Synthesis of a resmelitide intermediate

Abstract

The present application provides a synthesis method of a key intermediate of resmetirom, a compound of formula V, which comprises the following steps: subjecting a compound of formula IV to a hydrolysis reaction, or to a hydrolysis reaction and a deprotection reaction, to obtain a compound of formula V, wherein the compound of formula IV is obtained by subjecting a compound of formula II to a coupling reaction with a compound of formula III, as shown in the following reaction formula. The synthesis method has the advantages of short steps, high yield, low production cost, high purity of the obtained product, and suitability for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis, and more specifically, relates to a method for synthesizing resmetiro intermediates. Background Technology

[0002] On June 30, 2023, Madrigal Pharmaceuticals announced that it had submitted a rolling New Drug Application (NDA) to the FDA for resmetirom, an orally selective thyroid hormone receptor (THR)-β agonist for the treatment of patients with non-alcoholic steatohepatitis (NASH) with liver fibrosis. THR-β is highly expressed in the human liver and can regulate lipid metabolism, reducing LDL-C, triglycerides, and atherogenic lipoproteins. Furthermore, THR-β can reduce lipotoxicity and improve liver function by promoting fatty acid breakdown and stimulating mitochondrial biogeneration, thereby reducing hepatic fat. Therefore, THR-β agonists have the potential to regulate multiple hepatic metabolic pathways to treat NASH. Its structure is shown below:

[0003]

[0004] Regarding the synthesis methods of resimeltiro, there are currently only two synthetic routes reported by the original research company. Route 1 is the route disclosed in existing technology WO2007009913, as follows:

[0005]

[0006] Route 1

[0007] In this route, compound I is coupled with compound III-1 to obtain compound A2. Compound A2 is then hydrolyzed to obtain compound V. Subsequently, N-cyanoacetylurane (A3) reacts with compound V via a diazotization reaction to synthesize compound A4. Finally, compound A4 undergoes a cyclization reaction to obtain resmetiro. The biggest drawback of this route is that the coupling reaction in the first step lacks significant regioselectivity, resulting in a yield of only 50%. This low regioselectivity increases the difficulty of purifying compound A2, making it difficult to obtain a high-purity intermediate. In the second step, due to the low reactivity of chloropyridazine, the hydrolysis yield is also only 57%. The low yields of the first and second steps significantly reduce the overall yield of the route to only 13.2%, which is inconsistent with green chemistry and unfavorable for industrial production.

[0008] Route 2 is the route disclosed in existing technology WO2014043706, as follows:

[0009]

[0010] Route 2

[0011] To address the low regioselectivity of the compound route, this route used 3,6-dichloropyridazine (compound B1) in the coupling reaction to obtain a single-configuration compound B3. However, to introduce the isopropyl group, protection and deprotection steps of the amino group were necessary. The synthesis of the key intermediate, compound V, increased from two steps in route 1 to six steps, increasing the effective yield from 28% to 61.6%. Although the yield was significantly improved, the excessively long synthetic steps and cumbersome experimental operations greatly increased the production cost of the product. Furthermore, the synthesis used expensive and moisture-sensitive isopropenyl magnesium bromide, making the reaction conditions even more demanding.

[0012] In summary, existing synthetic methods for resimetiro suffer from drawbacks such as poor regioselectivity, long routes, and demanding conditions, making them unsuitable for industrial application and resulting in high product costs. The main problem stems from the synthesis of the key intermediate compound V. Therefore, there is an urgent need in the field to develop a low-cost, high-yield, simple, and industrially suitable method for synthesizing resimetiro intermediates. Summary of the Invention

[0013] To address the shortcomings in the preparation of the resimeltiro intermediate compound V in existing technologies, this invention provides a method for synthesizing compound V. This method is characterized by short steps, high yield, simple operation, and suitability for industrial production. To achieve the objectives of this invention, the following technical solution is adopted:

[0014] The method for synthesizing compound V includes the following steps:

[0015] Compound IV is subjected to hydrolysis, or hydrolysis and deamination, to obtain compound V, as shown in the following reaction formula:

[0016]

[0017] In Formula IV, R1 is an H or an amino protecting group.

