A method for synthesizing β-fluoroallyl phosphine

Abstract

The present application discloses a method for synthesizing β-fluoroallyl phosphine, and belongs to the field of organic synthesis technology. The method is based on difluorocyclopropane derivatives and phosphites or diaryl phosphine oxides as raw materials, under the catalysis of palladium and ligands, using dioxane as solvent, adding alkali, and preparing β-fluoroallyl phosphine derivatives. The method of the present invention has the advantages of low reaction cost, simple operation, and few side reactions. The method can construct β-fluoroallyl phosphine compounds in one step, which is suitable for large-scale production with a yield of up to 89%.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing beta-fluoroallyl phosphine. Background Art

[0002] Phosphine compounds are important components of many biologically active substances and are closely related to life activities. Fluorinated olefins are important reaction building blocks in organic synthesis and can also be used as monomers for the preparation of fluorinated polymer materials. Therefore, β-fluoroallyl phosphine with coexistence of phosphine and fluorine has important scientific research and application value.

[0003] The types of phosphorus-containing organic compounds that have been reported to be synthesized currently mainly include aryl phosphines, alkyl phosphines, alkynyl phosphines, alkenyl phosphines, etc., while no effective synthesis method has been invented for the synthesis of fluorine-containing allyl phosphine compounds.

[0004] In addition, it was found through literature review that in the reported synthesis methods for preparing the above-mentioned phosphorus-containing organic compounds, toxic phosphorus halides are often used as phosphine sources or unstable metal organics are used as reaction components to participate in the conversion, which has the disadvantages of harsh reaction conditions and being environmentally unfriendly.

[0005] In summary, the art still lacks an effective method for preparing fluorine-containing allyl phosphine derivatives using a safe, readily available and highly operable phosphine source. Summary of the invention

[0006] Technical issues solved:

[0007] The present application aims at the deficiencies of the prior art, solves the technical problems such as the harsh reaction process conditions and environmental unfriendliness, and provides a method for synthesizing β-fluoroallyl phosphine. The required raw materials are safe and easily available, the cost is low, the reaction conditions are mild, the yield is high, and the post-processing is simple.

[0008] Technical solution:

[0009] To achieve the above objectives, this application is implemented through the following technical solutions:

[0010] A method for synthesizing beta-fluoroallyl phosphine comprises taking 1,1-difluorocyclopropane derivatives and phosphite or diaryl phosphine oxide as reactants, reacting under the mixed action of palladium catalyst, phosphine ligand, base and solvent to obtain beta-fluoroallyl phosphine derivatives.

[0011] Furthermore, the specific steps of the synthesis method are:

[0012] The first step is to add 1,1-difluorocyclopropane derivatives and phosphite or diarylphosphine oxide derivatives into a reaction tube, and then add palladium catalyst, phosphine ligand, and base in sequence; exhaust the air in the reaction container and replace it with inert gas, then add solvent, seal it,

[0013] Stir at room temperature for 15 minutes, then heat to 90-120°C for reaction, the reaction time is 12-16 hours;

[0014] Step 2: Use thin layer chromatography to monitor the progress of the reaction until the reaction raw materials disappear completely; cool the reaction system, extract, use ethyl acetate as an extractant, wash twice with water, collect the organic phase, dry it over anhydrous sodium sulfate, concentrate it under reduced pressure, and then separate it by column chromatography to obtain β-fluoroallyl phosphine derivatives.

[0015] Further, the reaction formula of the method is as follows:

[0016]

[0017] In the formula, R 1 ,R 2 and R 3 These include, but are not limited to, aryl, heteroaryl, and alkyl.

[0018] Furthermore, the 1,1-difluorocyclopropane derivative is 2-(2,2-difluorocyclopropyl)naphthalene, 4-(2,2-difluorocyclopropyl)-N,N-dimethylaniline, 1-(2,2-difluorocyclopropyl)-2-methoxybenzene, (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl-4-(2,2-difluorocyclopropyl)benzoate or 8R, 9S, 13S, 14S)-3-(2,2-difluorocyclopropyl)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthrene-17-one; the phosphite is diisopropyl phosphite or ethyl phenylphosphonate; and the diaryl phosphine oxide is bis(p-methoxyphenyl)phosphine oxide.

