Mononuclear NNN-type divalent Cu-F metal complex, preparation method, intermediate and application of mononuclear NNN-type divalent Cu-F metal complex

Abstract

The invention discloses a mononuclear NNN type bivalent Cu-F metal complex, a preparation method, an intermediate and application of the mononuclear NNN type bivalent Cu-F metal complex. The invention provides a compound as shown in a formula d, and R1, R2, R3 and R4 are respectively and independently C1-C6 alkyl. The compound shown in the formula d provided by the invention is a novel metal complex, can be used as a fluorinating reagent to be combined with alkyl free radicals to obtain an alkyl fluorinated product, and has relatively high yield.

Description

Technical Field

[0001] This invention relates to a mononuclear NNN-type divalent Cu-F metal complex, its preparation method, intermediates, and applications. Background Technology

[0002] Because fluorine atoms have the highest electronegativity and the smallest atomic radius, introducing fluorine atoms into molecules can alter their lipid solubility, metabolic stability, and other properties. Over the past 20 years, approximately 20% of drug molecules and 50% of pesticide molecules on the market have contained one or more fluorine atoms. In addition, radioactive isotopes... 18 F has a suitable half-life (110 min) and low positron energy, and is widely used as a marker for positron emission tomography (Nat Rev Methods Primers, 2021, 1, 47.).

[0003] The construction of CF bonds in molecules mainly falls into two categories: one is the conversion of CX bonds to CF bonds through functional group transformation; the other is the construction of CF bonds from CH bonds under metal-mediated processes. The first category mainly includes nucleophilic fluorination (e.g., using metal fluoride salts such as potassium fluoride, high-valent iodide salts, DAST, etc.), electrophilic fluorination (e.g., NF reagents such as Selectfluor and NFSI), and radical fluorination (e.g., fluorine gas, xenon difluoride, etc.) (Chem. Rev. 2015, 115, 9073−9174.). The second category mainly includes the activation of CH bonds to construct CF bonds mediated by metals such as palladium (Pd) and copper (Cu) (Angew. Chem. Int. Ed. 2019, 58, 14824–14848.). In Cu-mediated reactions, divalent copper is mostly used as the metal reagent, and divalent Cu-F species may be obtained during the reaction to construct CF bonds.

[0004] Reported divalent Cu-F species are divided into hydrated and anhydrous types. The hydrated species include commercially available copper difluoride and some ligand-substituted copper difluoride. The anhydrous species are mostly polynuclear divalent copper-fluoride species with fluorine-bridged bonds. Most of the reported divalent copper-fluoride species are used as silicon-based activators and oxidants (J. Org. Chem. 2019, 84, 338−345.; Org. Lett., 2001, 25, 4111-4113.), with only a few reported as fluorinating agents (J. Am. Chem. Soc. 2018, 140, 19, 6169–6175.; Angew. Chem. Int. Ed. 2020, 132, 8460–8463.). Therefore, isolating divalent Cu-F species and exploring their reactivity is of great significance. Summary of the Invention

[0005] The technical problem to be solved by this invention is to overcome the shortcomings of existing technologies, such as the lack of application of divalent copper-fluorine species in fluorination reactions and the difficulty in separating metal complexes. This invention provides a mononuclear NNN-type divalent Cu-F metal complex, its preparation method, intermediates, and their applications. The mononuclear NNN-type divalent Cu-F metal complex provided by this invention is a novel metal complex that can be used as a fluorinating agent to combine with alkyl radicals to obtain alkyl fluorinated products with high yields.

[0006] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0007] This invention provides a compound as shown in formula d:

[0008]

[0009] R1, R2, R3 and R4 are independently C1 to C6 alkyl groups.

[0010] In some embodiments of the present invention, R1, R2, R3 and R4 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

[0011] Preferably, R1, R2, R3, and R4 are the same;

[0012] More preferably, R1, R2, R3 and R4 are isopropyl.

