A method for synthesizing organophosphonyl fluorides

Abstract

This invention discloses a method for synthesizing organophosphonic fluoride compounds. The method involves fluorinating organophosphonic oxides with fluorinating agents such as copper tetraacetonitrile hexafluorophosphate or copper tetraacetonitrile tetrafluoroborate to obtain organophosphonic fluoride compounds. The fluorinating agents used in this synthesis method are inexpensive, readily available, and stable, avoiding the use of expensive and unstable fluorinating agents. Furthermore, it enables efficient and selective conversion of organophosphonic oxides to organophosphonic fluoride compounds under mild conditions, and exhibits a wide range of functional group tolerances.

Description

Technical Field

[0001] This invention relates to a method for synthesizing organophosphonic fluoride compounds, and particularly to a method for synthesizing organophosphonic fluoride compounds from organophosphonic oxides under the action of fluorinating agents such as copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, sodium tetrafluoroborate, ammonium hexafluorophosphate, or potassium hexafluorophosphate, which belongs to the field of organic synthesis. Background Technology

[0002] Organophosphonic fluoride compounds contain phosphoryl fluoride bonds (O=PF) in their molecules and are a class of biologically active compounds, often used as probes or effective inhibitors in enzymatic reactions. Since the last century, the preparation, properties, and applications of organophosphonic fluoride compounds have received widespread attention and research.

[0003] The reaction of phosphine-containing organic compounds with specific fluorinating agents is an important route for preparing phosphoryl fluorine bonds. However, these reactions have drawbacks such as harsh reaction conditions, long reaction time, and the need to use expensive, unstable, and moisture-sensitive reagents.

[0004] In recent years, chemists have developed nucleophilic fluorination reactions between organophosphonic oxides containing P(O)-H bonds and fluoride ions, effectively synthesizing organophosphonic fluoride compounds under relatively mild reaction conditions. Due to the weak nucleophilic properties of fluoride ions, these reactions often require the addition of copper catalysts, chlorides, or other oxidants to first convert P(O)-H to other intermediates such as P(O)-Cl, and then prepare organophosphonic fluoride compounds through nucleophilic reactions with fluoride ions (J.Org.Chem.2016,81,10043-10048,Chem.Commun.,2014,50,10879-10882,Tetrahedron Letters 59(2018)2965–2969).

[0005] Recently, Chinese patent (CN 112174761A) disclosed the method of obtaining phosphoroyl fluoride products by using perfluoropolyether chain carboxylate fluorinating agents to fluorinate phosphoxy compounds. However, the selectivity of directly fluorinating phosphoxy compounds with perfluoropolyether chain carboxylate is relatively low, and the intermediate obtained needs to be further converted into phosphoroyl fluoride products by water. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the present invention aims to provide a method for the direct fluorination of organophosphoric oxides to synthesize organophosphoric fluoride compounds with high yield and high selectivity. This method uses fluorinating reagents with good stability, low cost, mild conditions, and simple steps, thus overcoming the shortcomings of existing methods for synthesizing organophosphoric fluoride compounds from organophosphoric oxides.

[0007] To achieve the above-mentioned technical objectives, the present invention provides a method for synthesizing organophosphonic fluoride compounds, wherein an organophosphonic oxide compound is subjected to a fluorination reaction in the presence of a fluorinating agent to obtain an organophosphonic fluoride compound;

[0008] The organophosphorus oxide has the following structural formula:

[0009] The organophosphonic fluoride compound has the following structural formula:

[0010] Among them, R1 and R2 are independently selected from C1 to C2. 10 The saturated aliphatic hydrocarbon group, phenyl, naphthyl, benzyl, or substituted phenyl group; wherein the substituted phenyl group contains a substituent of C1 to C2. 10 Alkyl or C1-C 10 Alkoxy;

[0011] The fluorinating agent includes at least one of copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, sodium tetrafluoroborate, ammonium hexafluorophosphate, and potassium hexafluorophosphate.