[0019] Furthermore, the palladium catalyst is palladium acetate, palladium chloride, diacetonitrile palladium dichloride, palladium trifluoroacetate, ditriphenylphosphine palladium dichloride, allyl palladium chloride or tetrakistriphenylphosphine palladium.

[0020] Furthermore, the phosphine ligand is a triphenylphosphine ligand derivative, a trialkylphosphine ligand derivative, a bidentate phosphine ligand, a Buchwald ligand or a carbene ligand.

[0021] Furthermore, the base is cesium carbonate, potassium carbonate, potassium tert-butoxide, potassium phosphate, sodium phosphate or lithium tert-butoxide.

[0022] Furthermore, the solvent is dioxane, acetonitrile, toluene, ethylene glycol dimethyl ether, tetrahydrofuran or 1,2-dichloroethane.

[0023] Furthermore, in the first step, the reaction is stirred with a magnetic stirrer at 500 to 700 rpm for 12 to 16 hours; in the second step, the mobile phase eluent used in the column chromatography is a volume ratio of petroleum ether to ethyl acetate of 2:1 to 1:2.

[0024] Furthermore, the molar ratio of the palladium catalyst to the ligand is 1:2; the molar ratio of the palladium catalyst to the 1,1-difluorocyclopropane derivative is 1:10; the molar ratio of the base to the 1,1-difluorocyclopropane derivative is 3:1; and the concentration of the 1,1-difluorocyclopropane derivative in the mixed solution containing the solvent is 0.1 mol / L.

[0025] The principle of the above-mentioned synthesis method of β-fluoroallyl phosphine is that under the action of palladium catalyst, difluorocyclopropane derivatives undergo ring opening and elimination reactions to produce β-fluoroallyl palladium intermediates, and then under the action of base, the phosphine atom in phosphite or diaryl phosphine oxide derivatives acts as a nucleophilic center to carry out nucleophilic attack on the β-fluoroallyl palladium intermediate, and finally produce β-fluoroallyl phosphine compounds.

[0026] Beneficial effects:

[0027] The present application provides a method for synthesizing β-fluoroallyl phosphine, which has the following beneficial effects compared with the prior art:

[0028] 1. The synthesis method of β-fluoroallyl phosphine provided by the present invention has low cost, simple operation steps, and can construct β-fluoroallyl phosphine in one step. The raw materials are easily available, and the solvent does not need to be further processed. The reaction is efficient and the yield is as high as 89%. At the same time, the product can be used in the synthesis of drugs.

[0029] 2. The method of the present invention can be used to produce active drug molecules containing β-fluoroallyl phosphine in a high yield in one step, making up for the shortcomings of multiple steps and low yield in the current synthesis of such molecules.

[0030] 3. The Z / E selectivity ratio of the β-fluoroallyl phosphine produced by the present invention is greater than 30:1; this excellent selectivity is difficult to achieve with the current prior art methods. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0032] A method for synthesizing β-fluoroallyl phosphine is shown in the following formula:

[0033]

[0034] In the formula, R 1 ,R 2 and R 3 These include, but are not limited to, aryl and alkyl.

[0035] The specific steps are:

[0036] (1) Add 1,1-difluorocyclopropane derivatives and phosphite or diarylphosphine oxide derivatives to a reaction tube, and then add palladium catalyst, phosphine ligand, and base in sequence; exhaust the air in the reaction vessel and replace it with an inert gas (such as argon, nitrogen, etc.), then add a solvent, seal it, stir at room temperature for 10 minutes, and then heat it to 90-120°C for reaction, and the reaction time is 12 to 16 hours.

[0037] (2) Use thin layer chromatography to monitor the progress of the reaction. When the reaction raw materials disappear completely, cool the reaction system, extract, use ethyl acetate as an extractant, wash twice with water, collect the organic phase, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then separate by column chromatography to obtain β-fluoroallyl phosphine derivatives.

[0038] The palladium catalyst is one of palladium acetate, palladium chloride, diacetonitrile palladium dichloride, palladium trifluoroacetate, ditriphenylphosphine palladium dichloride, allyl palladium chloride or tetrakistriphenylphosphine palladium.

[0039] The phosphine ligand is one of a triphenylphosphine ligand derivative, a bidentate phosphine ligand, a Buchwald ligand or a carbene ligand.