[0013] The present invention also provides a method for preparing a compound as shown in formula d, comprising the following steps: in a solvent, compound c and compound e react to generate a compound as shown in formula d;

[0014] ;

[0015] R1, R2, R3, and R4 are as described in any of the aforementioned schemes.

[0016] In some embodiments of the present invention, the solvent is selected from one or more of ether solvents, chlorinated hydrocarbon solvents and nitrile solvents, preferably from one or more of tetrahydrofuran, dichloromethane, acetonitrile dichloroethane and ethylene glycol dimethyl ether, more preferably dichloromethane, and most preferably ultra-dry dichloromethane.

[0017] In some embodiments of the present invention, the volume-to-mass ratio of the solvent to compound c is 10 mL / g to 100 mL / g, preferably 20 mL / g to 30 mL / g, and more preferably 23 mL / g.

[0018] In some embodiments of the present invention, the molar ratio of compound c to compound e is 1:(1~10), preferably 1:1.

[0019] In some embodiments of the present invention, the reaction temperature may be -30~30°C, preferably -20°C.

[0020] In some embodiments of the present invention, the reaction time is 10 min to 24 h, preferably 30 min.

[0021] In some embodiments of the present invention, the reaction is carried out under an inert gas selected from one or more of nitrogen, helium and argon, preferably argon.

[0022] In some embodiments of the present invention, the reaction includes the following post-processing steps: after the reaction is completed, the reaction solution is filtered through diatomaceous earth, washed (preferably with dichloromethane), concentrated, the solid is precipitated with n-pentane, and recrystallized (preferably with dichloromethane and n-pentane) to obtain the compound shown in formula d.

[0023] In some embodiments of the present invention, the method for preparing the compound as shown in formula d further includes a method for preparing compound c, which includes the following steps: in a solvent, compound b reacts with compound f to generate compound c.

[0024] ;

[0025] R1, R2, R3, and R4 are as described in any of the aforementioned schemes.

[0026] In some embodiments of the present invention, in the preparation method of compound c, the solvent is an ether solvent, preferably selected from one or more of tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether, more preferably tetrahydrofuran, and most preferably ultra-dry tetrahydrofuran.

[0027] In some embodiments of the present invention, in the preparation method of compound c, the volume-to-mass ratio of the solvent to compound b is 10 mL / g to 100 mL / g, preferably 15 mL / g to 25 mL / g, and more preferably 18.5 mL / g.

[0028] In some embodiments of the present invention, in the preparation method of compound c, the molar ratio of compound b to compound f is 1:(1~10), preferably 1:(3~7), and more preferably 1:3.

[0029] In some embodiments of the present invention, in the preparation method of compound c, the reaction temperature can be 10~100℃, preferably 25℃.

[0030] In some embodiments of the present invention, in the preparation method of compound c, the reaction time is 10 min to 120 min, preferably 20 min.

[0031] In some embodiments of the present invention, in the preparation method of compound c, the reaction is carried out under an inert gas selected from one or more of nitrogen, helium and argon, preferably argon.

[0032] In some embodiments of the present invention, the preparation method of compound c includes the following post-processing steps: after the reaction is completed, the reaction solution is filtered through diatomaceous earth, washed (preferably with tetrahydrofuran), concentrated, precipitated solid by adding diethyl ether, and recrystallized (preferably by recrystallization with tetrahydrofuran and diethyl ether) to obtain compound c.

[0033] In some embodiments of the present invention, the method for preparing compound c further includes a method for preparing compound b, which includes the following steps:

[0034] (1) In a solvent, cuprous salt (CuX) and fluoride salt (MF) react with TMSCF3 to form compound a;

[0035] (2) Compound a reacts with tetraphenylphosphine chloride to form compound b;

[0036] .

[0037] In some embodiments of the present invention, in the preparation method of compound b, the solvent is an ether solvent, preferably selected from one or more of tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether, more preferably tetrahydrofuran, and most preferably ultra-dry tetrahydrofuran.

[0038] In some embodiments of the present invention, in the preparation method of compound b, the cuprous salt may be cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, cuprous cyanide or cuprous oxide, preferably cuprous chloride.