[0012] In the organophosphonic fluoride compounds of this invention, R1 and R2 are substituent groups introduced by organophosphonic oxide compounds. Generally, R1 and R2 are relatively stable substituent groups and will not be fluorinated by fluorinating agents such as copper tetraacetonitrile hexafluorophosphate or copper tetraacetonitrile tetrafluoroborate. R1 and R2 can be the same substituent group or different substituent groups, but they are more commonly the same substituent group. R1 and R2 are independently selected from C1 to C2. 10 The saturated aliphatic hydrocarbon group, phenyl, naphthyl, benzyl, or substituted phenyl group; said substituted phenyl group contains C1 to C2. 10 saturated aliphatic hydrocarbon groups or C1-C 10 Alkyl groups. C1~C 10 The saturated aliphatic hydrocarbon group can be a straight-chain alkyl group, such as n-butyl, n-octyl, etc. When the number of carbon atoms is 3 or more, it may also contain cycloalkyl or branched alkyl groups, such as cyclohexyl, isopentyl, etc. The substituted phenyl group is a group derived from phenyl and contains common substituents on the benzene ring, such as C1-C2. 10 Alkyl or C1-C 10 Alkyl groups, etc., C1 to C 10 Alkyl groups such as methyl, ethyl, hexyl, octyl, etc., and when the number of carbon atoms is 3 or more, they can also be branched alkyl groups, such as isopropyl isopentyl, etc.; C1~C 10 Alkyl groups such as methoxy, propoxy, isobutoxy, etc.

[0013] The organophosphorus oxides of the present invention are commonly as follows: diphenylphosphine oxide, bis(p-methylphenyl)phosphine oxide, bis(p-methoxyphenyl)phosphine oxide, bis(m-methylphenyl)phosphine oxide, bis(m-methoxyphenyl)phosphine oxide, dibenzylphosphine oxide, dihexylphosphine oxide, 1,1'-dinaphthylphosphine oxide, and dicyclohexylphosphine oxide.

[0014] As a preferred embodiment, the molar ratio of the fluorinating agent to the organophosphorus oxide is 0.2–1.2:1. The preferred fluorinating agent contains 4 or 6 fluorine substituents, all of which can undergo fluorination reactions. Controlling the molar ratio of the fluorinating agent within a preferred range is beneficial for ensuring efficient fluorination of the organophosphorus oxide.

[0015] As a preferred embodiment, the fluorinating agent includes copper tetraacetonitrile hexafluorophosphate and / or copper tetraacetonitrile tetrafluoroborate. Fluorination reactions of organophosphorus oxides can also proceed smoothly using fluorinating agents such as sodium tetrafluoroborate, ammonium hexafluorophosphate, and potassium hexafluorophosphate, but the yield of the target product is relatively low. Copper tetraacetonitrile hexafluorophosphate and copper tetraacetonitrile tetrafluoroborate, however, have a more beneficial fluorination effect on organophosphorus oxides.

[0016] As a preferred embodiment, the fluorination reaction uses at least one of the following media: THF, CH3CN, 1,4-dioxane, CH2Cl2, toluene, DMF, DMSO, ethanol, methanol, choline chloride / urea, choline chloride / 1,3-propanediol, and choline chloride / glycerol. Different reaction media have a certain influence on the fluorination reaction of organophosphorus oxides. Through screening a large number of reaction media, the most preferred reaction media are THF and / or CH3CN.

[0017] As a preferred embodiment, the fluorination reaction is carried out under a protective atmosphere at a temperature above 40°C for at least 2 hours. As a more preferred embodiment, the fluorination reaction is carried out under a protective atmosphere at a temperature of 50°C–100°C for 4–8 hours. With increasing reaction temperature and reaction time, the fluorination efficiency of organophosphorus oxides increases, and the yield of the target product relatively improves. However, the yield of the target product reaches its peak at a reaction temperature of around 60°C and a reaction time of 6 hours. Further increasing the temperature or extending the reaction time may lead to side reactions, resulting in a decrease in the yield of the target product. The most preferred reaction temperature is 60–70°C, and the most preferred reaction time is 5–7 hours. The protective atmosphere may be nitrogen or an inert gas such as argon.

