Process for the preparation of a ralfinasin intermediate

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a refenacin intermediate. According to the method, 1-benzylpiperidin-4-ol is acylated by phenyl chloroformate to obtain an intermediate I-1, and the intermediate I-1 is aminolyzed by [1,1'-biphenyl]-2-amine to obtain a target compound 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate. According to the method, the use of the highly toxic isocyanate reagent is avoided, the synthesis route is simple, the operation is more convenient, the yield is higher, and the method is more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing a refennaxine intermediate. Background Technology

[0002] Revefenacin, chemically named 1-(2-(4-((4-carbamoylpiperidin-1-yl)methyl)-N-methylbenzamido)ethylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate, was first discovered and developed by Theravance Biopharmaceuticals in Ireland in collaboration with Mylan Pharmaceuticals in the United States. It is a novel long-acting anticholinergic drug approved for marketing in the United States on November 9, 2018. Its brand name is [omitted]. Rafenasine is a long-acting muscarinic receptor antagonist that inhibits tracheal constriction caused by the release of acetylcholine from parasympathetic nerve endings by binding to M3 muscarinic receptors on bronchial smooth muscle. Clinically, it is mainly used for the maintenance treatment of chronic obstructive pulmonary disease (COPD), including the maintenance treatment of chronic bronchitis and emphysema with dyspnea, and the prevention of acute exacerbations. Its chemical structure is as follows:

[0003]

[0004] There are few literature reports on the synthesis methods of refennaxine. Its synthetic routes are mainly concentrated in the Chinese patents CN1759108A, CN1882556A, CN1930125B, CN102958916B, US20050203133A1 published by the original research company, as well as the literature J.Med.Chem., 2015, 58(6), 2609-2622, etc. Among them, the classic route is to use 2-biphenyl isocyanate (2) as the starting material, and react it with 1-benzylpiperidin-4-ol (3) to obtain 1-benzylpiperidin-4-ol. After removing the benzyl group from 1,1'-biphenyl]-2-ylcarbamate, piperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (4) is obtained. This is then reductively amination with benzylmethyl (2-oxoethyl)carbamate using sodium triacetoxyborohydride, followed by removal of the benzyloxycarbonyl group to generate 1-(2-(methylamino)ethyl)piperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (5). (5) is then reacted with p-formylbenzoic acid, and finally reductively amination with piperidin-4-carboxamide (6) using sodium triacetoxyborohydride to obtain the target product 1. The relevant reaction routes are shown below:

[0005]

[0006] However, the above process has the following problems: ① The “linear” synthesis strategy is adopted, the reaction steps are relatively long, and most of the intermediates in each step are oily liquids with low melting points, which are difficult to purify, resulting in the easy inheritance of impurities, low yield of target product, high production cost, and great difficulty in industrialization; ② In the subsequent two-step reductive amination, the moisture content of the material will also lead to a serious reduction in yield or even failure of reaction.

[0007] As shown above, 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate can serve as a key intermediate in the preparation of refennaxine. Therefore, 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate can directly affect the production, market supply, and quality of this drug. The specific structural formula is as follows:

[0008]

[0009] However, although the above process achieves a yield of approximately 100% in the preparation of 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate, the material used, 2-biphenyl isocyanate (2), has high activity and is expensive, costing approximately 17,000 yuan / kg. The other material, 1-benzylpiperidin-4-ol (3), has a commercially available water content of approximately 0.2-0.5% and a low melting point of approximately 55-60°C, making it difficult to dry. Therefore, a large amount of the following impurities are generated during the reaction, further reducing the yield of the single-step reaction. The crude product obtained contains a low content of 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate, only about 70%, requiring further purification, which further reduces the yield of this step and increases production costs. The structures of the relevant impurities are as follows:

[0010]

[0011] In summary, given the many shortcomings in the current preparation of 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate, finding a simple, safe, mild reaction process with high yield and purity suitable for industrial production of 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate remains a problem that needs to be solved. Summary of the Invention

[0012] To address the numerous problems existing in the preparation of the refennaxine intermediate 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate, this invention provides a novel method for preparing 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate. This method features mild reaction conditions, a safe and simple operation, and yields a target product with high purity and high yield.