[0039] In some embodiments of the present invention, in the preparation method of compound b, the fluoride salt may be lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, magnesium fluoride, calcium fluoride, zirconium fluoride, manganese fluoride, iron fluoride, cobalt fluoride, nickel fluoride, silver fluoride, zinc fluoride, tetramethylammonium fluoride or tetrabutylammonium fluoride, preferably potassium fluoride.

[0040] In some embodiments of the present invention, in the preparation method of compound b, the volume-to-mass ratio of the solvent to the cuprous salt is 10 mL / g to 100 mL / g, preferably 15 mL / g to 25 mL / g, and more preferably 20 mL / g.

[0041] In some embodiments of the present invention, in the preparation method of compound b, the molar ratio of the cuprous salt to the fluoride salt can be 1:(1~10), preferably 1:(3~7).

[0042] In some embodiments of the present invention, in the preparation method of compound b, the molar ratio of the cuprous salt to the TMSCF3 can be 1:(1~10), preferably 1:(3~6).

[0043] In some embodiments of the present invention, in the preparation method of compound b, the molar ratio of tetraphenylphosphine chloride to cuprous salt can be 1:(1~10), preferably 1:1.

[0044] In some embodiments of the present invention, in the preparation method of compound b, in step (1) and / or step (2), the reaction temperature can be 10~100 °C, preferably 25 °C.

[0045] In some embodiments of the present invention, in the preparation method of compound b, in step (1) and / or step (2), the reaction is carried out under an inert gas selected from one or more of nitrogen, helium and argon, preferably argon.

[0046] In some embodiments of the present invention, in the preparation method of compound b, in step (1), the reaction time is 10 min to 24 h, preferably 30 min.

[0047] In some embodiments of the present invention, in the preparation method of compound b, in step (2), the reaction time is 10-100 min, preferably 30 min.

[0048] In some embodiments of the present invention, in the preparation method of compound b, in step (2), the reaction includes the following post-processing steps: after the reaction is completed, the reaction solution is filtered through diatomaceous earth, washed (preferably tetrahydrofuran), concentrated, precipitated solid by adding diethyl ether, and recrystallized (preferably by recrystallizing tetrahydrofuran and diethyl ether) to obtain compound b.

[0049] The present invention also provides a compound as shown in formula c:

[0050] .

[0051] The present invention also provides the use of a compound of formula d as described in any of the preceding claims as a fluorinating agent in a fluorination reaction; preferably, the fluorination reaction is an alkyl fluorination reaction.

[0052] In some embodiments of the present invention, the alkyl fluorination reaction includes the following steps:

[0053] In a solvent, compound I reacts with a compound as shown in formula d to form compound II;

[0054] ;

[0055] R1, R2, R3, and R4 are as described in any of the aforementioned schemes.

[0056] In some embodiments of the present invention, in the alkyl fluorination reaction, the solvent is selected from one or more of tetrahydrofuran, dichloromethane and acetonitrile, preferably dichloromethane, and more preferably ultra-dry dichloromethane.

[0057] In some embodiments of the present invention, in the alkyl fluorination reaction, the volume-to-mass ratio of the solvent to the compound as shown in formula d is 10 mL / g to 100 mL / g, preferably 25 mL / g to 35 mL / g, and more preferably 32 mL / g.

[0058] In some embodiments of the present invention, in the alkyl fluorination reaction, the molar ratio of compound I to the compound shown in formula d may be 1:(1~10), preferably 1:2.

[0059] In some embodiments of the present invention, the temperature of the alkyl fluorination reaction can be 10~100°C, preferably 25°C.

[0060] In some embodiments of the present invention, the alkyl fluorination reaction takes place for 10 min to 24 h, preferably 30 min.

[0061] In some embodiments of the present invention, the alkyl fluorination reaction is carried out under an inert gas selected from one or more of nitrogen, helium and argon, preferably argon.

[0062] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0063] The reagents and raw materials used in this invention are all commercially available.