[0018] In another preferred embodiment, R1 is H, Ac, or Bz.

[0019] In another preferred embodiment, when R1 is H, the hydrolysis reaction is carried out in the presence of a base or acid. The base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, or combinations thereof. In another more preferred embodiment, the base is selected from sodium hydroxide. In another preferred embodiment, the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In another more preferred embodiment, the acid is selected from hydrochloric acid.

[0020] In another preferred embodiment, when R1 is H or an amino protecting group, the hydrolysis reaction and the deamination reaction occur simultaneously in the presence of a base or acid. In another preferred embodiment, the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, or combinations thereof. In another more preferred embodiment, the base is selected from sodium hydroxide. In another preferred embodiment, the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In another more preferred embodiment, the acid is selected from hydrochloric acid.

[0021] In another preferred embodiment, the method for synthesizing compound V includes the following steps:

[0022] The compound of formula II and the compound of formula III are coupled together to give the compound of formula IV, as shown in the following reaction formula:

[0023]

[0024] In another preferred embodiment, the coupling reaction is carried out in the presence of a base selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, or combinations thereof. In yet another more preferred embodiment, the base is selected from potassium carbonate.

[0025] In another preferred embodiment, the method for synthesizing compound IV includes the following steps:

[0026] Reacting compound I with a fluorine reagent yields compound II.

[0027]

[0028] In another preferred embodiment, the fluorinating agent is selected from sodium fluoride, potassium fluoride, TBAF and ammonium fluoride or combinations thereof, more preferably sodium fluoride.

[0029] In another preferred embodiment, the method for synthesizing compound V includes the following steps:

[0030] (1) Reacting compound I with a fluorine reagent to produce compound II, the reaction is as follows:

[0031]

[0032] In another preferred embodiment, the method for synthesizing compound V further includes the following steps:

[0033] (2) A coupling reaction is carried out between compound II and compound III to generate compound IV.

[0034]

[0035] In Formulas III and IV, R1 is H or an amino protecting group, more preferably, R1 is H, Ac or Bz.

[0036] In another preferred embodiment, the method for synthesizing compound V further includes the following steps:

[0037] (3) Hydrolyze compound IV, or hydrolyze and deamination reaction, to obtain compound V, as shown in the following reaction formula:

[0038]

[0039] The present invention also provides a compound of formula V or a salt thereof, having a purity of not less than 99.0%.

[0040]

[0041] It contains one or more of the following impurities:

[0042] The content of each of the one or more impurities is not greater than 0.3%.

[0043] as well as

[0044] Other unknown impurities, optionally in a concentration not exceeding 0.1%.

[0045] In another preferred embodiment, the compound of formula V or a salt thereof is obtained using the synthetic method of the compound of formula V of the present invention. Attached Figure Description

[0046] Figure 1 The compound of formula I obtained in Example 1 1 H-NMR spectrum;

[0047] Figure 2 Compound IV-1 obtained in Example 3 1 H-NMR spectrum;

[0048] Figure 3 Compound IV-2 obtained in Example 5 1 H-NMR spectrum;

[0049] Figure 4 Compound V obtained in Example 6 1 H-NMR spectrum;

[0050] Figure 5 The HPLC chromatogram of compound V obtained in Example 6; Detailed Implementation

[0051] To address the shortcomings of existing methods for synthesizing the intermediate of formula V, resmetidine, the inventors of this application, through in-depth research, discovered that replacing the dichloropyridazine in the starting material with difluorine can solve the problem of poor regioselectivity in the coupling reaction between the starting material and 2,6-dichloro-4-aminophenol, significantly improving the yield. Furthermore, the introduction of the fluorine atom enhances the hydrolytic activity of the resulting pyridazine compound, greatly increasing the yield of the hydrolysis step to obtain compound V. This method demonstrates significant advantages in terms of experimental operability and cost.

[0052] Synthesis of Compound II

[0053] The compound of formula II in this invention is synthesized through the following steps:

[0054] (1) React compound I with a fluorine reagent to produce compound II.