[0018] After the fluorination reaction of the present invention is completed, dichloromethane, trichloromethane, diethyl ether, ethyl acetate or toluene is used as an extractant to separate the organophosphonic fluoride compound.

[0019] The reaction mechanism of the organophosphonic oxide compound of the present invention, which is converted into an organophosphonyl complex by fluorination, is as follows: Under appropriate temperature conditions, the organophosphonic oxide compound isomerizes into intermediate A. A undergoes a nucleophilic substitution reaction with the hexafluorophosphate group in copper tetraacetonitrile hexafluorophosphate to obtain intermediates B and F. - F - The intermediate B undergoes a nucleophilic substitution reaction to give intermediate C. Intermediate C loses a hydrogen ion to give the target product.

[0020]

[0021] Compared with existing technologies, the beneficial technical effects of the present invention are as follows:

[0022] 1) The fluorinating reagents used in this invention are all common commercially available fluorine-containing compounds, which are inexpensive and readily available, thus helping to reduce costs. They also have good stability, thus avoiding the use of expensive and unstable fluorinating reagents.

[0023] 2) The fluorinating reagents such as Cu(MeCN)4PF6, Cu(MeCN)4BF4, NaBF4, NH4PF6 or KPF6 used in this invention can synthesize organophosphonic fluoride compounds with high yield and high selectivity under relatively mild reaction conditions, and have a wide range of functional group tolerance. Detailed Implementation

[0024] To make the above-described features, advantages, and objectives of the present invention more apparent, a detailed description of specific embodiments of the present invention is provided below. Many specific details are set forth in the description below to provide a thorough understanding of the present invention. However, the present invention can be practiced in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0025] Example of optimal condition selection:

[0026] The following examples are examples using diphenylphosphine oxide as the reaction substrate, and the optimal reaction conditions were determined through optimization experiments: At room temperature, under nitrogen protection, 0.5 mmol of diphenylphosphine oxide, 0.5 mmol of Cu(MeCN)₄PF₆, and 5 mL of THF were added to a 25 mL two-necked flask. The flask was then placed in an oil bath reactor with magnetic stirring, and the reaction was carried out at 60 °C for 6 h. After the reaction was complete, 10 mL of water and 10 mL of ethyl acetate were added for extraction and separation. The product, diphenylphosphine fluoride, was obtained by column chromatography in 92% yield.

[0027] It is worth noting that the addition of water in the examples is only to promote phase separation and facilitate extraction and separation, and the addition of water does not affect the selectivity and yield of diphenylphosphine fluoride.

[0028] Diphenylphosphofluoride is a yellow, oily liquid.

[0029] 1 H NMR (500MHz, CDCl3): δ7.45-7.52(m,4H),7.58-7.64(m,2H),7.78-7.86(m,4H);

[0030] 13 C NMR (100MHz, CDCl3): δ128.7(dd,J=140.2,22.3Hz), 128.9(d,J=14.6Hz), 131.3(dd,J=11.5,1.7Hz), 133.6(d,J=2.5Hz);

[0031] 31 P NMR (162MHz, CDCl3): δ40.87 (d, J=1019.9Hz);

[0032] 19 F NMR (376MHz, CDCl3): δ-74.98 (d, J=1019.7Hz);

[0033] The following experimental groups 1-20, using the above examples as a reference, provide a comparative explanation of the conversion of diphenylphosphine oxide to diphenylphosphine fluoride under different conditions:

[0034]

[0035] The experimental groups 1-5 in the table above investigated the effects of different fluorinating agents on the fluorination reaction of organophosphorus oxides. The experiments showed that copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, sodium tetrafluoroborate, ammonium hexafluorophosphate, and potassium hexafluorophosphate could all be used as fluorinating agents to facilitate the fluorination reaction of organophosphorus oxides. However, when copper tetraacetonitrile hexafluorophosphate or copper tetraacetonitrile tetrafluoroborate was used as the fluorinating agent, the yield of the target product could reach about 90%, which was significantly better than other fluorinating agents.