[0040] The base is one of cesium carbonate, potassium carbonate, potassium tert-butoxide, potassium phosphate, sodium phosphate or lithium tert-butoxide.

[0041] The solvent is one of dioxane, acetonitrile, toluene, ethylene glycol dimethyl ether, tetrahydrofuran or 1,2-dichloroethane.

[0042] The molar ratio of the palladium catalyst to the ligand is 1:2; the molar ratio of the palladium catalyst to the 1,1-difluorocyclopropane derivative is 1:10; the molar ratio of the base to the 1,1-difluorocyclopropane derivative is 3:1; and the concentration of the 1,1-difluorocyclopropane derivative in the mixed solution containing the solvent is 0.1 mol / L.

[0043] The mobile phase eluent used in column chromatography: the volume ratio of petroleum ether and ethyl acetate is 2:1 to 1:2.

[0044] Embodiment 1:

[0045] A method for synthesizing β-fluoroallyl phosphine, synthesis of diisopropyl (Z)-(2-fluoro-3-(naphthalene-2-yl)allyl)phosphonate

[0046]

[0047] 2-(2,2-difluorocyclopropyl)naphthalene (81.6 mg, 0.4 mmol), diisopropyl phosphite (76.4 mg, 0.46 mmol), allyl palladium chloride (21.8 mg, 0.06 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (46.3 mg, 0.08 mmol) and potassium phosphate (168.8 mg, 0.8 mmol) were added to a 25 mL pressure-resistant reaction tube, and argon was filled in a vacuum. Then 4 ml of 1,4-dioxane was added, sealed, stirred at room temperature for 15 minutes, and then placed in a magnetic stirrer at a temperature of 110 ° C and stirred for 12 hours. After the reaction was complete, 1 mL of water was added to quench, extracted with ethyl acetate 3 times, the organic phases were combined, dried over anhydrous Na2SO4, and dried by spin drying, and finally purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a colorless liquid product (102 mg, yield 74%).

[0048] 1 H NMR (400MHz, CDCl3) δ7.81(s,1H),7.71(t,J=7.5Hz,3H),7.56(d,J=8.6Hz,1H),7.40–7.33(m,2H),5.73(d d,J=38.4,4.5Hz,1H),4.70(h,J=6.4Hz,2H),2.85(dd,J=21.5,19.1Hz,2H),1.26(dd,J=6.3,2.7Hz,12H). 13 C NMR (101MHz, CDCl3) δ133.46,132.51,130.81,128.13,128.05,127.61,127.55,127.50,127.48,126.55,126.54,126.48, 126.23,126.06,109.89,109.81,109.78,109.70,71.41,71.35,34.01,33.72,32.59,32.30,24.18,24.14,24.04,23.99. 19 F NMR (376MHz, CDCl3) δ-95.87 (d, J=5.2Hz). 31 P NMR (162MHz, CDCl3) δ20.38 (d, J = 5.2Hz). HRMS (ESI) m / z: [M+H] +Calculate for C 19 H 25 FO3P 351.1520; found:351.1533.

[0049] Embodiment 2:

[0050] A method for synthesizing β-fluoroallyl phosphine, synthesis of diisopropyl (Z)-(3-(4-(dimethylamino)phenyl)-2-fluoroallyl)phosphonate

[0051]

[0052] 4-(2,2-difluorocyclopropyl)-N,N-dimethylaniline (78.8 mg, 0.4 mmol), diisopropyl phosphite (76.4 mg, 0.46 mmol), allylpalladium chloride (21.8 mg, 0.06 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46.3 mg, 0.08 mmol) and potassium phosphate (168.8 mg, 0.8 mmol) were added to a 25 mL pressure-resistant reaction tube, and the tube was evacuated and filled with argon. Subsequently, 4 ml of 1,4-dioxane was added, the tube was sealed, stirred at room temperature for 15 minutes, and then placed in a magnetic stirrer at 110°C and stirred for 14 hours. After the reaction was complete, 1 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous Na2SO4, and spin-dried. Finally, the product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a colorless liquid (118 mg, yield 86%).

