Process for the preparation of a pegvisomant intermediate

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a plerixafor intermediate. The preparation method of the plerixafor intermediate 1,4,8,11-tetraazacyclotetradecane provided by the application is as follows: N,N'-di(2-aminoethyl)-1,3-propanediamine is used as a starting material, is reacted with N,N-dimethylformamide dimethyl acetal, is then cyclized with 1,3-dibromopropane, and is hydrolyzed by an alkali to obtain a target product, so that the whole synthesis method is simple in operation and 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 plexafor intermediate. Background Technology

[0002] Plerixafor, marketed as Mozobil, is a small-molecule monoclonal antibody targeted therapy developed by Genzyme Corporation. It was first approved by the FDA as an orphan drug in December 2008, and two years later, in July 2010, it was approved for clinical use in my country. This drug is a hematopoietic stem cell activator, stimulating the proliferation and differentiation of hematopoietic stem cells into the bloodstream. Since most remission and progression cases of non-Hodgkin's lymphoma and multiple myeloma require peripheral blood autologous hematopoietic stem cell transplantation, plerixafor combined with G-CSF can significantly increase the number of CD34+ cells in the peripheral blood of patients, ensuring the success of autologous hematopoietic stem cell transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. Clinical studies have shown that praxavir can significantly increase the number of white blood cells in patients and promote the flow of hematopoietic stem cells from the bone marrow into the bloodstream, and has a synergistic effect with granulocyte colony-stimulating factor (G-CSF); it has been used in the clinical treatment of stem cell transplantation for patients with multiple myeloma and non-Hodgkin lymphoma.

[0003] Plorazor belongs to the class of azahexacyclic compounds, with the chemical name 1,1'-[1,4-phenylene di(methylene)]-di-1,4,8,11-tetraazacyclotetradecane, and its chemical structural formula is as follows:

[0004]

[0005] Currently, there are many publicly disclosed methods for the preparation of plerixafor, such as patents WO0028987, WO0226721A1, WO2014125499A1, IN2011CH2459, CN1273455C and literature Inorg.Chem., 1987, 26(21):3527-3533, Tetrahedron Letters, 44(2003)2481-2483, Bioorg.Med.Chem., 2009, 17(4):1486-1493, J.Med.Chem., 1995, 38, 2, 366-378, J.Med.Chem., 1999, 42, 2, 229-241, Synthesis of plerixafor, China Pharmaceutical Industry Magazine, 2 007,38(6):398-400、Improved Synthesis Process of Plexafor, Synthetic Chemistry, 2015,23(8):774-777 Using 1,4,8,11-tetraazacyclotetradecane as raw material, after N1, N4, N8 triple protection, it is bridged with 1,4-di(halomethyl)benzene, and deprotected to obtain the finished product, where R is p-toluenesulfonyl, methanesulfonyl, trifluoroacetyl, tert-butoxycarbonyl, etc. The synthetic route is as follows:

[0006]

[0007] The synthetic process of the antitumor drug praxavir was studied in the Journal of Suzhou University, 2018, 33(10):107-109. Using DMF-DMA as a protecting group, selective triprotection of 1,4,8,11-tetraazacyclotetradecane was achieved at N1, N4, and N8-, without the need for column separation. The deprotection conditions were mild, and the overall yield was 60.37%. However, this process requires strict anhydrous treatment of the reaction solvent and argon protection during the addition of the protecting group, making the operation relatively cumbersome. The synthetic route is as follows:

[0008]

[0009] The literature New J. Chem., 2001, 25, 1168-1174 and WO2017037639A1 describes a synthetic route that uses N,N'-bis(2-aminoethyl)-1,3-propanediamine and glyoxal as starting materials, followed by reaction with 1,4-dibromomethylbenzene and hydrolysis to obtain the target product. The synthetic route is as follows:

[0010]

[0011] The literature Org. Prep. Proced. Int., 50:588-591, 2018 directly uses 1,4,8,11-tetraazacyclotetradecane and 1,4-dibromomethylbenzene as raw materials to obtain the target product with a high yield of 92% and a high purity of 99.6% under the action of a phase transfer catalyst, but this process has not been scaled up for verification. The synthetic route is as follows:

[0012]

