Preparation method of alplsutentan

Abstract

The invention discloses a preparation method of alplsutentan. The invention relates to a preparation method of a compound as shown in a formula I. The preparation method is a method 1 or a method 2, and the method 1 comprises the following steps: in an organic solvent, in the presence of organic alkali, carrying out substitution reaction on a compound 13-1 and a compound 6 to generate the compound as shown in the formula I; the method 2 comprises the following steps: in an organic solvent, in the presence of organic alkali, carrying out substitution reaction on a compound 13-2 and a compound 6 to generate a compound as shown in a formula II; in an alcohol solvent, the compound shown in the formula II and a Boc protecting group removing reagent are subjected to a protecting group removing reaction, and the compound shown in the formula I is generated. The preparation method provided by the invention has the advantages of high yield, economical steps and lower comprehensive production cost, and is more suitable for industrial production of alpoxivan. # imgabs0 # imgabs1 #

Description

Technical Field

[0001] The present invention relates to a method for preparing aprexitentan. Background Art

[0002] In patients with hypertension, ET-1 can cause endothelial dysfunction, vascular hypertrophy and remodeling, sympathetic nerve activation, and increased aldosterone synthesis. Aprocitentan is a dual endothelin (ET) A / B receptor (ETA / ETB) antagonist that inhibits the binding of ET-1 to ETA and ETB receptors, thereby lowering blood pressure.

[0003] Treatment with aprexitentan reduced the urine albumin-creatinine ratio by about 50%, the estimated glomerular filtration rate decreased slightly and steadily, and the level of N-terminal natriuretic peptide type B precursor hormone in the blood increased moderately and steadily. In addition, compared with current drugs for the treatment of refractory hypertension, aprexitentan has the outstanding advantage that it does not cause any increase in blood potassium levels, which is the main problem with spironolactone, the current first-choice drug for the treatment of refractory hypertension.

[0004] There are three main publicly reported synthetic routes of Aprexitentan:

[0005] ;

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

[0007] ;

[0008] Route 2 (WO2015121397) is an improved version of the original research route. It mainly adjusts the order of ethylene glycol side chain splicing. The route is shorter and does not require deprotection. However, the byproducts produced by fluoride anions may affect the quality of the product apremilastan. In the post-processing purification process, it is necessary to overcome the adverse effects of a large number of related fluorine-containing byproducts on equipment corrosion and the environment, and there are many post-processing steps. In addition, the use of excessive non-standard fluorination reagents such as tetrabutylammonium fluoride hydrate or cesium fluoride increases the cost of raw materials, which is not conducive to industrial production.

[0009] ;

[0010] Route 3 (CN117736152A) reports a method for synthesizing the compound of formula I. This method is mainly to circumvent patents, resulting in a lengthy synthesis route and relatively poor economic benefits.

[0011] In addition, when the compound 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 Cl-containing side. In addition, since sulfonamide has a certain acidity, nucleophilic substitution often requires the addition of a base, which further enhances the negative charge of the aromatic ring, which further increases the difficulty of the reaction.

[0012] . Summary of the invention

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

[0014] The present invention provides a method for preparing a compound as shown in formula I, which is method 1 or method 2.

[0015] Method 1 includes the following steps:

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

[0017] ;

[0018] Method 2 includes the following steps:

[0019] 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;

[0020] In an alcohol solvent, the compound represented by formula II is subjected to a deprotection reaction with a Boc protecting group removal reagent to generate a compound represented by formula I;

[0021] .

[0022] The reagents, operations and conditions used in the substitution reactions in Method 1 and Method 2 can all be conventional in the art, and the preferred embodiments of the present invention are as follows.

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

[0024] In 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 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 method 1 and method 2, the organic base is an alkali metal alkoxide, preferably an alkali metal tertiary alkoxide; for example, potassium tert-butoxide.

[0027] In 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 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 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 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 method 1 and method 2, the temperature of the substitution reaction is 50-100°C, such as 70-80°C.

[0032] In method 1 and method 2, 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 terminated when the compound 13-1 or compound 13-2 disappears or its content no longer changes. The substitution reaction time is preferably 2 to 6 hours, for example 4 hours.

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

[0034] In method 1 and method 2, the substitution reaction comprises 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 preferably dropwise addition.

[0035] The reagents, operations and conditions used in the deprotection reaction in the method 2 can all be conventional in the art, and the preferred embodiments of the present invention are as follows.

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

[0037] In method 2, the Boc protecting group removal reagent is an acidic reagent; for example, trifluoroacetic acid, hydrochloric acid or sulfuric acid; preferably, the acidic reagent can be used with the alcohol solvent in the form of an acidic alcohol solution;

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

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

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

[0041] In method 2, the deprotection reaction comprises the following steps: after the substitution reaction is completed, the mixed solution containing the compound shown in formula II is cooled to 20-30°C; the organic phase obtained by water extraction is washed (for example, with a saturated sodium chloride solution), concentrated to dryness and dissolved in methanol, and a 4 mol / L hydrochloric acid methanol solution is added to carry out a deprotection reaction; the addition is preferably dropwise addition.

