A method for photocatalytic synthesis of fulvestrant intermediates using pentafluorochloroethane and its application

Abstract

This invention belongs to the fields of pharmaceutical chemistry and photocatalysis, and discloses a method for the photocatalytic synthesis of fulvestrant intermediates using pentafluorochloroethane and its applications. The method uses allyl ester compounds as substrates and pentafluorochloroethane (Freon-115) as a perfluoroalkylating agent. Under visible light irradiation, a specific photocatalytic redox system is constructed, and a boron-containing activator is introduced to synergistically activate the inert C-Cl bond, achieving the pentafluoroethylation-hydrogenation reaction of allyl esters to efficiently synthesize pentafluoropentyl benzoate. The method of this invention features mild reaction conditions, avoiding the use of highly toxic tin reagents in traditional processes, and simultaneously achieving high-value utilization of industrial waste gas Freon-115, demonstrating significant atom economy and promising industrial application prospects.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and photocatalysis technology, specifically relating to a method for synthesizing fulvestrant intermediates using pentafluorochloroethane photocatalysis and its application. Background Technology

[0002] Fulvestrant is a selective estrogen receptor degrader (SERD) used clinically to treat hormone receptor-positive (HR) patients. + Fulvestrant is used to treat advanced breast cancer. Its mechanism of action differs from traditional selective estrogen receptor modulators (SERMs, such as tamoxifen). Upon binding to the estrogen receptor (ER), fulvestrant not only antagonizes its function but also induces a conformational change in the ER protein, allowing it to be recognized and degraded by the intracellular ubiquitin-proteasome system, achieving deep and sustained inhibition of the estrogen signaling pathway. This mechanism helps overcome some resistance to SERM or aromatase inhibitors. Based on its unique mechanism of action, fulvestrant has become a cornerstone of combination therapies (e.g., in combination with CDK4 / 6 inhibitors). Its chemical structure is as follows:

[0003] Pentafluoropentanol (CF3CF2(CH2)3OH) is a key higher intermediate in the synthesis of fulvestrant, a selective estrogen receptor degrader, via its perfluoropentyl side chain. The pentafluoropentyl (CF3CF2(CH2)3OH) in this intermediate molecule... - The pentafluoropentanol fragment is the core group that ultimately constructs the fulvestrant drug molecule and endows it with key physicochemical properties (such as enhanced lipophilicity, metabolic stability, and specific binding ability to target proteins). Therefore, developing an efficient, highly selective, and industrially viable pentafluoropentanol synthesis process is of great significance for ensuring the quality and accessibility of fulvestrant.

[0004] Existing synthetic processes mostly employ the free radical addition of allyl acetate with perfluoroiodinane, followed by deiodination and reduction. This route has significant drawbacks: firstly, it requires the use of expensive and unstable perfluoroiodinane reagents; secondly, the deiodination step usually relies on highly toxic tributyltin hydride (n-Bu3SnH) or requires high-pressure hydrogenation conditions, which not only puts a heavy environmental burden on the environment but also poses significant safety risks.

[0005] On the other hand, pentafluorochloroethane (Freon-115, R115) is a major byproduct in the production of refrigerants and hexafluoroethane. Due to its extremely long atmospheric lifetime and high global warming potential (GWP), its harmless disposal has always been a challenge for industry. Converting it into high-value-added fluorinated building blocks would have enormous environmental and economic benefits. However, the C-Cl bond energy in the R115 molecule is extremely high (approximately 406 kJ / mol), and the molecule itself has a high electron cloud density, making it extremely difficult to reduce and activate. Conventional chemical methods are insufficient to achieve its conversion under mild conditions.

[0006] Therefore, developing a green new process that can efficiently activate the inert C-Cl bond in R115 under mild conditions and apply it to the synthesis of fulvestrant intermediates is a technical challenge that urgently needs to be solved. Summary of the Invention

[0007] The purpose of this invention is to provide a method for the photocatalytic synthesis of fulvestrant intermediates using pentafluorochloroethane and its applications. This method, through the design of a unique photo-redox catalytic cycle and the introduction of a specific boron-containing activator, successfully achieves the activation of the inert C-Cl bond in pentafluorochloroethane under visible light, and then reacts it with allyl ester via a radical addition-hydrogen atom transfer reaction to prepare the fulvestrant intermediate pentafluoropentyl benzoate.