[0013] As shown above, 1,4,8,11-tetraazacyclotetradecane (cyclam) is used as a key intermediate in the preparation of plexafor in various synthetic strategies. Therefore, cyclam can directly affect the production, market supply, and quality of this drug. Its structural formula is shown below:

[0014]

[0015] Currently, the main methods for preparing cyclam include the following:

[0016] In US patent US5811544A, 1,3-diaminopropane is used as a starting material. It first reacts with 2 equiv of chloroacetyl chloride to generate an amide, then reacts with 1 equiv of 1,3-diaminopropane for cyclization, followed by reduction with 65% red aluminum toluene solution to obtain cyclam. Although the literature describes only three steps, the second step, the high-temperature cyclization of 1,3-diaminopropane and the amide generated in the first step, takes a long time (24 hours), and the cyclized product is impure, producing numerous impurities as shown below. This requires column chromatography purification, limiting its industrial application. The synthetic route is as follows:

[0017]

[0018] International patent WO9705123A1 describes a method using bis-(3-aminopropyl)ethylenediamine as a starting material. First, it undergoes sulfonation with p-toluenesulfonyl chloride, followed by cyclization with 1,2-bis(p-toluenesulfonyloxy)ethane. The protection is then removed by reaction with 48% hydrobromic acid and glacial acetic acid, and finally, alkalization yields cyclam. The advantages of this method are high yields in the first substitution step and the second cyclization step, and a significantly shortened cyclization time in the second step. However, the use of a 48% hydrobromic acid / glacial acetic acid system for Ts removal results in a yield of only 72.0%, affecting the overall yield. The synthetic route is as follows:

[0019]

[0020] The literature Tetrahedron Letters, 1992, 33(38):5505-5508 describes a method using bis-(3-aminopropyl)ethylenediamine as a starting material. First, it undergoes sulfonation with trifluoromethanesulfonic anhydride, followed by cyclization with 1,2-dibromoethane in the presence of potassium carbonate. Finally, the protecting group is removed using sodium / liquid ammonia to obtain cyclam. This method has several drawbacks. The first step uses trifluoromethanesulfonic anhydride as the sulfonating agent, resulting in a low yield. The second step requires a cyclization temperature of 110℃, which is too high and prone to side reactions. The third step involves the removal of the trifluoromethanesulfonyl group, using sodium / liquid ammonia, and requires dropwise addition at -33℃, making the process complex and unsuitable for industrial application. The combined yield of the second and third steps is only 57.2%. The synthetic route is as follows:

[0021]

[0022] In the literature Bulletin of the Academy of Sciences of the USSR Division of Chemical Science, 36(2):372-376, ethylenediamine was used as a raw material, and it underwent a substitution reaction with 1,3-dibromopropane to generate di(2-aminoethyl)propanediamine. Then, it was sulfonated with p-toluenesulfonyl chloride under the action of sodium ethoxide, and then cyclamed with 1,3-bis(p-toluenesulfonyloxy)propane. Finally, it was deprotected with concentrated sulfuric acid and alkalized to obtain cyclam.

[0023] However, this method uses ethylenediamine as a starting material, which undergoes a substitution reaction with 1,3-dibromopropane to generate di(2-aminoethyl)propanediamine, readily producing cyclopentane as a byproduct. The yield of this step is low, only 42.0%. Sulfonation with p-toluenesulfonyl chloride under the action of sodium ethoxide yields only 52.1%; cyclization with 1,3-bis(p-toluenesulfonyloxy)propane yields 65.3%; and finally, deprotection with concentrated sulfuric acid yields 81.0%. As can be seen, the overall yield of this method is not high. The synthetic route is as follows:

[0024]

[0025] Arkivoc, 2006(4):212-233. Cycloam is obtained by cyclizing 1,3-propanediamine with diethyl oxalate to form an amide, followed by reduction with borane, and finally acidification followed by alkalization. This method uses ultrasound during the borane reduction process after cyclization with 1,3-propanediamine and diethyl oxalate, resulting in a total yield of only 19.0%, making it unsuitable for industrial scale-up. The synthetic route is as follows:

[0026]

[0027] Given the many shortcomings in the current preparation of cyclam, finding a simple, mild, safe, and easy-to-operate preparation process suitable for industrial-scale cyclam production, with high product yield and purity, remains a problem that needs to be solved. Summary of the Invention

[0028] To address the numerous problems existing in the current preparation of 1,4,8,11-tetraazacyclotetradecane, a plerusoxuridine-related intermediate, this invention provides a novel method for preparing 1,4,8,11-tetraazacyclotetradecane. This method features mild reaction conditions, a safe and simple operation, and yields a target product with high purity and yield.