[0036] The experimental groups 1 and 6-7 in the table above investigated the effect of different amounts of fluorinating agent on the fluorination reaction of organophosphorus oxides. The experiments showed that increasing the amount of fluorinating agent is beneficial to improving the yield of the target product, but when the amount of fluorinating agent increases to a certain level, the effect on the yield of the target product is not significant.

[0037] The experimental groups 1 and 8-15 in the table above investigated the effects of different reaction temperatures and times on the fluorination reaction of organophosphorus oxides. The experiments showed that within a certain range, increasing the reaction temperature and reaction time is beneficial for the fluorination reaction of organophosphorus oxides and can increase the yield of the target product. However, the yield of the target product reaches its peak at a reaction temperature of around 60℃ and a reaction time of 6 hours. Further increasing the temperature or extending the reaction time may lead to side reactions, resulting in a decrease in the yield of the target product. On the other hand, if the reaction temperature is too low or the reaction time is too short, the yield of the target product will decrease significantly. Therefore, the optimal reaction temperature is 60-70℃ and the optimal reaction time is 5-7 hours.

[0038] The table above shows the effects of different reaction media on the fluorination reaction of organophosphorus oxides in experimental groups 1, 16-20. The experiments show that tetrahydrofuran or acetonitrile is the best reaction medium, which can significantly promote the fluorination reaction and help it reach its optimal state. Although organic solvents such as methanol, ethanol, and DMSO, as well as eutectic solvents such as choline chloride / urea (ChCl / Urea), choline chloride / 1,3-propanediol (ChCl / 1,3-propanediol), and choline chloride / glycerol (ChCl / Glycerine) can all facilitate the reaction, their effects are far inferior to those of tetrahydrofuran.

[0039] Examples 1-8 below, under optimal reaction conditions, investigated the reaction effects of different organophosphorus oxides on the conversion to organophosphoryl fluorides. The specific steps are as follows:

[0040] Under nitrogen protection at room temperature, 0.5 mmol of organophosphorus oxide, 0.5 mmol of Cu(MeCN)₄PF₆, and 5 mL of THF were added to a 25 mL two-necked flask. The flask was then placed in an oil bath reactor with magnetic stirring and reacted at 60 °C for 6 h. After the reaction was complete, 10 mL of water and 10 mL of ethyl acetate were added for extraction and separation, and the target product was obtained by column chromatography.

[0041] Example 1

[0042] The structural formula of the target product is as follows:

[0043]

[0044] The target product is a yellow liquid with a yield of 89%.

[0045] 1 H NMR (500MHz, CDCl3): δ2.38(s,6H),7.26-7.30(m,4H),7.66-7.74(m,4H);

[0046] 13C NMR (100MHz, CDCl3): δ21.5, 125.6 (dd, J = 143.6, 22.1Hz), 129.4 (d, J = 14.3Hz), 131.1 (dd, J = 11.6, 1.9Hz), 144.2 (d, J = 2.5Hz);

[0047] 31 P NMR (162MHz, CDCl3): δ41.98 (d, J=1016.2Hz);

[0048] 19 F NMR (376MHz, CDCl3): δ-75.26 (d, J=1016.9Hz).

[0049] Example 2

[0050] The structural formula of the target product is as follows:

[0051]

[0052] The target product is a colorless liquid with a yield of 87%.