[0053] 1 H NMR (400MHz, CDCl3) δ7.30(d,J=8.6Hz,2H),6.60(d,J=8.7Hz,2H),5.47(dd,J=39.4,4.6Hz,1H ),4.79–4.56(m,2H),2.88(s,6H),2.78(dd,J=21.3,19.1Hz,2H),1.26(dd,J=6.2,4.2Hz,12H). 13 C NMR (101MHz, CDCl3) δ149.59,129.59,129.57,129.52,129.50,121.76,112.29,109.65,109.57 ,109.54,109.46,71.25,71.19,40.53,33.84,33.55,32.42,32.13,24.23,24.19,24.07,24.02. 19 F NMR (376MHz, CDCl3) δ-101.34 (d, J=6.1Hz). 31P NMR (162MHz, CDCl3) δ21.03 (d, J = 5.7Hz). HRMS (ESI) m / z: [M+H] + Calculate for C 17 H 28 FO3PN 344.1785; found:344.1779.

[0054] Embodiment 3:

[0055] A method for synthesizing β-fluoroallyl phosphine, synthesis of diisopropyl (Z)-(2-fluoro-3-(2-methoxyphenyl)allyl)phosphonate

[0056]

[0057] 1-(2,2-difluorocyclopropyl)-2-methoxybenzene (73.6 mg, 0.4 mmol), diisopropyl phosphite (76.4 mg, 0.46 mmol), allyl palladium chloride (21.8 mg, 0.06 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (46.3 mg, 0.08 mmol) and potassium phosphate (168.8 mg, 0.8 mmol) were added to a 25 mL pressure-resistant reaction tube, and argon was filled in a vacuum. Then 4 ml of 1,4-dioxane was added, sealed, stirred at room temperature for 15 minutes, and then placed in a magnetic stirrer at a temperature of 110 ° C and stirred for 14 hours. After the reaction was complete, 1 mL of water was added to quench, extracted with ethyl acetate 3 times, the organic phases were combined, dried over anhydrous Na2SO4, and dried by spin drying. Finally, the product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain a colorless liquid (94 mg, yield 71%).

[0058] 1 H NMR (400MHz, CDCl3) δ7.67(dd,J=7.8,1.6Hz,1H),7.14(td,J=7.9,1.7Hz,1H),6.86(t,J=7.6Hz,1H),6.78(d,J=8.3Hz,1H),6.0 1(dd,J=39.4,4.6Hz,1H),4.69(dp,J=7.8,6.2Hz,2H),3.74(s,3H),2.83(dd,J=21.4,19.1Hz,2H),1.27(dd,J=6.2,2.2Hz,12H). 13C NMR (101MHz, CDCl3) δ156.02,129.94,129.92,129.81,129.79,128.43,128.41,120.65,110.46,103.34 ,103.27,103.23,103.16,71.32,71.25,55.54,34.13,33.84,32.71,32.42,24.19,24.15,24.01,23.96. 19 F NMR (376MHz, CDCl3) δ-98.46 (d, J=5.9Hz). 31 P NMR (162MHz, CDCl3) δ20.58 (d, J = 5.9Hz). HRMS (ESI) m / z: [M+H] + Calculate for C 16 H 25 FO4P 331.1469; found:331.1458.

[0059] Example 4

[0060] A method for synthesizing β-fluoroallyl phosphine, synthesis of diisopropyl (Z)-(3-(3-chlorophenyl)-2-fluoroallyl)phosphonate

[0061]

[0062] 1-(2,2-difluorocyclopropyl)-2-methoxybenzene (75.2 mg, 0.4 mmol), diisopropyl phosphite (76.4 mg, 0.46 mmol), allyl palladium chloride (21.8 mg, 0.06 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (46.3 mg, 0.08 mmol) and potassium phosphate (168.8 mg, 0.8 mmol) were added to a 25 mL pressure-resistant reaction tube, and argon was filled in a vacuum. Then 4 ml of 1,4-dioxane was added, sealed, stirred at room temperature for 15 minutes, and then placed in a magnetic stirrer at a temperature of 110 ° C and stirred for 14 hours. After the reaction was complete, 1 mL of water was added to quench, extracted with ethyl acetate 3 times, the organic phases were combined, dried over anhydrous Na2SO4, and dried by spin drying. Finally, the product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain a colorless liquid (92 mg, yield 69%).