[0029] The specific technical solution of the present invention is as follows:

[0030] A method for preparing the plexafor intermediate 1,4,8,11-tetraazacyclotetradecane, characterized in that the preparation method includes the following steps:

[0031] Step 1: At room temperature, add compound SM-1 and N,N-dimethylformamide dimethyl acetal (DMF-DMA) to organic solvent A, and control the temperature T. A After the reaction was completed, compound I-1 was obtained through post-treatment.

[0032] Step 2: At room temperature, add the acid-binding agent to organic solvent B, and control the temperature T. B Add the solvent B solution of compound I-1 and 1,3-dibromopropane. After the addition is complete, continue to control the temperature at T. B After the reaction was completed and detected, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. Then, in a sealed apparatus, it was added to an aqueous solution of alkali, and the temperature was controlled at T. C The reaction was completed, and after post-processing, compound I was obtained.

[0033] The synthesis route is as follows:

[0034]

[0035] Preferably, the organic solvent A mentioned in step 1 is selected from toluene, xylene or a combination thereof, with toluene being the most preferred.

[0036] Preferably, the molar ratio of compound SM-1 to N,N-dimethylformamide dimethyl acetal in step 1 is 1:2.0 to 3.0, more preferably 1:2.3.

[0037] Preferably, the reaction temperature T in step 1 A The temperature range is 100–140℃, with 105–110℃ being preferred.

[0038] Preferably, the acid-binding agent mentioned in step 2 is selected from potassium carbonate and sodium carbonate.

[0039] Preferably, the organic solvent B mentioned in step 2 is selected from one or a combination of acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide, with acetonitrile being the most preferred.

[0040] Preferably, the alkali mentioned in step 2 is selected from one or a combination of NaOH, KOH, and LiOH, with KOH being the most preferred.

[0041] Preferably, the molar ratio of compound I-1, 1,3-dibromopropane, acid binder, and base in step 2 is 1:1.1-1.8:1.05-1.5:8-15, more preferably 1:1.3:1.2:12.

[0042] Preferably, the reaction temperature T in step 2 B The temperature should be 70–100℃, preferably 75–80℃; T C The temperature range is 80–100℃, preferably 95–100℃.

[0043] In a preferred embodiment, post-processing is required after the reaction is completed. The post-processing of step 1 is as follows: the reaction solution is cooled and concentrated to dryness under reduced pressure, and then recrystallized from tetrahydrofuran to obtain compound I-1. The post-processing of step 2 is as follows: toluene is added to the reaction solution, and the mixture is extracted and filtered at 90-95°C. The organic phases are combined, washed with saturated sodium carbonate, washed with saturated brine, and the organic phase is concentrated to dryness under reduced pressure to obtain the target product I.

[0044] The beneficial effects of this invention are:

[0045] 1. This invention provides a simple and efficient method for preparing the plexafor-related intermediate 1,4,8,11-tetraazacyclotetradecane. Starting with N,N'-di(2-aminoethyl)-1,3-propanediamine, it is first reacted with N,N-dimethylformamide dimethyl acetal, then cyclized with 1,3-dibromopropane, and finally hydrolyzed with alkaline solution to obtain the target product. The entire synthesis method is simple to operate and suitable for industrial production.

[0046] 2. This process effectively avoids the introduction and removal of protecting groups such as Ts- by changing the reaction conditions, resulting in high atom economy, shortened reaction steps, and reduced production time.

[0047] 3. The target product obtained by this process has a high yield and purity. Detailed Implementation

[0048] 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.