[0013] This invention is specifically achieved through the following technical solution:

[0014] A method for preparing the refennaxine intermediate 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate, wherein 1-benzylpiperidin-4-ol is acylated by SM-2 to obtain intermediate I-1, and intermediate I-1 is subjected to [1,1'-biphenyl]-2-amine aminolysis to obtain the target compound 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate, as shown in the following reaction formula:

[0015]

[0016] Wherein, R is H or NO2;

[0017] A method for preparing the refennaxine intermediate 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate as shown in Formula I, the specific steps of which are as follows:

[0018] Step 1. Add SM-1 and the acid-binding agent to the reaction solvent, and control the temperature T. 1A Add SM-2, temperature control T 1B After the reaction is completed, intermediate I-1 is obtained through post-processing;

[0019] Preferably, SM-2 in step 1 is phenyl chloroformate or phenyl p-nitrochloroformate, with phenyl chloroformate being the preferred choice.

[0020] Preferably, the acid-binding agent mentioned in step 1 includes, but is not limited to, one or a combination of K2CO3, Na2CO3, triethylamine, N,N-diisopropylethylamine, and pyridine, with triethylamine being the most preferred.

[0021] Preferably, the reaction solvent in step 1 is one or a combination of dichloromethane and chloroform, with dichloromethane being the most preferred.

[0022] Preferably, the molar ratio of SM-1 to SM-2 and the acid binder in step 1 is 1:1.2-3.0:2.2-5.0, more preferably 1:1.6:2.8.

[0023] Preferably, the T mentioned in step 1 1A The temperature range is -10 to 10°C, preferably 0 to 5°C; the reaction temperature T 1B The temperature range is 15–40℃, with 25–30℃ being preferred.

[0024] In a preferred embodiment, the post-processing step in step 1 is as follows: add purified water to the reaction solution, adjust the pH of the aqueous phase to 1-3 with hydrochloric acid, separate the phases, wash the aqueous phase with dichloromethane, adjust the pH of the aqueous phase to 9-10 with sodium hydroxide solution, extract with an organic solvent, wash the organic phase with saturated brine, dry, filter, and concentrate the filtrate to dryness under reduced pressure to obtain intermediate I-1.

[0025] Preferably, the extraction solvent includes, but is not limited to, one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, with dichloromethane being the most preferred.

[0026] Step 2. Add intermediates I-1 and SM-3 to the reaction solvent, control the temperature until the reaction is complete, and obtain the target compound I after post-treatment.

[0027] Preferably, the reaction solvent in step 2 is one or a combination of dichloromethane and chloroform, with dichloromethane being the most preferred.

[0028] Preferably, the molar ratio of I-1 to SM-3 in step 2 is 1:1.1 to 2.5, more preferably 1:1.2.

[0029] Preferably, the reaction temperature in step 2 is 20–50°C, more preferably 30–35°C.

[0030] In a preferred embodiment, the post-processing step 2 is as follows: After the reaction is complete, the reaction solution is concentrated to dryness under reduced pressure, and then recrystallized from the dichloromethane-methanol system to obtain the target product I. The volume ratio of dichloromethane to methanol is 2-4:1, preferably 3:1.