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

[0043] In method 2, after the deprotection reaction is completed, the following post-treatment steps are included: the reaction solution is concentrated, redissolved in an aromatic hydrocarbon solvent (such as toluene), the obtained organic phase is treated with activated carbon (for example, heating to 60-100°C and stirring; for example, 80°C), filtered (for example, filtered using a silica gel pad at a temperature of 15-40°C), the filtrate is concentrated, and the obtained oily liquid is recrystallized.

[0044] In method 1 and method 2, the recrystallization preferably includes the following steps: the oily liquid is dissolved in an alcohol solvent, an alkaline solution is added, and the mixture is mixed at a temperature of 60 to 100° C., then cooled to 0 to 20° C., stirred, solids are precipitated, filtered, and vacuum dried.

[0045] In one embodiment, the mixing temperature is, for example, 80°C.

[0046] In one embodiment, the cooling temperature is 5°C.

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

[0048] In a certain embodiment, the alkaline 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 a certain embodiment, the volume ratio of the alcohol solvent to the alkaline solution is preferably 1:(1-4); for example, 1:2.

[0050] In one embodiment, the method for preparing the compound of formula I further comprises the following steps: in an organic solvent, in the presence of an organic base, subjecting compound 1 to a substitution reaction with compound 2 to generate compound 13;

[0051] ;

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

[0053] The reagents, operations and conditions used in the substitution reaction can all be conventional in the art, and the preferred embodiments of the present invention are as follows.

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

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

[0056] In one 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 one embodiment, the organic solvent is a sulfone solvent or a pyrrolidone solvent; for example, DMSO, NMP or sulfolane.

[0058] In a certain embodiment, the molar volume ratio of the 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 one embodiment, the temperature of the substitution reaction is 10-40°C; for example, 25°C.

[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 terminated when the compound 1 disappears or its content no longer changes. The substitution reaction time is preferably 12 to 20 hours.

[0061] In a certain embodiment, the substitution reaction preferably comprises the following steps: under nitrogen protection, in an organic solvent, mixing the compound 2 and the organic base, adding the compound 1, and reacting at 10-40°C.

[0062] In a certain embodiment, the materials for the substitution reaction are the compound 2, the organic base, the compound 1 and the organic solvent.

[0063] In one embodiment, after the substitution reaction is completed, the following post-treatment steps are included: adding water to the reaction solution to precipitate solids, filtering, washing the filter cake, and drying.

[0064] The present invention provides 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, subjecting compound 13-2 to a substitution reaction with compound 6 to generate a compound as shown in formula II;

[0065] .

[0066] In one embodiment, the reagents, procedures and conditions of the substitution reaction are the same as those of the substitution reaction in Method 2.

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

[0068] .

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

[0070] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

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

[0072] The positive and progressive effects of the present invention are: using compound 1 as the starting material, a compound as shown in formula I is obtained through two-step nucleophilic substitution, without the need for fluorination by a fluorine reagent, and has the advantages of easy availability of raw materials, economical steps, environmental friendliness, and low comprehensive production cost, and is more suitable for the industrial production of aprexitentan. DETAILED DESCRIPTION

[0073] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0074] DMSO: dimethyl sulfoxide

[0075] NMP: N-methylpyrrolidone

[0076]

[0077] Example 1: Synthesis of Compound 6

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

[0079] 300 mL of a mixed solvent (n-heptane / methyl tert-butyl ether = 5 / 1) was added to the crude product, and the mixture was slurried at room temperature for 2 hours, filtered, and dried 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 to a jacketed bottle in sequence, and then 73.8 g of potassium tert-butoxide was added. After stirring for 0.5 hour, 100 g of compound 1 was added in batches; the mixture was stirred at room temperature for 16 hours. After the reaction was completed by LC-MS detection, 1 L of purified water was added dropwise to the system. Solids were precipitated during the process; the mixture was filtered, rinsed with purified water, and dried to obtain 93.3 g of an off-white solid with a yield of 78.6%.