[0055]

[0056] Fluorinating agents that can be used in this invention include, but are not limited to, sodium fluoride, potassium fluoride, TBAF, and ammonium fluoride. The amount of fluorinating agent used is the amount commonly used in the art for carrying out such reactions; for example, the molar ratio of the fluorinating agent to the compound of formula I is 2 to 6:1, more preferably 3.0 to 5.0:1.

[0057] The reaction solvent used in this step is a commonly used solvent in the art for carrying out such reactions, such as DMF, DMSO, DMAc, etc.

[0058] The reaction temperature for this step is the temperature commonly used in the art for carrying out such reactions, for example, 70–150°C, more preferably 120–130°C.

[0059] The post-processing of the reaction solution in this step is relatively simple. For example, after the reaction is completed, water is added directly to the reaction solution, and then the organic phase is extracted and concentrated to obtain the crude product of compound II. The crude product can be slurried with an organic solvent (e.g., a mixture of ethyl acetate and petroleum ether) to obtain the purity required for the next reaction.

[0060] Synthesis of Formula IV compounds

[0061] The compound of formula IV in this invention is synthesized through the following steps:

[0062] (2) The compound of formula II and the compound of formula III undergo a coupling reaction in the presence of a base, as shown in the following reaction formula:

[0063]

[0064] In Formulas III and IV, R1 is H or an amino protecting group; more preferably, R1 is H, Ac, or Bz.

[0065] The base used in this step is a commonly used base for this type of coupling reaction, such as a carbonate or tert-butoxide. Examples include sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, and sodium tert-butoxide. The amount of base used is the conventional amount for this type of coupling reaction; for example, the molar ratio of base to compound II is 1.0–5.0:1, more preferably 2.0–4.0:1.

[0066] The reaction solvent used in this step is a commonly used solvent in this field for carrying out such reactions, such as DMF, DMAc, DMSO, etc.

[0067] In this step, the reaction temperature is the temperature commonly used in the art for carrying out such reactions, for example, 70–150°C, more preferably 90–120°C.

[0068] In this step, the molar ratio of compound II to compound III in the reaction system is preferably 1:1.0 to 3.0, more preferably 1:1.0 to 1.5, and most preferably 1:1.1.

[0069] The post-processing of the reaction solution in this step is relatively simple. For example, after the reaction is completed, water is added directly to the reaction solution, and then the organic phase is extracted and concentrated to obtain the crude product of Formula IV. The crude product can be slurried with an organic solvent (e.g., a mixture of ethyl acetate and petroleum ether) to obtain the purity required for the next reaction.

[0070] Synthesis of compound V

[0071] The compound of formula IV in this invention is synthesized through the following steps:

[0072] (3) Hydrolyze compound IV in the presence of a base or acid, or hydrolyze and deamination reaction to obtain compound V, as shown in the following reaction formula:

[0073]

[0074] When R1 in compound IV is H or a base-sensitive amino protecting group, this step preferably uses a base to hydrolyze compound IV while simultaneously removing the amino protecting group. The base used is a commonly used base for this type of hydrolysis reaction, such as lithium hydroxide, sodium hydroxide, or potassium hydroxide. The amount of base used is the conventional amount for this type of hydrolysis reaction; for example, the molar ratio of base to compound IV is 5–15:1, more preferably 6–12:1.

[0075] When R1 in compound IV is an acid-sensitive amino protecting group, this step preferably uses an acid to hydrolyze compound IV while simultaneously removing the amino protecting group. The acid used is a commonly used acid for this type of hydrolysis reaction, such as hydrochloric acid, sulfuric acid, or phosphoric acid. The amount of acid used is the conventional amount for this type of hydrolysis reaction; for example, the molar ratio of acid to compound IV is 5–20:1, more preferably 8–15:1.

[0076] The reaction solvent used in this step is a commonly used solvent in the art for carrying out such reactions, such as methanol, ethanol, isopropanol, water, or a combination of methanol, ethanol, or isopropanol and water, preferably water.

[0077] In this step, the reaction temperature is the temperature commonly used in the art for carrying out such hydrolysis reactions, for example, 70–120°C, more preferably 80–100°C.