[0031] The beneficial effects of this invention are:

[0032] This invention provides a simple and efficient method for preparing the intermediate 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate, a refennaxine intermediate. Starting with 1-benzylpiperidin-4-ol, the method involves acylation with phenyl chloroformate followed by aminolysis with [1,1'-biphenyl]-2-amine to obtain the target compound, 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate. Although the steps are somewhat prolonged, the lower reactivity of phenyl chloroformate compared to 2-biphenyl isocyanate effectively avoids the generation of related impurities. Furthermore, the entire synthetic method is simple to operate under mild conditions. The target product obtained through this process exhibits high yield and purity, making it suitable for large-scale industrial production. Detailed Implementation

[0033] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0034] Confirmation of the structure of the compound obtained in this invention:

[0035]

[0036] ESI-TOF +-HRMS(m / z):312.1383[M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ7.41~7.35(m,2H),7.29~7.19(m,8H),4.95~4.85(m,1H),3.65(s,2H),2.82~2.71(m,2H),2.48~2.38(m,2H),2.31~2.21(m,2H),2.09~1.99(m,2H); 13 C NMR(151MHz,DMSO-d6)δ156.86,152.40,138.23,129.21,128.81,127.95,127.03,126.55,119.76,70.45,63.66,50.79,30.94。

[0037]

[0038] ESI-TOF + -HRMS(m / z):357.1546[M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ8.23(d,J=7.42Hz,2H),7.46(d,J=7.45Hz,2H),7.29~7.19(m,5H),4.92~4.84(m,1H),3.65(s,2H),2.80~2.72(m,2H),2.48~2.40(m,2H),2.29~2.20(m,2H),2.09~2.00(m,2H); 13 C NMR(151MHz,DMSO-d6)δ157.73,156.04,146.95,138.19,128.76,127.64,126.38,123.25,121.33,70.85,63.48,50.61,30.85。

[0039]

[0040] ESI-TOF + -HRMS(m / z):387.2104[M+H] + ; 1H NMR(600MHz, DMSO-d6)δ8.66(s,1H),7.40~7.42(m,2H),7.35~7.37(m,3H),7.33~7.34(m,2H),7.27~7.32(m,6H),7.2 3~7.25(m,1H),7.44~7.48(m,1H),3.42(s,2H),2.56(s,2H),2.10~2.13(m,2H),1.72(d,J=9.78Hz,2H),1.41~1.46(m 2H); 13 C NMR(151MHz,DMSO-d6)δ153.84,139.13,138.37,137.41,134.65,130.13,128.60,128.5 2,128.13,128.05,127.71,127.03,126.88,126.76,125.95,69.95,61.81,50.12,30.63.

[0041] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0042] Synthesis of I-1:

[0043] Example 1

[0044] SM-1 (19.13 g, 0.10 mol) and triethylamine (28.33 g, 0.28 mol) were added to dichloromethane (100 ml). Phenyl chloroformate (SM-2-1, 25.05 g, 0.16 mol) was added while maintaining the temperature at 0–5 °C. The reaction was continued at 25–30 °C. After the reaction was confirmed to be complete, purified water (500 ml) was added to the reaction solution. The pH of the aqueous phase was adjusted to 2 with hydrochloric acid. The mixture was separated, and the aqueous phase was washed again with dichloromethane (150 ml × 2). The pH of the aqueous phase was adjusted to 10 with sodium hydroxide solution, and the mixture was extracted with dichloromethane (150 ml × 3). The organic phase was washed with saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 96.8% and a purity of 98.5%. The reaction route is as follows:

[0045]

[0046] Example 2

[0047] SM-1 (19.13 g, 0.10 mol) and K2CO3 (38.70 g, 0.28 mol) were added to dichloromethane (100 ml). Phenyl chloroformate (SM-2-1, 18.79 g, 0.12 mol) was added at a controlled temperature of 5–10 °C. The reaction was continued at a controlled temperature of 30–35 °C. After the reaction was confirmed to be complete, purified water (500 ml) was added to the reaction solution. The pH of the aqueous phase was adjusted to 2 with hydrochloric acid. The mixture was separated, and the aqueous phase was washed again with dichloromethane (150 ml × 2). The pH of the aqueous phase was adjusted to 10 with sodium hydroxide solution, and the mixture was extracted with dichloromethane (150 ml × 3). The organic phase was washed with saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 94.7% and a purity of 98.3%.