[0053] 1 H NMR (500MHz, CDCl3): δ3.87(s,6H),6.90(m,4H),7.6(m,4H);

[0054] 13 C NMR (100MHz, CDCl3): δ55.31, 114.23 (d, J = 15.0Hz), 120.14 (d, J = 149.0, 23.9Hz), 133.26 (d, J = 11.0, 2.0Hz), 163.32 (d, J = 3.0Hz);

[0055] 31 P NMR (162MHz, CDCl3): δ42.38 (d, J=1010.7Hz);

[0056] 19 F NMR (376MHz, CDCl3): δ72.72 (d, J=1010.4Hz).

[0057] Example 3

[0058] The structural formula of the target product is as follows:

[0059]

[0060] The target product is a colorless oily liquid with a yield of 89%.

[0061] 1 H NMR (500MHz, CDCl3): δ2.46(s,6H),7.35-7.42(m,4H),7.56-7.70(m,4H);

[0062] 13 C NMR (100MHz, CDCl3): δ22.0, 127.8 (dd, J=11.5, 2.3Hz), 129.1 (d, J=15.0Hz), 129.6 (dd, J=139.8, 21.6Hz), 132.3 (dd, J=11.6, 2.4Hz), 133.7 (d, J=2.3Hz), 139.2 (d, J=13.6Hz);

[0063] 31 P NMR (162MHz, CDCl3): δ41.66 (d, J=1020.2Hz);

[0064] 19 F NMR (376MHz, CDCl3): δ-75.51 (d, J=1020.5Hz).

[0065] Example 4

[0066] The structural formula of the target product is as follows:

[0067]

[0068] The target product is a white solid with a yield of 82%.

[0069] 1 H NMR (300MHz, CDCl3): δ3.76(s,6H),7.10-7.16(m,2H),7.29-7.42(m,6H);

[0070] 13 C NMR (100MHz, CDCl3): δ54.7, 115.6 (dd, J = 12.2, 2.4Hz), 120.1 (d, J = 2.6Hz), 124.1 (dd, J =11.4, 2.1Hz), 129.1 (dd, J = 140.2, 22.5Hz), 130.7 (d, J = 17.2Hz), 160.1 (d, J = 17.2Hz);

[0071] 31 P NMR (162MHz, CDCl3): δ40.7 (d, J=1019.8Hz);

[0072] 19F NMR (376MHz, CDCl3): δ-74.9 (d, J=1019.8Hz).

[0073] Example 5

[0074] The structural formula of the target product is as follows:

[0075]

[0076] The target product is a colorless liquid with a yield of 86%.

[0077] 1 H NMR (500MHz, CDCl3): 3.16 (dd, J=16.0, J=8.7Hz, 4H), 7.19-7.23 (m, 4H), 7.31-7.40 (m, 6H);

[0078] 13 C NMR (100MHz, CDCl3): δ35.0 (dd, J = 86.3, 14.8Hz), 127.3 (d, J = 3.8Hz), 128.6 (d, J = 2.9Hz), 129.7 (d, J = 7.7Hz), 130.2 (d, J = 5.9Hz);

[0079] 31 P NMR (162MHz, CDCl3): δ58.16 (d, J=1039.8Hz);

[0080] 19 F NMR (376MHz, CDCl3): δ-77.22 (d, J=1039.8Hz).

[0081] Example 6

[0082] The structural formula of the target product is as follows:

[0083]

[0084] The target product is a yellow liquid with a yield of 79%.

[0085] 1 H NMR (500MHz, CDCl3): 1.09–1.29 (m, 6H), 1.35–1.55 (m, 4H), 1.72 (d, J = 1.7Hz, 2H), 1.75–1.90 (m, 8H), 1.90–1.98 (m, 2H);

[0086] 13C NMR (400MHz, CDCl3): δ24.53 (dd, J = 4.5, 90.3Hz), 25.82 (dd, J = 3.0, 11.2Hz), 34.39 (d, J = 13.8Hz), 35.21 (d, J = 12.8Hz);

[0087] 31 P NMR (162MHz, CDCl3): δ70.65 (d, J=1033.8Hz);

[0088] 19 F NMR (376MHz, CDCl3): δ-95.06 (d, J=1033.8Hz).