[0063] 1H NMR(400MHz, CDCl3) δ7.49(d,J=2.0Hz,1H),7.35–7.31(m,1H),7.22(dd,J=14.5,7.8Hz,2H),5.63(dd,J=37.6 ,4.5Hz,1H),4.76(ddt,J=12.2,7.5,6.1Hz,2H),2.88(dd,J=21.6,19.2Hz,2H),1.34(dd,J=6.2,4.4Hz,12H). 13 C NMR (101MHz, CDCl3) δ134.87,134.31,129.68,128.36,128.34,128.28,128.26,127.28,127.26,126.62,126.60, 126.55,108.59,108.51,108.48,108.41,71.42,71.35,33.82,33.53,32.40,32.12,24.11,24.07,23.98,23.93. 19 F NMR (376MHz, CDCl3) δ-94.05 (d, J=4.6Hz). 31 P NMR (162MHz, CDCl3) δ19.96 (d, J = 4.4Hz). HRMS (ESI) m / z: [M+H] + Calculate for C 15 H 22 FClO3P 355.0974; found:355.0977.

[0064] Example 5

[0065] A method for synthesizing β-fluoroallyl phosphine, and synthesis of diethyl (Z)-(2-fluoro-3-(naphthalene-2-yl)allyl)phosphonate

[0066]

[0067] 2-(2,2-difluorocyclopropyl)naphthalene (81.6 mg, 0.4 mmol), diethyl phosphite (63.5 mg, 0.46 mmol), allyl palladium chloride (21.8 mg, 0.06 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (46.3 mg, 0.08 mmol) and potassium phosphate (168.8 mg, 0.8 mmol) were added to a 25 mL pressure-resistant reaction tube, and argon was filled in a vacuum. Then 4 ml of 1,4-dioxane was added, sealed, stirred at room temperature for 15 minutes, and then placed in a magnetic stirrer at a temperature of 110 ° C and stirred for 12 hours. After the reaction was complete, 1 mL of water was added to quench, extracted with ethyl acetate 3 times, the organic phases were combined, dried over anhydrous Na2SO4, and dried by spin drying. Finally, the product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a colorless liquid (115 mg, yield 89%).

[0068] 1 H NMR (400MHz, CDCl3) δ7.82(s,1H),7.71(dd,J=7.2,3.6Hz,3H),7.56(dd,J=8.6,1.7Hz,1H),7.37(td,J=5.9,5.3, 3.2Hz, 2H), 5.75 (dd, J=38.3, 4.5Hz, 1H), 4.21–4.02 (m, 4H), 2.89 (dd, J=21.5, 19.4Hz, 2H), 1.27 (t, J=7.0Hz, 6H). 13 C NMR (101MHz, CDCl3) δ133.47,132.59,130.68,128.15,128.08,127.71,127.68,127.63,126.56,126.54,126.48,1 26.47,126.28,126.13,110.07,110.00,109.96,109.89,62.73,62.66,32.99,32.70,31.59,31.29,16.55,16.49. 19 F NMR (376MHz, CDCl3) δ-96.58 (d, J=6.0Hz). 31 P NMR (162MHz, CDCl3) δ22.35 (d, J = 5.9Hz). HRMS (ESI) m / z: [M+H] + Calculate for C 17 H 21 FO3P323.1207; found:323.1216.

[0069] Embodiment 6:

[0070] A method for synthesizing β-fluoroallylphosphine, synthesis of ethyl (Z)-(2-fluoro-3-(naphthalene-2-yl)allyl)(phenyl)phosphonate

[0071]

[0072] 2-(2,2-difluorocyclopropyl)naphthalene (81.6 mg, 0.4 mmol), ethyl phenylphosphonate (78.2 mg, 0.46 mmol), allylpalladium chloride (21.8 mg, 0.06 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (46.3 mg, 0.08 mmol) and potassium phosphate (168.8 mg, 0.8 mmol) were added to a 25 mL pressure-resistant reaction tube, and argon was filled in a vacuum. Then 4 ml of 1,4-dioxane was added, sealed, stirred at room temperature for 15 minutes, and then placed in a magnetic stirrer at a temperature of 110 ° C and stirred for 12 hours. After the reaction is complete, 1 mL of water is added to quench, extracted with ethyl acetate 3 times, the organic phases are combined, dried over anhydrous Na2SO4, and dried by spin drying, and finally purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a colorless liquid product (93 mg, yield 66%).

