: In an organic solvent and in the presence of an organic base, compound 13-1 is subjected to a substitution reaction with compound 6 to produce a compound as shown in Formula I. ； Method 2 includes the following steps: In an organic solvent and in the presence of an organic base, compound 13-2 is subjected to a substitution reaction with compound 6 to produce a compound as shown in formula II. In an alcohol solvent, the compound shown in Formula II is reacted with a deprotecting agent to generate the compound shown in Formula I. ； In methods 1 and 2, the organic base is an alkali metal alkoxide; In Method 1, the molar ratio of compound 13-1 to the organic base is 1:(0.8~6). In method 2, the molar ratio of compound 13-2 to the organic base is 1:(0.8~6). In method 1, the molar ratio of compound 13-1 to compound 6 is 1:(0.5~4). In method 2, the molar ratio of compound 13-2 to compound 6 is 1:(0.5~4). In methods 1 and 2, the temperature of the substitution reaction is 50~100℃.

2. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) In methods 1 and 2, the organic solvent is an aromatic hydrocarbon solvent; (2) In method 1, the molar volume ratio of compound 13-1 to the organic solvent is (0.05~1) mol / L; (3) In method 2, the molar volume ratio of compound 13-2 to the organic solvent is (0.05~1) mol / L; (4) In methods 1 and 2, the organic base is an alkali metal tertiary alkoxide; (5) In method 1, the molar ratio of compound 13-1 to the organic base is 1:(1.5~4). (6) In method 2, the molar ratio of compound 13-2 to the organic base is 1:(1.5~4). (7) In method 1, the molar ratio of compound 13-1 to compound 6 is 1:(0.9~2). (8) In method 2, the molar ratio of compound 13-2 to compound 6 is 1:(0.9~2). (9) In methods 1 and 2, the temperature of the substitution reaction is 70~80℃; (10) In methods 1 and 2, the raw materials for the substitution reaction are compound 13-1 or compound 13-2, the organic base, compound 6 and the organic solvent; (11) In method 2, the alcohol solvent is methanol; (12) In method 2, the Boc-protecting group removal reagent is an acidic reagent; (13) In method 2, the temperature of the deprotection reaction is 10~40℃.

3. The preparation method according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1) In methods 1 and 2, the organic solvent is toluene; (2) In method 1, the molar volume ratio of compound 13-1 to the organic solvent is (0.1~0.5) mol / L; (3) In method 2, the molar volume ratio of compound 13-2 to the organic solvent is (0.1~0.5) mol / L; (4) In methods 1 and 2, the organic base is potassium tert-butoxide; (5) In method 1, the molar ratio of compound 13-1 to the organic base is 1:3.5; (6) In method 2, the molar ratio of compound 13-2 to the organic base is 1:2; (7) In method 1, the molar ratio of compound 13-1 to compound 6 is 1:1.1; (8) In method 2, the molar ratio of compound 13-2 to compound 6 is 1:1.2; (9) In method 2, the Boc-protecting group removal reagent is an acidic reagent; the acidic reagent is trifluoroacetic acid, hydrochloric acid or sulfuric acid; (10) In method 2, the temperature of the deprotection reaction is 25°C.

4. The preparation method according to claim 3, characterized in that, It satisfies one or more of the following conditions: (1) In method 1, the molar volume ratio of compound 13-1 to the organic solvent is 0.2 mol / L; (2) In method 2, the molar volume ratio of compound 13-2 to the organic solvent is 0.34 mol / L; (3) In method 2, the Boc deprotecting reagent is an acidic reagent; the acidic reagent and the alcohol solvent are used in the form of an acidic alcohol solution.

5. The preparation method according to claim 4, characterized in that, It satisfies one or two of the following conditions: (1) In Method 1 and Method 2, the substitution reaction includes the following steps: under nitrogen protection, in an organic solvent, the compound 13-1 or compound 13-2 is mixed with the organic base at room temperature, the compound 6 is added, and the reaction is carried out at 70~80°C. (2) In method 2, the acidic alcohol solution is a hydrochloric acid methanol solution.

6. The preparation method according to claim 5, characterized in that, It satisfies one or two of the following conditions: (1) In Method 1 and Method 2, the substitution reaction includes the following steps: under nitrogen protection, in an organic solvent, the compound 13-1 or compound 13-2 is mixed with the organic base at room temperature, the compound 6 is added, and the reaction is carried out at 70~80°C; the addition is dropwise. (2) In method 2, the acidic alcohol solution is a 2~8 mol / L hydrochloric acid methanol solution.