[0083] Example 3: Synthesis of Compound Formula I

[0084] Under nitrogen protection, 35g of compound 13-1 was added to 350mL of toluene, 37.7g of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 0.5 hours; 23.2g of compound 6 was dissolved in 100mL of toluene, and the mixture was added dropwise to the mixed solution of compound 13-1, and the mixture was slowly heated to 70-80°C, and the mixture was kept warm for 4 hours. The reaction was complete when detected by LC-MS; the mixture was cooled to 20-30°C, 175mL of water was added dropwise to the reaction solution, and the mixture was stirred for 0.5 hours. The aqueous phase was separated, and the organic phase was washed once with 175mL of saturated sodium chloride; 3.5g of activated carbon was added to the organic phase, the mixture was heated to 80°C and stirred for 2 hours, cooled to room temperature, filtered through a silica gel pad, and the filtrate was concentrated to obtain an oily liquid; the mixture was redissolved in 70mL of ethanol, and 140mL of 5% sodium hydroxide solution, heated to 80°C and stirred for 0.5 hour, cooled to 5°C, stirred, precipitated solid, filtered, and vacuum dried to obtain 40.0 g of compound I, yield 76.1%, 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 added to a jacketed bottle in sequence, and then 110.74 g of potassium tert-butoxide was added. After stirring for 0.5 hour, 100 g of compound 1 was added in batches; the mixture was stirred at room temperature for 16 hours. After the reaction was completed by LC-MS detection, 1 L of 1N hydrochloric acid aqueous solution was slowly added dropwise to the system to adjust the pH to 4-5. Solids were precipitated during the process; the mixture was filtered, rinsed with purified water, and dried to obtain 125.7 g of light brown solid, with a yield of 82.4%, MS = 463.0 (M+1), 363.0 (M+1-100).

[0088] Example 5: Synthesis of Compound Formula I

[0089] Under nitrogen protection, add 70g of compound 13-2 (R=boc) to 350mL of toluene, add 33.8g of potassium tert-butoxide, and stir at room temperature for 0.5 hour; dissolve 39.2g of compound 6 in 100mL of toluene, add dropwise to the mixed solution of compound 13-2, slowly raise the temperature to 70~80℃, keep warm for 4 hours, and the reaction is complete by LC-MS detection, and the content of the product in the reaction solution is detected to be 85%; cool to 20~30℃, add dropwise 175mL of water to the reaction solution, stir for 0.5 hour, separate the aqueous phase, and wash the organic phase once with 175mL of saturated sodium chloride; concentrate to dryness and redissolve in 350mL of methanol;

[0090] 100 mL of 4 M hydrochloric acid methanol solution was added dropwise to the above methanol solution, and the mixture was stirred at room temperature for 3 hours. The reaction was complete when detected by LC-MS. The mixture was concentrated to dryness and redissolved in 350 mL of toluene. 3.5 g of activated carbon was added, the mixture was heated to 80 ° C and stirred for 2 hours, cooled to room temperature, filtered through a silica gel pad, and the filtrate was concentrated to dryness to obtain an oily liquid. The mixture was redissolved in 70 mL of ethanol, 140 mL of 5% sodium hydroxide solution was added dropwise, the mixture was heated to 80 ° C and stirred for 0.5 hour, cooled to 5 ° C, stirred, a solid was precipitated, filtered, and dried in vacuo to obtain 45.8 g of compound 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 cyclopentane were added to a jacketed bottle in sequence, and then 110.74 g of potassium tert-butoxide was added. After stirring for 0.5 hour, 100 g of compound 1 was added in batches; the mixture was stirred at room temperature for 16 hours. After the reaction was completed by LC-MS detection, 1 L of 1N hydrochloric acid aqueous solution was added dropwise to the system. Solids were precipitated during the process; the mixture was filtered, rinsed with purified water, and dried to obtain 125.7 g of light brown solid with a yield of 84.2%.

[0094] Under nitrogen protection, add 70g of compound 13-3 (R=Bn) to 350mL of toluene, add 34.6g of potassium tert-butoxide, and stir at room temperature for 0.5 hour; dissolve 40.5g of compound 6 in 100mL of toluene, add dropwise to the mixed solution of compound 13, slowly raise the temperature to 70-80℃, keep warm for 4 hours, and the reaction is complete when detected by LC-MS; cool to 20-30℃, add dropwise 175mL of water to the reaction solution, stir for 0.5 hour, separate the aqueous phase, and wash the organic phase once with 175mL of saturated sodium chloride; concentrate to dryness and redissolve in 350mL of methanol;

[0095] 7 g of palladium carbon was added to the above methanol solution, and the atmosphere was replaced with nitrogen and then replaced with hydrogen. The pressure was maintained at 0.1-0.2 MPa and the reaction was carried out for 1 hour. LC-MS detected that the reaction was complete. When the obtained reaction solution was tested, it was found that the bromine on the benzene ring in the product was unstable and some of the bromine in the product would be removed. MS=467.1 (M+1, one bromine was removed), 389.1 (M+1, two bromines were removed).