[0049] This invention uses HPLC to determine the purity of cyclam, and the chromatographic conditions are as follows:

[0050] Column: Kromasil 100-5-C 18 A 4.6×250mm or equivalent chromatographic column and a ghost peak trapping column (Welch Ghost-Buster Column 4.6×50mm is recommended);

[0051] Column: Supelco LC-ABE C 18 Column (4.6 mm × 150 mm, 5 μm) or equivalent chromatographic column;

[0052] Mobile phase A: 0.1% aqueous phosphoric acid solution; Mobile phase B: acetonitrile;

[0053] Acetonitrile: 25 mmol / L ammonium dihydrogen phosphate (adjusted to pH 5.0 with sodium hydroxide) (25:75);

[0054] Gradient elution:

[0055]

[0056] Column temperature: 30℃;

[0057] Detection wavelength: 200nm;

[0058] Flow rate: 1.2 ml / min;

[0059] Injection volume: 10 μl.

[0060] The structural confirmation data of compound I-1 obtained in this invention are as follows:

[0061]

[0062] ESI-HRMS (m / z): 181.1327 [M+H] + ; 1 H NMR (600MHz, CDCl3) δ: 7.51 (s, 2H), 3.51 (t, J = 6.4Hz, 2H), 3.34 (t, J = 6.4Hz, 2H) ),3.24~3.27(m,2H),3.10~3.13(m,4H),3.01~3.04(m,2H),1.85~1.87(m,2H); 13C NMR (125MHz, CDCl3) δ: 145.67, 55.15, 52.92, 48.89, 23.60.

[0063] The structural confirmation data for compound I obtained in this invention are as follows:

[0064]

[0065] ESI-HRMS (m / z): 201.2035 [M+H] + ; 1 H NMR (600MHz, CDCl3) δ: 2.76 (t, J = 6.4Hz, 8H), 2.70 (s, 8H), 2.18 (s, 4H), 1.73 ~ 1.75 (m, 4H); 13 C NMR (125MHz, CDCl3) δ: 50.03, 47.64, 30.15.

[0066] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0067] Synthesis of I-1:

[0068] Example 1

[0069] At room temperature, compound SM-1 (32.05 g, 0.2 mol) and DMF-DMA (54.82 g, 0.46 mol) were added to toluene (300 ml), and the reaction was carried out at 105–110 °C. After the reaction was completed, the reaction solution was cooled and concentrated to dryness under reduced pressure. After recrystallization from tetrahydrofuran (120 ml), compound I-1 was obtained with a yield of 98.6% and a purity of 99.89%.

[0070] Example 2

[0071] At room temperature, compound SM-1 (32.05 g, 0.2 mol) and DMF-DMA (47.67 g, 0.40 mol) were added to xylene (300 ml), and the reaction was carried out at 120–125 °C. After the reaction was completed, the reaction solution was cooled and concentrated to dryness under reduced pressure. After recrystallization from tetrahydrofuran, compound I-1 was obtained with a yield of 93.6% and a purity of 99.55%.

[0072] Example 3

[0073] At room temperature, compound SM-1 (32.05 g, 0.2 mol) and DMF-DMA (42.90 g, 0.36 mol) were added to toluene (300 ml), and the reaction was carried out at 95–100 °C. After the reaction was completed, the reaction solution was cooled and concentrated to dryness under reduced pressure. After recrystallization from tetrahydrofuran (120 ml), compound I-1 was obtained, with a yield of 85.6% and a purity of 95.66%.

[0074] Example 4

[0075] At room temperature, compound SM-1 (32.05 g, 0.2 mol) and DMF-DMA (71.50 g, 0.6 mol) were added to xylene (300 ml), and the reaction was carried out at 135–140 °C. After the reaction was completed, the reaction solution was cooled and concentrated to dryness under reduced pressure. After recrystallization from tetrahydrofuran (120 ml), compound I-1 was obtained, with a yield of 95.3% and a purity of 99.36%.

[0076] Example 5

[0077] At room temperature, compound SM-1 (32.05 g, 0.2 mol) and DMF-DMA (76.26 g, 0.64 mol) were added to xylene (300 ml), and the reaction was carried out at 140–145 °C. After the reaction was completed, the reaction solution was cooled and concentrated to dryness under reduced pressure. After recrystallization from tetrahydrofuran (120 ml), compound I-1 was obtained, with a yield of 86.3% and a purity of 92.56%.