[0064] The positive and progressive effects of this invention are as follows:

[0065] (1) This invention provides a novel mononuclear NNN-type divalent Cu-F metal complex and its preparation method;

[0066] (2) The metal complex provided by the present invention can be used as a fluorinating agent to combine with alkyl free radicals to obtain alkyl fluorinated products with a high yield. Attached Figure Description

[0067] Figure 1 The single-crystal diffraction model diagram of complex d;

[0068] Figure 2 The fluorine spectrum of compound 2 in Example 2 is shown. Detailed Implementation

[0069] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0070] Example 1 Preparation of mononuclear metal complexes

[0071] Step 1:

[0072]

[0073] In a glove box under an argon atmosphere, CuCl (20 mmol, 1.98 g), KF (140 mmol, 8.13 g), and TMSCF3 (90 mmol, 12.8 g) were added to a 100 mL reaction flask, along with 40 mL of THF solvent. The reaction was carried out at room temperature (25 °C) for 30 min. Subsequently, tetraphenylphosphine chloride (20 mmol, 7.4 g) was added to the reaction solution and reacted for another 30 min. The solution was filtered through diatomaceous earth and washed with THF. The solution was concentrated under reduced pressure to 1 / 3 of its volume, and 100 mL of diethyl ether was added, precipitating a white solid. Recrystallization was performed using a THF / diethyl ether (v / v) ratio of 1:10 (total 50 mL) to obtain the final target product (6.5 g, 60%).

[0074] Step 2:

[0075]

[0076] In a glove box under an argon atmosphere, complex b (1 mmol, 540 mg) and ligand (3 mmol, 916 mg, prepared according to the literature method: Journal of Organometallic Chemistry, 2019, 881, 139-149.) were added to a 20 mL reaction flask, along with 10 mL of THF solvent. The reaction was carried out at room temperature (25 °C) for 20 min. After the reaction was complete, the solution was filtered through diatomaceous earth and washed with THF. The solution was then concentrated under reduced pressure to 1 / 3 of its volume, and 30 mL of diethyl ether was added to obtain a pale yellow solid. The THF / diethyl ether (v / v) ratio was 1:10 (total 20 mL), and the mixture was further recrystallized to obtain complex c (403 mg, 90%).

[0077] 1 ¹H NMR (400 MHz, dichloromethane-d²) δ 7.72 (t, J = 7.7 Hz, 1 H), 7.39 (d, J = 7.7 Hz, 2 H), 3.97 (s, 4 H), 3.18 (hept, J = 6.5 Hz, 4 H), 1.09 (d, J = 6.5 Hz, 24 H) ppm.

[0078] 19 F NMR (376 MHz, dichloromethane-d2) δ -25.5 ppm.

[0079] Step 3:

[0080]

[0081] In a glove box under an argon atmosphere, complex c (1 mmol, 437 mg) was added to a 20 mL reaction flask, followed by 10 mL of solvent DCM. The mixture was pre-cooled at -20 °C. Then, an oxidizing agent (1 mmol, 1.04 g, prepared according to literature method: Organometallics 2022, 41, 18, 2648–2655) was added to the reaction solution, and the reaction was carried out at -20 °C for 30 min. After the reaction was complete, the solution was filtered through diatomaceous earth and washed with DCM. The solution was then concentrated under reduced pressure to 1 / 3 of its volume, and 50 mL of n-pentane was added to obtain a blue solid. Further recrystallization of DCM / n-pentane (v / v) = 1:10 (total 20 mL) yielded complex d (876 mg, 70%). Using a low-temperature liquid-phase diffusion method, complex d was dissolved in 0.5 mL of DCM in a 4 mL vial, then transferred to a 20 mL flask. 10 mL of n-pentane was added to the flask, and the mixture was allowed to stand at low temperature. Single-crystal diffraction tests were performed on the cultured complex d (X-ray crystallography was conducted on a Bruker D8 Venture diffractometer using filtered Cu-Kα or Mo-Kα radiation). The results are as follows: Figure 1 .