[0008] To achieve the above objectives, the present invention adopts the following technical solution: A method for synthesizing fulvestrant intermediates using pentafluorochloroethane photocatalysis includes: using allyl ester compounds as raw materials, adding a boron-containing activator, a hydrogen atom transfer reagent and a photocatalyst, reacting in an organic solvent under a pentafluorochloroethane atmosphere, and then separating and purifying to obtain the target product, fulvestrant intermediate pentafluoropentyl benzoate.

[0009]

[0010] The photocatalyst is preferably a photocatalyst with a strong reduction potential, including but not limited to one of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN), 10-phenylphenthiazine (PTH), anthracene-9,10-dianitrile, cerium oxide, iron oxide, and polymeric carbon nitride.

[0011] The hydrogen atom transfer reagent is used to quench free radical intermediates and is one of 2,4,6-triisopropylthiophenol, pentafluorothiophenol, sodium thiophenolate, tert-butylthiol, diphenyl disulfide, or isopropanol, preferably a sterically hindered thiophenol compound, such as 2,4,6-triisopropylthiophenol.

[0012] The boron-containing activator plays a crucial synergistic activation role, and is preferably an amine-borane complex, including trimethylamine-borane and triethylamine-borane. This type of cocatalyst can synergistically interact with the active species generated by the photocatalytic cycle to promote the breaking of C-Cl bonds and the generation of perfluoroalkyl radicals.

[0013] The light source used is a light source with a wavelength of 200 nm to 500 nm, such as one or a combination of LED lamps, xenon lamps or mercury lamps.

[0014] An application of pentafluoropentyl benzoate prepared by the above method in the synthesis of fulvestrant.

[0015] (1) Turning waste into treasure: Innovatively using industrial by-product R115 as a fluorine source, solving the environmental problems that are difficult to deal with and significantly reducing raw material costs.

[0016] (2) Green and safe: The reaction is carried out at room temperature and under visible light, avoiding the use of high temperature, high pressure and highly toxic tin reagents, which is in line with the principles of green chemistry.

[0017] (3) High efficiency conversion: By introducing a boron-containing activator, the activation efficiency of inert C-Cl bonds is significantly improved, and the yield of the target product is good, which is suitable for further industrial development. Attached Figure Description

[0018] Figure 1 The crude product of the reaction mixture of Example 1 19 F NMR spectrum.

[0019] Figure 2 The crude product of the reaction mixture in Example 2 19 F NMR spectrum.

[0020] Figure 3 The purified product of Example 1 1 H NMR spectrum.

[0021] Figure 4 The purified product of Example 1 13 C10 NMR spectrum.

[0022] Figure 5 The purified product of Example 1 19 F NMR spectrum. Detailed Implementation

[0023] The present invention will be further described in detail below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto. Example 1

[0024] In a 10 mL pressure-resistant glass reaction tube equipped with a magnetic stirrer, photocatalyst 4CzIPN (5 mg), boron-containing activator I (trimethylamine-borane complex, 33 mg), hydrogen atom transfer reagent 2,4,6-triisopropylbenzenethiophenol (7 mg), and substrate allyl benzoate (16 mg) were added sequentially. Trimethylacetonitrile was added as a solvent. The reaction tube was subjected to a freeze-evacuation-thawing cycle to remove oxygen, followed by purging with pentafluorochloroethane (Freon-115) gas until the reaction system was in its atmosphere. The reaction mixture was irradiated with a 50 W blue LED (wavelength 465 nm) at a constant temperature of 25 °C and stirred for 18 hours. After the reaction was completed, the reaction mixture was analyzed by ¹ 9 10⁻⁶ F NMR (using p-fluorobenzonitrile as an internal standard) was used to analyze the reaction mixture (see attached). Figure 1 The yield of pentafluoropentyl benzoate was calculated to be 64%. The reaction solution was concentrated and purified by column chromatography to obtain the target product, pentafluoropentyl benzoate.