[0078] Synthesis of I

[0079] Example 6

[0080] At room temperature, potassium carbonate (16.58 g, 0.12 mol) was added to acetonitrile (90 ml). The temperature was maintained at 75–80 °C. A solution of compound I-1 (18.02 g, 0.10 mol) and 1,3-dibromopropane (26.25 g, 0.13 mol) in acetonitrile (60 ml) was then added. After the addition was complete, the reaction was continued at 75–80 °C. Once the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The solution was then transferred to a sealed container and... The solution of potassium hydroxide (67.33 g, 1.2 mol) in purified water (240 ml) was added and the reaction was carried out at a controlled temperature of 95–100 °C. After the reaction was completed, toluene (80 ml × 4) was added to the reaction solution, and the mixture was extracted and filtered at 90–95 °C. The organic phases were combined, washed with saturated sodium carbonate (80 ml), washed with saturated brine (80 ml), and concentrated under reduced pressure to dryness to obtain the target product I, with a yield of 98.8% and an HPLC purity of 99.92%.

[0081] Example 7

[0082] At room temperature, potassium carbonate (16.58 g, 0.12 mol) was added to acetonitrile (90 ml). The temperature was maintained at 70–75 °C. Then, a solution of compound I-1 (18.02 g, 0.10 mol) and 1,3-dibromopropane (22.21 g, 0.11 mol) in acetonitrile (60 ml) was added. After the addition was complete, the reaction was continued at 70–75 °C. Once the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The solution was then placed in a sealed apparatus and... The solution of potassium hydroxide (44.89 g, 0.8 mol) in purified water (240 ml) was added and the reaction was carried out at 70–75 °C. After the reaction was completed, toluene (80 ml × 4) was added to the reaction solution and the mixture was extracted and filtered at 90–95 °C. The organic phases were combined, washed with saturated sodium carbonate (80 ml), washed with saturated brine (80 ml), and concentrated under reduced pressure to dryness to obtain the target product I, with a yield of 93.3% and an HPLC purity of 99.68%.

[0083] Example 8

[0084] At room temperature, potassium carbonate (16.58 g, 0.12 mol) was added to acetonitrile (90 ml). The temperature was maintained at 75–80 °C. Then, a solution of compound I-1 (18.02 g, 0.10 mol) and 1,3-dibromopropane (36.34 g, 0.18 mol) in acetonitrile (60 ml) was added. After the addition was complete, the reaction was continued at 75–80 °C. Once the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The solution was then transferred to a sealed container and... The solution of potassium hydroxide (84.16 g, 1.5 mol) in purified water (240 ml) was added and the reaction was carried out at a controlled temperature of 95–100 °C. After the reaction was completed, toluene (80 ml × 4) was added to the reaction solution, and the mixture was extracted and filtered at 90–95 °C. The organic phases were combined, washed with saturated sodium carbonate (80 ml), washed with saturated brine (80 ml), and concentrated under reduced pressure to dryness to obtain the target product I, with a yield of 94.8% and an HPLC purity of 99.52%.

[0085] Example 9

[0086] At room temperature, potassium carbonate (14.51 g, 0.105 mol) was added to N,N-dimethylformamide (90 ml). The mixture was then added to a solution of compound I-1 (18.02 g, 0.10 mol) and 1,3-dibromopropane (26.25 g, 0.13 mol) in N,N-dimethylformamide (60 ml) while maintaining the temperature at 95–100 °C. After the addition was complete, the reaction was continued at 95–100 °C. Once the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. In a closed apparatus, sodium hydroxide (48.0 g, 1.2 mol) was added to a purified water solution (240 ml), and the reaction was carried out at a controlled temperature of 95–100 °C. After the reaction was detected to be complete, toluene (80 ml × 4) was added to the reaction solution, and the mixture was extracted and filtered at 90–95 °C. The organic phases were combined, washed with saturated sodium carbonate (80 ml), washed with saturated brine (80 ml), and the organic phase was concentrated to dryness under reduced pressure to obtain the target product I, with a yield of 94.3% and an HPLC purity of 99.68%.