[0048] Example 3

[0049] SM-1 (19.13 g, 0.10 mol) and Na2CO3 (29.68 g, 0.28 mol) were added to dichloromethane (100 ml). Phenyl chloroformate (SM-2-1, 17.22 g, 0.11 mol) was added at a controlled temperature of 5–10 °C. The reaction was carried out at 35–40 °C. After the reaction was confirmed to be complete, purified water (500 ml) was added to the reaction solution. The pH of the aqueous phase was adjusted to 2 with hydrochloric acid. The mixture was separated, and the aqueous phase was washed with dichloromethane (150 ml × 2). The pH of the aqueous phase was adjusted to 10 with sodium hydroxide solution, and the mixture was extracted with dichloromethane (150 ml × 3). The organic phase was washed with saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 93.5% and a purity of 98.2%.

[0050] Example 4

[0051] SM-1 (19.13 g, 0.10 mol) and N,N-diisopropylethylamine (36.19 g, 0.28 mol) were added to dichloromethane (100 ml). Phenyl chloroformate (SM-2-1, 46.97 g, 0.30 mol) was added at a controlled temperature of -5 to 0 °C. The reaction was carried out at a controlled temperature of 20 to 25 °C. After the reaction was confirmed to be complete, purified water (500 ml) was added to the reaction solution. The pH of the aqueous phase was adjusted to 2 with hydrochloric acid. The mixture was separated, and the aqueous phase was washed again with dichloromethane (150 ml × 2). The pH of the aqueous phase was adjusted to 10 with sodium hydroxide solution, and the mixture was extracted with dichloromethane (150 ml × 3). The organic phase was washed with saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 95.8% and a purity of 97.6%.

[0052] Example 5

[0053] SM-1 (19.13 g, 0.10 mol) and pyridine (22.15 g, 0.28 mol) were added to dichloromethane (100 ml). Phenyl chloroformate (SM-2-1, 48.54 g, 0.31 mol) was added at a controlled temperature of -10 to 0 °C. The reaction was carried out at a controlled temperature of 15 to 20 °C. After the reaction was confirmed to be complete, purified water (500 ml) was added to the reaction solution. The pH of the aqueous phase was adjusted to 2 with hydrochloric acid. The mixture was separated, and the aqueous phase was washed again with dichloromethane (150 ml × 2). The pH of the aqueous phase was adjusted to 10 with sodium hydroxide solution. The mixture was extracted with methyl tert-butyl ether (150 ml × 3). The organic phase was washed with saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 95.7% and a purity of 97.5%.

[0054] Example 6

[0055] SM-1 (19.13 g, 0.10 mol) and triethylamine (22.26 g, 0.22 mol) were added to dichloromethane (100 ml). The mixture was heated to 5–10 °C, and then phenyl p-nitrochloroformate (SM-2-2, 32.25 g, 0.16 mol) was added. The reaction was continued at 30–35 °C. After the reaction was confirmed to be complete, purified water (500 ml) was added to the reaction solution. The pH of the aqueous phase was adjusted to 2 with hydrochloric acid. The mixture was separated, and the aqueous phase was washed again with dichloromethane (150 ml × 2). The pH of the aqueous phase was adjusted to 9 with sodium hydroxide solution, and then extracted with dichloromethane (150 ml × 3). The organic phase was washed with saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-2, with a yield of 95.1% and a purity of 98.0%. The reaction route is as follows:

[0056]

[0057] Example 7

[0058] SM-1 (19.13 g, 0.10 mol) and triethylamine (21.25 g, 0.21 mol) were added to chloroform (100 ml). Phenyl chloroformate (SM-2-1, 25.05 g, 0.16 mol) was added at a controlled temperature of 5–10 °C. The reaction was carried out at a controlled temperature of 30–35 °C. After the reaction was confirmed to be complete, purified water (500 ml) was added to the reaction solution. The pH of the aqueous phase was adjusted to 2 with hydrochloric acid. The mixture was separated, and the aqueous phase was washed with chloroform (150 ml × 2). The pH of the aqueous phase was adjusted to 10 with sodium hydroxide solution, and the mixture was extracted with chloroform (150 ml × 3). The organic phase was washed with saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 94.8% and a purity of 97.9%.