[0078] In one specific embodiment of the present invention, the method for synthesizing compound V includes the following steps:

[0079] (1) Reacting compound I with a fluorine reagent to produce compound II, thus producing compound II.

[0080] (2) A coupling reaction is carried out between compound II and compound III to generate compound IV.

[0081] (3) Hydrolyze compound IV to obtain compound V.

[0082] The reaction formula is as follows:

[0083]

[0084] Compared with the synthesis methods of Formula V compounds disclosed in the prior art, the advantages of the synthesis method of the present invention are as follows:

[0085] 1) By replacing the dichloro of the starting material dichloropyridazine with difluorine, the regioselectivity and yield of the coupling reaction between the starting material and 2,6-dichloro-4-aminophenol were greatly improved, and the hydrolytic activity of the resulting pyridazine compound was also improved, and the yield of the hydrolysis reaction was also significantly increased.

[0086] 2) The synthesis method of compound V of this invention has high yield, short steps, low cost, stable quality, and high purity, and is suitable for industrial production.

[0087] 3) The impurities of the compound V obtained by the synthesis method of the present invention can be effectively controlled, with no unknown impurities greater than 0.10%, which is beneficial to the product quality control of API.

[0088] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. The processes, conditions, reagents, experimental methods, etc., for implementing the present invention, except as specifically mentioned below, are all common knowledge and general knowledge in the art, and the present invention does not have any particular limitations.

[0089] In the following examples, the synthesis of the reactant compound I was carried out in accordance with the method described in prior art WO2007009913.

[0090] Example 1: Preparation of Compound II

[0091]

[0092] Under nitrogen protection, DMF (1.0 L), compound I (100.0 g, 99.2% purity, 0.52 mol), and sodium fluoride (87.9 g, 2.09 mol) were added to the reactor. The temperature was raised to 120–130 °C. After about 16 h, TLC monitoring showed that the conversion of the compound shown in Formula I was basically complete. About 2.0 L of distilled water was added, and the mixture was extracted three times with ethyl acetate (1.0 L each time). The organic phases were combined and washed twice with saturated brine (1.0 L each time). The mixture was dried and concentrated under reduced pressure. The crude product was slurried with ethyl acetate:petroleum ether = 1:5 (1.0 L), filtered, and 77.6 g of solid was obtained with a purity of 97.8% and a molar yield of 92.3%. 1 H NMR (300MHz, d6-DMSO): δ7.86 (d, J = 10.0 Hz, 1H), 3.18-3.05 (m, 1H), 1.26 (d, J = 9.2 Hz, 6H).

[0093] Example 2 Preparation of Compound II

[0094]

[0095] Under nitrogen protection, DMSO (1.0 L), compound I (100.0 g, 99.2% purity, 0.52 mol), and potassium fluoride (120.6 g, 2.07 mol) were added to the reactor. The temperature was raised to 120–130 °C. After about 16 h, TLC monitoring showed that the conversion of the compound shown in Formula I was basically complete. About 2.0 L of distilled water was added, and the mixture was extracted three times with ethyl acetate (1.0 L each time). The organic phases were combined and washed twice with saturated brine (1.0 L each time). The mixture was dried and concentrated under reduced pressure. The crude product was slurried with ethyl acetate:petroleum ether = 1:5 (1.0 L), filtered, and 74.9 g of solid was obtained with a purity of 96.7% and a molar yield of 88.3%.

[0096] Example 3: Preparation of compound IV-1 (R1 = H)

[0097]

[0098] Under nitrogen protection, DMF (1.0 L), compound II (100.0 g, purity 97.8%, 0.619 mol), compound III-1 (132.7 g, 0.743 mol), and potassium carbonate (256.6 g, 1.857 mol) were added to the reactor. The temperature was raised to 110–120 °C. After about 16 h, TLC monitoring showed that the conversion of the compound shown in formula II was basically complete. About 1.0 L of distilled water was added, and the mixture was extracted three times with ethyl acetate (about 1.0 L each time). The organic phases were combined and washed twice with saturated brine (about 1.0 L each time). The mixture was dried and concentrated under reduced pressure. The crude product was slurried with ethyl acetate:petroleum ether = 1:3 (about 1.0 L), filtered, and 172.3 g of solid was obtained with a purity of 98.7% and a molar yield of 86.5%. 1 ¹H NMR (300MHz, d⁶-DMSO): δ 7.71 (d, J = 10.00, ¹H), 6.70 (s, 2H), 5.67 (s, 2H), 3.13–3.04 (m, ¹H), 1.33 (d, J = 9.20, 6H). See also Figure 2 .