Claims

1. A method for preparing a compound as shown in formula I, which is method 1 or method 2, Method 1 includes the following steps: In an organic solvent, in the presence of an organic base, compound 13-1 is subjected to a substitution reaction with compound 6 to generate a compound as shown in formula I; ； Method 2 includes 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; In an alcohol solvent, the compound represented by formula II is subjected to a deprotection reaction with a Boc protecting group removal reagent to generate a compound represented by formula I; 。 2. The preparation method according to claim 1, characterized in that It meets one or more of the following conditions: (1) In method 1 and method 2, the organic solvent is an aromatic hydrocarbon solvent, such as toluene; (2) In 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; (3) In 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; (4) In method 1 and method 2, the organic base is an alkali metal alkoxide, preferably an alkali metal tertiary alkoxide; for example, potassium tert-butoxide; (5) In 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; (6) In 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; (7) In 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; (8) In 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; (9) In method 1 and method 2, the temperature of the substitution reaction is 50-100°C, for example, 70-80°C; (10) In method 1 and method 2, the raw materials for the substitution reaction are the compound 13-1 or compound 13-2, the organic base, the 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; for example, trifluoroacetic acid, hydrochloric acid or sulfuric acid; preferably, the acidic reagent can be used with the alcohol solvent in the form of an acidic alcohol solution; (13) In method 2, the temperature of the deprotection reaction is 10-40°C, for example, 25°C.

3. The preparation method according to claim 2, characterized in that: It meets one or both of the following conditions: (1) In method 1 and method 2, the substitution reaction comprises the following steps: under nitrogen protection, in an organic solvent, mixing the compound 13-1 or compound 13-2 with the organic base at room temperature, adding the compound 6, and reacting at 70-80°C; the adding is preferably dropwise; (2) In method 2, the acidic alcohol solution is preferably a hydrochloric acid methanol solution; for example, a 2-8 mol / L hydrochloric acid methanol solution; Another example is 4 mol / L hydrochloric acid methanol solution.

4. The preparation method according to any one of claims 1 to 3, characterized in that In method 2, the deprotection reaction comprises the following steps: after the substitution reaction is completed, the mixed solution containing the compound shown in formula II is cooled to 20-30°C; the organic phase obtained by extraction with water is washed, concentrated to dryness, dissolved in methanol, and subjected to a deprotection reaction with a 4 mol / L hydrochloric acid methanol solution; the addition is preferably dropwise addition.

5. The preparation method according to claim 4, characterized in that: It meets one or both of the following conditions: (1) In method 1, after the substitution reaction is completed, the following post-treatment steps are included: cooling the reaction solution, adding water for extraction, washing the organic phase, treating the obtained organic phase with activated carbon, filtering, concentrating the filtrate, and recrystallizing the obtained oily liquid; (2) In method 2, after the deprotection reaction is completed, the following post-treatment steps are included: the reaction solution is concentrated, redissolved in an aromatic hydrocarbon solvent, the obtained organic phase is treated with activated carbon, filtered, the filtrate is concentrated, and the obtained oily liquid is recrystallized.

6. The preparation method according to claim 5, characterized in that: In method 1 and method 2, the recrystallization includes the following steps: the oily liquid is dissolved in an alcohol solvent, an alkaline solution is added, and the mixture is mixed at a temperature of 60 to 100° C., then cooled to 0 to 20° C., stirred, solids are precipitated, filtered, and vacuum dried.

7. The preparation method according to claim 1, characterized in that: The method for preparing the compound of formula I further comprises the following steps: in an organic solvent, in the presence of an organic base, subjecting compound 1 to a substitution reaction with compound 2 to generate compound 13; ； R is H or Boc.

8. The preparation method according to claim 7, characterized in that: It meets one or more of the following conditions: (1) The organic base is an alkali metal alkoxide, preferably an alkali metal tertiary alkoxide; for example, potassium tert-butoxide; (2) The molar ratio of the compound 1 to the organic base is 1:(1-6); preferably 1:(1.5-3.5); for example 1:2; (3) The molar ratio of compound 1 to compound 2 is 1:(1-4); preferably 1:(1.5-3); for example 1:2; (4) The organic solvent is a sulfone solvent or a pyrrolidone solvent; for example, DMSO, NMP or sulfolane; (5) The molar volume ratio of the 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; (6) The temperature of the substitution reaction is 10-40°C, for example 25°C; (7) The substitution reaction preferably comprises the following steps: under nitrogen protection, in an organic solvent, mixing the compound 2 and the organic base, adding the compound 1, and reacting at 10-40°C (8) The materials for the substitution reaction are the compound 2, the organic base, the compound 1 and the organic solvent; (9) After the substitution reaction is completed, the following post-treatment steps are included: adding water to the reaction solution to precipitate solids, filtering, washing the filter cake, and drying.

9. 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, subjecting compound 13-2 to a substitution reaction with compound 6 to generate a compound as shown in formula II; ； Preferably, the reagents, operations and conditions of the substitution reaction are as described in the substitution reaction in method 2 according to any one of claims 2 to 6.

10. A compound having the structure shown below: 。

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