[0082] Elemental analysis was performed on complex d under the following test conditions, and the results are shown in Table 1:

[0083] Test conditions: Anhydrous and oxygen-free

[0084] Instrument Model: Elementar Vario MicroCube

[0085] Table 1 Elemental Analysis Results

[0086]

[0087] Example 2: Application Case

[0088]

[0089] In a glove box under an argon atmosphere, complex d (0.05 mmol, 62.5 mg) and Gomberg dimer (compound 1, 0.025 mmol, 12.2 mg, prepared according to the literature: Angew. Chem. Int. Ed. 2016, 55, 14439.) were added to a 10 mL reaction flask, along with solvent DCM (2 mL). The reaction was carried out at room temperature (25 °C) for 30 min. After the reaction was complete, fluorobenzene (50 μL, 1 M acetonitrile standard solution) was added as an internal standard. Fluorofluorescence spectra were used to monitor the yield of compound 2, which was 95%. The fluorofluorescence spectrum of compound 2 is shown below. Figure 2 As shown.

Claims

1. A compound as shown in formula d: ； in, R1, R2, R3 and R4 are independently C1 to C6 alkyl groups.

2. The compound according to claim 1, characterized in that, R1, R2, R3 and R4 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably, R1, R2, R3 and R4 are the same; more preferably, R1, R2, R3 and R4 are isopropyl.

3. A method for preparing a compound as shown in formula d, characterized in that, It includes the following steps: in a solvent, compound c and compound e react to produce a compound as shown in formula d; ； R1, R2, R3 and R4 are as described in claim 1 or 2.

4. The preparation method according to claim 3, characterized in that, The preparation method satisfies one or more of the following conditions: (1) The solvent is selected from one or more of ether solvents, chlorinated hydrocarbon solvents and nitrile solvents, preferably selected from one or more of tetrahydrofuran, dichloromethane, acetonitrile, dichloroethane and ethylene glycol dimethyl ether, more preferably dichloromethane, and most preferably ultra-dry dichloromethane; (2) The volume-to-mass ratio of the solvent to compound c is 10 mL / g to 100 mL / g, preferably 20 mL / g to 30 mL / g, and more preferably 23 mL / g; (3) The molar ratio of compound c to compound e is 1:(1~10), preferably 1:1; (4) The reaction temperature is -30~30℃, preferably -20℃; (5) The reaction time is 10 min to 24 h, preferably 30 min; (6) The reaction is carried out under an inert gas, wherein the inert gas is selected from one or more of nitrogen, helium and argon, preferably argon; (7) The reaction includes the following post-processing steps: after the reaction is completed, the reaction solution is filtered through diatomaceous earth, washed (preferably washed with dichloromethane), concentrated, precipitated with n-pentane, and recrystallized (preferably recrystallized with dichloromethane and n-pentane) to obtain the compound shown in formula d.

5. The preparation method according to claim 3, characterized in that, The method for preparing the compound as shown in formula d further includes a method for preparing compound c, which includes the following steps: in a solvent, compound b reacts with compound f to generate compound c; ； R1, R2, R3 and R4 are as described in claim 1 or 2.

6. The preparation method according to claim 5, characterized in that, In the preparation method of compound c, the preparation method of compound c satisfies one or more of the following conditions: (1) The solvent is an ether solvent, preferably selected from one or more of tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether, more preferably tetrahydrofuran, and most preferably ultra-dry tetrahydrofuran; (2) The volume-to-mass ratio of the solvent to the compound b is 10 mL / g to 100 mL / g, preferably 15 mL / g to 25 mL / g, and more preferably 18.5 mL / g; (3) The molar ratio of compound b to compound f is 1:(1~10), preferably 1:(3~7), and more preferably 1:3; (4) The reaction temperature is 10~100℃, preferably 25℃; (5) The reaction time is 10 min to 120 min, preferably 20 min; (6) The reaction is carried out under an inert gas, wherein the inert gas is selected from one or more of nitrogen, helium and argon, preferably argon; (7) The reaction includes the following post-processing steps: After the reaction is completed, the reaction solution is filtered through diatomaceous earth, washed (preferably with tetrahydrofuran), concentrated, and precipitated solid by adding diethyl ether. The solid is then recrystallized (preferably by recrystallizing with tetrahydrofuran and diethyl ether) to obtain compound c.