[0099] Example 4: Preparation of compound IV-1 (R1 = H)

[0100]

[0101] Under nitrogen protection, DMAc (1.0 L), compound II (100.0 g, purity 97.8%, 0.619 mol), compound III-1 (132.7 g, 0.743 mol), and potassium carbonate (256.6 g, 1.857 mol) were added to the reactor. The temperature was raised to 110–120 °C. After about 16 h, TLC monitoring showed that the conversion of the compound shown in formula II was basically complete. About 1.0 L of distilled water was added, and the mixture was extracted three times with ethyl acetate (about 1.0 L each time). The organic phases were combined and washed twice with saturated brine (about 1.0 L each time). The mixture was dried and concentrated under reduced pressure. The crude product was slurried with ethyl acetate:petroleum ether = 1:3 (1.0 L). After filtration, 159.8 g of solid with a purity of 97.7% and a molar yield of 79.4% was obtained.

[0102] Example 5: Preparation of compound IV-2 (R1 = Ac)

[0103]

[0104] Under nitrogen protection, DMF (1.0 L), compound II (100.0 g, purity 97.8%, 0.619 mol), compound III-2 (149.9 g, 0.681 mol), and potassium carbonate (255.9 g, 1.86 mol) were added to the reactor. The temperature was raised to 110–120 °C. After about 16 h, TLC monitoring showed that the conversion of the compound shown in formula II was basically complete. About 1.0 L of distilled water was added, and the mixture was extracted three times with ethyl acetate (about 1.0 L each time). The organic phases were combined and washed twice with saturated brine (about 1.0 L each time). The mixture was dried and concentrated under reduced pressure. The crude product was slurried with ethyl acetate:petroleum ether = 1:3 (1.0 L), filtered, and 194.7 g of solid was obtained with a purity of 98.5% and a molar yield of 86.6%. 1 H NMR (300MHz, d6-DMSO): δ10.37 (s, 1H), 7.98-7.82 (m, 3H), 3.16-3.04 (m, 1H), 1.28 (d, J = 9.20, 6H).

[0105] Example 6: Preparation of Compound V

[0106]

[0107] Under nitrogen protection, 1.0 L of 3 mol / L sodium hydroxide and 100.0 g of compound IV-2 (98.5% purity, 0.275 mol) were added to the reactor. The temperature was raised to 90–100 °C. After about 16 h, TLC monitoring showed that the conversion of the compound IV-2 was basically complete. Distilled water was added, and the pH of the system was adjusted to 5–6 with 1 N hydrochloric acid. The mixture was then filtered under reduced pressure. The filter cake was washed twice with water (about 0.3 L each time) and dried to obtain 73.6 g of solid with a purity of 99.16% and a molar yield of 84.8%. 1 H NMR (300MHz, d6-DMSO): δ12.14(s,1H),7.28(s,1H),6.69(s,2H),5.63(s,2H),3.07-2.98(m,1H),1.17(d,J=9.20,6H). 1 The original H NMR spectrum can be found in [reference]. Figure 4 See the original HPLC chromatogram. Figure 5 .

[0108] The inventors analyzed, characterized, and verified the main components and impurities of the product obtained in Example 6. The contents of the main components and impurities are shown in Table 1 below, and the structures of the impurities are shown below.

[0109] Table 1

[0110] RT 10.26min 12.27min 17.47min 18.58min 29.15min content 0.05％ 0.29％ 0.07％ 99.16％ 0.10％

[0111]

[0112] Impurities 1 and 2 are generated by the coupling reaction and are regioselective impurities; impurities 3 and 4 are impurities resulting from the ether bond breakage during hydrolysis. In compound V, these impurities have been thoroughly studied and well controlled, with their contents all less than 0.3%, laying the foundation for subsequent product quality studies.