[0087] Example 10

[0088] At room temperature, sodium carbonate (15.90 g, 0.15 mol) was added to N,N-dimethylformamide (90 ml). The mixture was then added to a solution of compound I-1 (18.02 g, 0.10 mol) and 1,3-dibromopropane (26.25 g, 0.13 mol) in N,N-dimethylformamide (60 ml) at a controlled temperature of 75–80 °C. After the addition was complete, the reaction was continued at 75–80 °C. Once the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. In a closed apparatus, lithium hydroxide (28.74 g, 1.2 mol) was added to a purified water (240 ml) solution, and the reaction was carried out at a controlled temperature of 95–100 °C. After the reaction was detected to be complete, toluene (80 ml × 4) was added to the reaction solution, and the mixture was extracted and filtered at 90–95 °C. The organic phases were combined, washed with saturated sodium carbonate (80 ml), washed with saturated brine (80 ml), and the organic phase was concentrated to dryness under reduced pressure to obtain the target product I, with a yield of 95.0% and an HPLC purity of 99.40%.

[0089] Example 11

[0090] At room temperature, potassium carbonate (13.82 g, 0.1 mol) was added to acetonitrile (90 ml). A solution of compound I-1 (18.02 g, 0.10 mol) and 1,3-dibromopropane (20.19 g, 0.1 mol) in acetonitrile (60 ml) was added while maintaining the temperature at 65–70 °C. After the addition was complete, the reaction was continued at 65–70 °C. Once the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The solution was then transferred to a sealed container and added to… Potassium hydroxide (39.28 g, 0.7 mol) was reacted in purified water (240 ml) at a controlled temperature of 75–80 °C. After the reaction was detected to be complete, toluene (80 ml × 4) was added to the reaction solution, and the mixture was extracted and filtered at 90–95 °C. The organic phases were combined, washed with saturated sodium carbonate (80 ml), washed with saturated brine (80 ml), and concentrated under reduced pressure to dryness to obtain the target product I, with a yield of 83.2% and an HPLC purity of 98.65%.

[0091] Example 12

[0092] At room temperature, potassium carbonate (24.50 g, 0.17 mol) was added to N,N-dimethylacetamide (90 ml). The temperature was maintained at 100–105 °C. A solution of compound I-1 (18.02 g, 0.10 mol) and 1,3-dibromopropane (40.38 g, 0.2 mol) in N,N-dimethylacetamide (60 ml) was then added. After the addition was complete, the reaction was continued at 100–105 °C. Once the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. In a closed apparatus, potassium hydroxide (95.39 g, 1.7 mol) was added to a purified water solution (240 ml). The reaction was carried out at a controlled temperature of 100–105 °C. After the reaction was detected to be complete, toluene (80 ml × 4) was added to the reaction solution, and the mixture was extracted and filtered at 90–95 °C. The organic phases were combined, washed with saturated sodium carbonate (80 ml), washed with saturated brine (80 ml), and concentrated under reduced pressure to dryness to obtain the target product I, with a yield of 85.0% and an HPLC purity of 97.89%.

Claims

1. A method for preparing a plexafor intermediate, characterized in that, The preparation method includes the following steps: Step 1: At room temperature, 32.05 g of compound SM-1 and 54.82 g of DMF-DMA were added to 300 ml of toluene and reacted at a controlled temperature of 105~110℃. After the reaction was completed, the reaction solution was cooled and concentrated to dryness under reduced pressure. After recrystallization from 120 ml of tetrahydrofuran, compound I-1 was obtained. Step 2: At room temperature, add 16.58 g of potassium carbonate to 90 ml of acetonitrile. While maintaining the temperature at 75-80℃, add 18.02 g of compound I-1 and 26.25 g of 1,3-dibromopropane in 60 ml of acetonitrile solution. After the addition is complete, continue the reaction at 75-80℃. After the reaction is complete, filter the reaction solution and concentrate the filtrate to dryness under reduced pressure. In a closed apparatus, add the filtrate to 240 ml of purified aqueous solution containing 67.33 g of potassium hydroxide. Continue the reaction at 95-100℃. After the reaction is complete, add toluene to the reaction solution and extract and filter at 90-95℃. Combine the organic phases, wash with saturated sodium carbonate and saturated brine, and concentrate the organic phase to dryness under reduced pressure to obtain the target product I. The synthesis route is as follows: 。

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