[0025] The product characterization data are as follows (see appendix) Figures 3-5 ):

[0026] Pentafluoroamyl benzoate is a colorless or pale yellow liquid. 1 H NMR (600 MHz, CDCl3) δ 8.06-8.01(m, 2H), 7.58 (ddt, J = 8.8, 7.2, 1.7 Hz, 1H), 7.49-7.43 (m, 2H), 4.40 (t, J =6.2 Hz, 2H), 2.28-2.17 (m, 2H). 13 C NMR (151 MHz, CDCl3) δ 166.44, 133.25, 129.94, 129.64, 128.54, 63.47, 27.97, 27.82, 27.68, 20.33. 19 F NMR (565 MHz, CDCl3) δ -85.31 (s), -118.14 (t, J =17.6 Hz). Example 2

[0027] Scale-up experiments were conducted in a 500 mL three-necked flask. The photocatalyst 4CzIPN (250 mg), boron-containing activator I (1.65 g), hydrogen atom transfer reagent 2,4,6-triisopropylbenzenethiophenol (350 mg), and allyl benzoate (811 mg) were added. Solvent and gas treatment procedures were the same as in Example 1. The reaction was carried out at 25 °C under symmetrical irradiation with two 50W 465 nm LED lamps for 48 hours. A 3 mL sample was taken for further analysis.¹ 9 F NMR analysis (see appendix) Figure 2 The yield of pentafluoroamyl benzoate was determined to be 73%. Example 3

[0028] Except for replacing the photocatalyst with polymeric carbon nitride (g-C3N4), the other conditions were the same as in Example 1. After 18 hours of reaction, the target product was detected. Example 4

[0029] Except for replacing the substrate with allyl phenylacetate (17 mg), the other conditions were the same as in Example 1. After 18 hours of reaction, the target product pentafluoroamyl phenylacetate was detected. Example 5

[0030] Except for replacing the substrate with allyl 4-hydroxybenzoate (17 mg), the conditions were the same as in Example 1. After 18 hours of reaction, the target product, pentafluoropentyl 4-hydroxybenzoate, was detected.

[0031] The above-described embodiments are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for photocatalytic synthesis of fulvestrant intermediates using pentafluorochloroethane, characterized in that, Includes the following steps: Under the conditions of photocatalyst, boron-containing activator and hydrogen atom transfer reagent, allyl ester compounds are used as substrates and photocatalytically reacted with pentafluorochloroethane in an organic solvent under the atmosphere of a specific wavelength light source to obtain the pentafluoropentylated product, a key intermediate of fulvestrant.

2. The method according to claim 1, characterized in that, The boron-containing activator includes borane compounds; the photocatalyst includes organic photocatalysts or inorganic semiconductor photocatalysts; and the organic solvent is a nitrile solvent.

3. The method according to claim 12, characterized in that, The borane compounds include complexes formed by aza-Lewis bases and boranes.

4. The method according to claim 2, characterized in that, The photocatalyst includes, but is not limited to, one or more of the following: donor-acceptor conjugated molecules, phenothiazine derivatives, anthracene derivatives, conjugated polymers, or transition metal oxides.

5. The method according to claim 2, characterized in that, The nitrile solvents include alkyl nitrile solvents with high steric hindrance.

6. The method according to claim 1, characterized in that, The hydrogen atom transfer reagents include, but are not limited to, one or more of thiols, thiophenols, disulfides, or alcohols with active hydrogen atoms.

7. The method according to claim 1, characterized in that, The specific light source is a light source with a wavelength range of 200 nm to 500 nm.

8. The method according to claim 1, characterized in that, The allyl ester compounds include, but are not limited to, one or more of allyl benzoate, allyl phenylacetate, or allyl 4-hydroxybenzoate; the pentafluoroethylated product is one of pentafluoropentyl benzoate, pentafluoropentyl phenylacetate, or pentafluoropentyl 4-hydroxybenzoate.

9. The method according to claim 1, characterized in that, The mass ratio of the allyl ester compound, the boron-containing activator, the hydrogen atom transfer reagent, and the photocatalyst is 16:10-45:2-10:2-8.

10. The use of pentafluoropentyl benzoate prepared by the method according to any one of claims 1-9 in the synthesis of fulvestrant.

Images