[0113] Example 7 Preparation of Compound V

[0114]

[0115] Under nitrogen protection, 1.0 L of 3N hydrochloric acid and 100.0 g (98.5% 0.275 mol) of compound IV-2 were added to the reactor. The temperature was raised to 90–100 °C. After about 16 h, TLC monitoring showed that the conversion of the compound IV-2 was basically complete. Distilled water was added, and the pH was adjusted to 5–6 with 3 mol / L sodium hydroxide. The mixture was then filtered under reduced pressure. The filter cake was washed twice with water (about 0.3 L each time) and dried to obtain 71.1 g of solid with a purity of 99.1% and a molar yield of 81.9%.

[0116] Example 8: Preparation of Compound V

[0117]

[0118] Under nitrogen protection, 1.0 L of 3 mol / L potassium hydroxide and 100.0 g of compound IV-1 (97.7% purity, 0.307 mol) were added to the reactor. The temperature was raised to 90–100 °C. After about 16 h, TLC monitoring showed that the conversion of compound IV-1 was basically complete. Distilled water (1.0 L) was added, and the pH of the system was adjusted to 5–6 with 1 N hydrochloric acid. The mixture was then filtered under reduced pressure. The filter cake was washed twice with water (about 0.3 L each time) and dried to obtain 81.1 g of solid with a purity of 99.3%, and the yield was 83.4% after conversion.

[0119] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for synthesizing compound V, characterized in that, The synthesis method includes the following steps: The compound of formula II and the compound of formula III are coupled together to give the compound of formula IV, as shown in the following reaction formula: ， as well as Compound IV is subjected to hydrolysis, or hydrolysis and deamination reaction, to obtain compound V, as shown in the following reaction formula: ， In Formulas III and IV, R1 is an H or an amino protecting group.

2. The method for synthesizing compound V according to claim 1, characterized in that, R1 is H, Ac, or Bz.

3. The method for synthesizing compound V according to claim 1, characterized in that, When R1 is H, the hydrolysis reaction is carried out in the presence of a base or acid, and When R1 is an amino protecting group, the hydrolysis reaction and the deamination reaction occur simultaneously in the presence of a base or acid.

4. The method for synthesizing compound V according to claim 3, characterized in that, The alkali is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, or a combination thereof. The acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof.

5. The method for synthesizing compound V according to claim 3, characterized in that, The alkali is selected from sodium hydroxide. The acid is selected from hydrochloric acid.

6. The method for synthesizing compound V according to claim 1, characterized in that, The coupling reaction is carried out in the presence of a base, which is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, or combinations thereof.

7. The method for synthesizing compound V according to claim 6, characterized in that, The base used in the coupling reaction is selected from potassium carbonate.

8. The method for synthesizing compound V according to claim 1, characterized in that, The method for synthesizing compounds of formula II includes the following steps: The compound of formula I is reacted with a fluorinating agent to give the compound of formula II, as shown in the following reaction formula: 。 9. The method for synthesizing compound V according to claim 8, characterized in that, The fluorinating agent is selected from sodium fluoride, potassium fluoride, TBAF and ammonium fluoride or combinations thereof.

10. The method for synthesizing compound V according to claim 8, characterized in that, The fluorinating agent is selected from sodium fluoride.

11. A method for synthesizing a compound of formula V, characterized in that, The structural formula of compound V is as follows: The synthesis method includes the following steps: (1) Reacting compound I with a fluorinating reagent to produce compound II, the reaction is as follows: ,as well as (2) The compound of formula II and the compound of formula III undergo a coupling reaction to generate the compound of formula IV. ， In Formulas III and IV, R1 is an H or an amino protecting group.

12. The synthesis method according to claim 11, characterized in that, In Equations III and IV, R1 is H, Ac, or Bz.

13. The method for synthesizing compound V according to claim 11, characterized in that, The fluorinating agent is selected from sodium fluoride, potassium fluoride, TBAF and ammonium fluoride or combinations thereof.

14. The method for synthesizing compound V according to claim 11, characterized in that, The coupling reaction is carried out in the presence of a base, which is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, or combinations thereof.

Images