[0059] Example 8

[0060] SM-1 (19.13 g, 0.10 mol) and triethylamine (50.60 g, 0.50 mol) were added to dichloromethane (100 ml). Phenyl chloroformate (SM-2-1, 25.05 g, 0.16 mol) was added at -5 to 0 °C, and the reaction was carried out at 20 to 25 °C. After the reaction was confirmed to be complete, purified water (500 ml) was added to the reaction solution. The pH of the aqueous phase was adjusted to 3 with hydrochloric acid. The mixture was separated, and the aqueous phase was washed again with dichloromethane (150 ml × 2). The pH of the aqueous phase was adjusted to 10 with sodium hydroxide solution, and the mixture was extracted with ethyl acetate (150 ml × 3). The organic phase was washed with saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 95.6% and a purity of 97.8%.

[0061] Example 9

[0062] SM-1 (19.13 g, 0.10 mol) and triethylamine (51.61 g, 0.51 mol) were added to dichloromethane (100 ml). Phenyl chloroformate (SM-2-1, 25.05 g, 0.16 mol) was added at -5 to 0 °C, and the reaction was carried out at 20 to 25 °C. After the reaction was confirmed to be complete, purified water (500 ml) was added to the reaction solution. The pH of the aqueous phase was adjusted to 1 with hydrochloric acid. The mixture was separated, and the aqueous phase was washed with dichloromethane (150 ml × 2). The pH of the aqueous phase was adjusted to 10 with sodium hydroxide solution, and the mixture was extracted with chloroform (150 ml × 3). The organic phase was washed with saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 95.7% and a purity of 97.5%.

[0063] Synthesis of I:

[0064] Example 10

[0065] Intermediate I-1-1 (15.57 g, 0.05 mol) and SM-3 (10.15 g, 0.06 mol) were added to dichloromethane (120 ml). The reaction was carried out at a controlled temperature of 30–35 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure and then analyzed using a dichloromethane-methanol system (V... 二氯甲烷 :V 甲醇 The target product I was obtained by recrystallization (ratio 3:1, 50 ml) with a yield of 98.7% and a purity of 99.8%. The reaction route is as follows:

[0066]

[0067] Example 11

[0068] Intermediate I-1-1 (15.57 g, 0.05 mol) and SM-3 (9.31 g, 0.055 mol) were added to dichloromethane (120 ml). The reaction was carried out at a controlled temperature of 30–35 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure and then analyzed using a dichloromethane-methanol system (V). 二氯甲烷 :V 甲醇 The target product I was obtained by recrystallization at a ratio of 2:1 (40 ml), with a yield of 97.5% and a purity of 99.6%.

[0069] Example 12

[0070] Intermediate I-1-1 (15.57 g, 0.05 mol) and SM-3 (8.88 g, 0.0525 mol) were added to dichloromethane (120 ml). The reaction was carried out at a controlled temperature of 45–50 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure and then analyzed using a dichloromethane-methanol system (V... 二氯甲烷 :V 甲醇 The target product I was obtained by recrystallization (4:1, 70 ml) with a yield of 96.3% and a purity of 99.6%.

[0071] Example 13

[0072] Intermediate I-1-1 (15.57 g, 0.05 mol) and SM-3 (12.69 g, 0.075 mol) were added to dichloromethane (120 ml). The reaction was carried out at a controlled temperature of 25–30 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure and then analyzed using a dichloromethane-methanol system (V... 二氯甲烷 :V 甲醇 The target product I was obtained by recrystallization at a ratio of 3:1 (50 ml), with a yield of 97.6% and a purity of 99.7%.