7. The preparation method according to claim 6, characterized in that, In Method 2, the acidic alcohol solution is a 4 mol / L hydrochloric acid-methanol solution.

8. The preparation method according to any one of claims 1 to 7, characterized in that, In Method 2, the deprotection reaction includes the following steps: after the substitution reaction is completed, the mixture containing the compound shown in Formula II is cooled to 20~30℃; the organic phase obtained by water extraction is washed, concentrated to dryness and then dissolved in methanol, and subjected to a deprotection reaction with a 4 mol / L hydrochloric acid methanol solution.

9. The preparation method according to claim 8, characterized in that, It satisfies one or two of the following conditions: (1) In method 1, after the substitution reaction is completed, the following post-processing steps are included: cooling the reaction solution, extracting with water, washing the organic phase, treating the obtained organic phase with activated carbon in sequence, filtering, concentrating the filtrate, and recrystallizing the obtained oily liquid. (2) In method 2, after the deprotection reaction is completed, the following post-processing steps are included: the reaction solution is concentrated, redissolved in an aromatic hydrocarbon solvent, the resulting organic phase is treated with activated carbon in sequence, filtered, the filtrate is concentrated, and the resulting oily liquid is recrystallized.

10. The preparation method according to claim 9, characterized in that, In methods 1 and 2, the recrystallization includes the following steps: the oily liquid is dissolved in an alcohol solvent, an alkaline solution is added, the mixture is mixed at a temperature of 60~100℃, then cooled to 0~20℃, stirred, the solid is precipitated, filtered, and vacuum dried.

11. The preparation method according to claim 1, characterized in that, The method for preparing the compound as shown in Formula I further includes a method for preparing compound 13, which includes the following steps: in an organic solvent, in the presence of an organic base, compound 1 and compound 2 undergo a substitution reaction to generate compound 13; ； R is either H or Boc.

12. The preparation method according to claim 11, characterized in that, In the preparation method of compound 13, one or more of the following conditions are satisfied: (1) The organic base is an alkali metal alkoxide; (2) The molar ratio of compound 1 to the organic base is 1:(1~6); (3) The molar ratio of compound 1 to compound 2 is 1:(1~4); (4) The organic solvent is a sulfone solvent or a pyrrolidone solvent; (5) The molar volume ratio of compound 1 to the organic solvent is (0.2~2) mol / L; (6) The temperature of the substitution reaction is 10~40℃; (7) The materials for the substitution reaction are compound 2, the organic base, compound 1 and the organic solvent; (8) After the substitution reaction is completed, the following post-processing steps are included: add water to the reaction solution to precipitate solid, filter, wash the filter cake, and dry.

13. The preparation method according to claim 12, characterized in that, In the preparation method of compound 13, one or more of the following conditions are satisfied: (1) The organic base is an alkali metal tertiary alkoxide; (2) The molar ratio of compound 1 to the organic base is 1:(1.5~3.5); (3) The molar ratio of compound 1 to compound 2 is 1:(1.5~3); (4) The organic solvent is DMSO, NMP or sulfolane; (5) The molar volume ratio of compound 1 to the organic solvent is (0.4~0.8) mol / L; (6) The temperature of the substitution reaction is 25°C.

14. The preparation method according to claim 13, characterized in that, In the preparation method of compound 13, one or more of the following conditions are satisfied: (1) The organic base is potassium tert-butoxide; (2) The molar ratio of compound 1 to the organic base is 1:2; (3) The molar ratio of compound 1 to compound 2 is 1:2; (4) The molar volume ratio of compound 1 to the organic solvent is 0.66 mol / L.

15. The preparation method according to claim 11, characterized in that, In the preparation method of compound 13, the substitution reaction includes the following steps: under nitrogen protection, in an organic solvent, compound 2 and the organic base are mixed, compound 1 is added, and the reaction is carried out at 10~40°C.

16. A method for preparing a compound as shown in Formula II, comprising the following steps: in an organic solvent, in the presence of an organic base, reacting compound 13-2 with compound 6 by a substitution reaction to generate a compound as shown in Formula II; ； The organic base is an alkali metal alkoxide; The molar ratio of compound 13-2 to the organic base is 1:(0.8~6). The molar ratio of compound 13-2 to compound 6 is 1:(0.5~4). The temperature for the substitution reaction is 50~100℃.

17. The preparation method according to claim 16, characterized in that, The reagents, procedures, and conditions for the substitution reaction are as described in Method 2 of any one of claims 2 to 10.

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