7. The preparation method according to claim 5, characterized in that, The method for preparing compound c further includes a method for preparing compound b, which includes the following steps: (a) In a solvent, cuprous salt CuX, fluoride salt MF, and TMSCF3 react to form compound a; (b) Compound a reacts with tetraphenylphosphine chloride to form compound b; ； Preferably, in the method for preparing compound b, the method for preparing compound b satisfies one or more of the following conditions: (1) The solvent is an ether solvent, preferably selected from one or more of tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether, more preferably tetrahydrofuran, and most preferably ultra-dry tetrahydrofuran; (2) The cuprous salt is cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, cuprous cyanide or cuprous oxide, preferably cuprous chloride; (3) The fluoride salt is lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, magnesium fluoride, calcium fluoride, zirconium fluoride, manganese fluoride, iron fluoride, cobalt fluoride, nickel fluoride, silver fluoride, zinc fluoride, tetramethylammonium fluoride or tetrabutylammonium fluoride, preferably potassium fluoride; (4) The volume-to-mass ratio of the solvent to the cuprous salt is 10 mL / g to 100 mL / g, preferably 15 mL / g to 25 mL / g, and more preferably 20 mL / g; (5) The molar ratio of the cuprous salt to the fluoride salt is 1:(1~10), preferably 1:(3~7); (6) The molar ratio of the cuprous salt to the TMSCF3 is 1:(1~10), preferably 1:(3~6); (7) The molar ratio of the tetraphenylphosphine chloride to the cuprous salt is 1:(1~10), preferably 1:1; (8) In step (a), the reaction temperature is 10~100 ℃, preferably 25 ℃; (9) In step (b), the reaction temperature is 10~100 ℃, preferably 25 ℃; (10) In step (a), the reaction is carried out under an inert gas, wherein the inert gas is selected from one or more of nitrogen, helium and argon, preferably argon; (11) In step (b), the reaction is carried out under an inert gas, wherein the inert gas is selected from one or more of nitrogen, helium and argon, preferably argon; (12) In step (a), the reaction time is 10 min to 24 h, preferably 30 min; (13) In step (b), the reaction time is 10 to 100 min, preferably 30 min; (14) In step (b), the reaction includes the following post-processing steps: after the reaction is completed, the reaction solution is filtered through diatomaceous earth, washed (preferably tetrahydrofuran), concentrated, precipitated solid by adding diethyl ether, and recrystallized (preferably by recrystallizing tetrahydrofuran and diethyl ether) to obtain compound b.

8. A compound as shown in formula c: 。 9. The use of a compound of formula d as described in claim 1 or 2 as a fluorinating agent in a fluorination reaction; Preferably, the fluorination reaction is an alkyl fluorination reaction; More preferably, the alkyl fluorination reaction comprises the following steps: In a solvent, compound I reacts with a compound as shown in formula d to form compound II; ； in, R1, R2, R3 and R4 are as described in claim 1 or 2.

10. The application as described in claim 9, characterized in that, The alkyl fluorination reaction satisfies one or more of the following conditions: (1) The solvent is selected from one or more of tetrahydrofuran, dichloromethane and acetonitrile, preferably dichloromethane, and more preferably ultra-dry dichloromethane; (2) The volume-to-mass ratio of the solvent to the compound shown in formula d is 10 mL / g to 100 mL / g, preferably 25 mL / g to 35 mL / g, and more preferably 32 mL / g; (3) The molar ratio of compound I to the compound shown in formula d is 1:(1~10), preferably 1:2; (4) The reaction temperature is 10~100 ℃, preferably 25 ℃; (5) The reaction time is 10 min to 24 h, preferably 30 min; (6) The reaction is carried out under an inert gas, which is selected from one or more of nitrogen, helium and argon, preferably argon.

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