[0073] Example 14

[0074] Intermediate I-1-1 (15.57 g, 0.05 mol) and SM-3 (13.54 g, 0.08 mol) were added to dichloromethane (120 ml). The reaction was carried out at a controlled temperature of 20–25 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure and then analyzed using a dichloromethane-methanol system (V... 二氯甲烷 :V 甲醇 The target product I was obtained by recrystallization at a ratio of 3:1 (50 ml), with a yield of 96.7% and a purity of 99.5%.

[0075] Example 15

[0076] Intermediate I-1-2 (17.82 g, 0.05 mol) and SM-3 (10.15 g, 0.06 mol) were added to chloroform (120 ml). The reaction was carried out at a controlled temperature of 30–35 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure and then subjected to a dichloromethane-methanol system (V... 二氯甲烷 :V 甲醇 The target product I was obtained by recrystallization (ratio 3:1, 50 ml) with a yield of 98.4% and a purity of 99.7%. The reaction route is as follows:

[0077]

Claims

1. A method for preparing a revanasine intermediate, characterized in that, The process includes the following steps: 1-Benzylpiperidin-4-ol is acylated with SM-2 to obtain intermediate I-1, and intermediate I-1 is aminolyzed with [1,1'-biphenyl]-2-amine to obtain the target compound 1-benzylpiperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate, as shown in the following reaction formula: ； Where R is H or NO2.

2. The preparation method according to claim 1, characterized in that, The specific steps are as follows: Step 1. Add SM-1 and the acid-binding agent to the reaction solvent, and control the temperature T. 1A Add SM-2, temperature control T 1B After the reaction is completed, intermediate I-1 is obtained through post-processing; Step 2. Add intermediates I-1 and SM-3 to the reaction solvent, control the temperature until the reaction is complete, and obtain the target compound I after post-treatment.

3. The preparation method according to claim 1 or 2, characterized in that, The SM-2 mentioned in step 1 is either phenyl chloroformate or phenyl p-nitrochloroformate.

4. The preparation method according to claim 2, characterized in that, The acid-binding agent mentioned in step 1 is K2CO3, Na2CO3, triethylamine, N , N - One or a combination of diisopropylethylamine, pyridine.

5. The preparation method according to claim 2, characterized in that, The reaction solvents mentioned in steps 1 and 2 are one or a combination of dichloromethane and chloroform.

6. The preparation method according to claim 2, characterized in that, The molar ratio of SM-1 to SM-2 and the acid-binding agent mentioned in step 1 is 1: 1.2-3.0: 2.2-5.0; the T mentioned in step 1 1A -10 to 10℃; reaction temperature T 1B The temperature ranges from 15 to 40 degrees Celsius.

7. The preparation method according to claim 2, characterized in that, The T mentioned in step 1 1A The temperature ranges from 0 to 5℃; the reaction temperature T 1B The temperature is 25-30℃.

8. The preparation method according to claim 2, characterized in that, The molar ratio of I-1 to SM-3 in step 2 is 1:1.1 to 2.5; the reaction temperature in step 2 is 20 to 50°C.

9. The preparation method according to claim 2, characterized in that, The reaction temperature described in step 2 is 30–35°C.

10. The preparation method according to claim 2, characterized in that, The post-processing steps described in step 1 are as follows: Add purified water to the reaction solution, adjust the pH of the aqueous phase to 1-3 with hydrochloric acid, separate the phases, continue washing the aqueous phase with dichloromethane, adjust the pH of the aqueous phase to 9-10 with sodium hydroxide solution, extract with organic solvent, wash the organic phase with saturated brine, dry, filter, and concentrate the filtrate to dryness under reduced pressure to obtain intermediate I-1.

11. The preparation method according to claim 10, characterized in that, The extraction solvent is one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether.

12. The preparation method according to claim 2, characterized in that, The post-processing steps described in step 2 are as follows: After the reaction is complete, the reaction solution is concentrated to dryness under reduced pressure, and then recrystallized from the dichloromethane-methanol system to obtain the target product I.

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