[0089] Example 7

[0090] The structural formula of the target product is as follows:

[0091]

[0092] The target product is a white solid with a yield of 87%.

[0093] 1 H NMR (500MHz, CDCl3): δ7.50-7.63(m,6H),7.88-7.94(m,2H),7.99(dd,J=16.7,7.6Hz,2H),8.13(d,J=7.9Hz,2H),8.53-8.62(m,2H);

[0094] 13 C NMR (100MHz, CDCl3): δ124.8 (d, J = 15.8Hz), 125.5 (dd, J = 136.7, 18.6Hz), 126.6 (d, J = 5.8Hz), 127.3, 128.4, 1 29.7(d,J=1.8Hz), 133.3(d,J=11.2Hz), 133.8(d,J=11.6Hz), 134.5(dd,J=11.8,4.2Hz), 134.9(d,J=2.9Hz);

[0095] 31 P NMR (162MHz, CDCl3): δ44.56 (d, J=1020.7Hz);

[0096] 19 F NMR (376MHz, CDCl3): δ-68.07 (d, J=1020.7Hz).

[0097] Example 8

[0098] The structural formula of the target product is as follows:

[0099]

[0100] The target product is a colorless liquid with a yield of 68%.

[0101] 1 H NMR (500MHz, CDCl3): δ0.82 (t, J=6.6Hz, 6H), 1.24-1.36 (m, 8H), 1.38-1.47 (m, 4H), 1.56-1.70 (m, 4H), 1.79-1.91 (m, 4H);

[0102] 13 C NMR (100MHz, CDCl3): δ14.3, 21.5 (d, J = 4.8Hz), 22.5, 28.1 (dd, J = 88.3, ​​14.1Hz), 30.5 (d, J = 14.2Hz), 31.6;

[0103] 31 P NMR (162MHz, CDCl3): δ70.53 (d, J=1017.7Hz);

[0104] 19 F NMR (376MHz, CDCl3): δ-78.67 (d, J=1017.7Hz).

Claims

1. A method for synthesizing an organophosphonic fluoride compound, characterized in that: Organophosphorus oxides undergo fluorination reactions in the presence of fluorinating agents to yield organophosphoryl fluorides; The organophosphorus oxide has the following structural formula: ； The organophosphonic fluoride compound has the following structural formula: ； Among them, R1 and R2 are independently selected from C1 to C2. 10 The saturated aliphatic hydrocarbon group, phenyl, naphthyl, benzyl, or substituted phenyl group; wherein the substituted phenyl group contains a substituent of C1~C2. 10 Alkyl or C1~C 10 Alkoxy; The fluorination reaction is carried out under a protective atmosphere at a temperature of 50°C to 100°C for 4 to 8 hours. The fluorinating agent is copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, sodium tetrafluoroborate, ammonium hexafluorophosphate, or potassium hexafluorophosphate.

2. The method for synthesizing an organophosphonic fluoride compound according to claim 1, characterized in that: The molar ratio of the fluorinating agent to the organophosphorus oxide is 0.2~1.2:

1.

3. The method for synthesizing an organophosphonic fluoride compound according to claim 1 or 2, characterized in that: The fluorinating agent is copper tetraacetonitrile hexafluorophosphate or copper tetraacetonitrile tetrafluoroborate.

4. The method for synthesizing an organophosphonic fluoride compound according to claim 1, characterized in that: The fluorination reaction is carried out in the following media: THF, CH3CN, 1,4-dioxane, CH2Cl2, toluene, DMF, DMSO, ethanol, methanol, choline chloride / urea, choline chloride / 1,3-propanediol, or choline chloride / glycerol.

5. The method for synthesizing an organophosphonic fluoride compound according to claim 4, characterized in that: The fluorination reaction uses THF or CH3CN as the reaction medium.

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