[0073] 1 H NMR (400MHz, CDCl3) δ7.89–7.73(m,6H),7.58–7.41(m,6H),5.66(dd,J=38.4,4.3Hz,1H),4.20( dt,J=10.1,7.2Hz,1H),4.03(dt,J=10.1,7.3Hz,1H),3.23–3.00(m,2H),1.36(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ133.44,132.83,132.80,132.55,132.53,132.03,131 .94,130.70,130.55,129.26,128.80,128.68,128.13,128.01,127.62,127. 60,127.55,127.52,126.53,126.47,126.45,126.25,126.10,110.43,110.36,110.34,110.26,61.60,61.53,37.06,36.78,36.10,35.82,16.64,16.58. 19 F NMR (376MHz, CDCl3) δ-95.50 (d, J=8.0Hz). 31P NMR (162MHz, CDCl3) δ36.50 (d, J = 7.8Hz). HRMS (ESI) m / z: [M+H] + Calculate for C 21 H 21 FO2P 355.1258; found:355.1258.

[0074] Embodiment 7:

[0075] A method for synthesizing β-fluoroallyl phosphine, and a method for synthesizing (Z)-(2-fluoro-3-(naphthalene-2-yl)allyl)bis(4-methoxyphenyl)phosphine oxide

[0076]

[0077] 2-(2,2-difluorocyclopropyl)naphthalene (81.6 mg, 0.4 mmol), bis(p-methoxyphenyl)phosphine oxide (120.5 mg, 0.46 mmol), allylpalladium chloride (21.8 mg, 0.06 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (46.3 mg, 0.08 mmol) and potassium phosphate (168.8 mg, 0.8 mmol) were added to a 25 mL pressure-resistant reaction tube, and the tube was evacuated and filled with argon. Subsequently, 4 ml of 1,4-dioxane was added, the tube was sealed, stirred at room temperature for 15 minutes, and then placed in a magnetic stirrer at 110°C and stirred for 12 hours. After the reaction was complete, 1 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous Na2SO4, and spin-dried. Finally, the product was purified by column chromatography (petroleum ether / ethyl acetate = 2:1 to 1:1) to obtain a colorless liquid (139 mg, yield 78%).

[0078] 1 H NMR(400MHz, CDCl3)δ7.80–7.68(m,8H),7.51(dd,J=8.6,1.7Hz,1H),7.47–7.39(m,2H),6.98(d d,J=8.8,2.4Hz,4H),5.76(dd,J=39.0,3.7Hz,1H),3.82(s,6H),3.41(dd,J=18.9,14.3Hz,2H). 13C NMR (101MHz, CDCl3) δ162.66,162.63,133.37,133.15,133.05,132.47,132.45,128.12,127.91,127.67,127.65,127.58 ,126.62,126.55,126.20,126.05,123.68,122.61,114.34,114.21,110.88,110.80,110.72,55.45,37.27,36.88,36.61. 19 F NMR (376MHz, CDCl3) δ-93.62 (d, J=6.1Hz). 31 P NMR (162MHz, CDCl3) δ27.70 (d, J = 5.9Hz). HRMS (ESI) m / z: [M+H] + Calculate for C 27 H 25 FO3P447.1520; found:447.1526.

[0079] Example 8

[0080] A method for synthesizing β-fluoroallylphosphine, and the synthesis of (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl-4-((Z)-3-(diisopropoxyphosphoryl)-2-fluoroprop-1-en-1-yl)benzoate

[0081]

[0082] To a 25 mL pressure-resistant reaction tube, (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl-4-(2,2-difluorocyclopropyl)benzoate (134.4 mg, 0.4 mmol), diisopropyl phosphite (76.4 mg, 0.46 mmol), allylpalladium chloride (21.8 mg, 0.06 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46.3 mg, 0.08 mmol) and potassium phosphate (168.8 mg, 0.8 mmol) were added in sequence, and the tube was evacuated and filled with argon. Subsequently, 4 ml of 1,4-dioxane was added, the tube was sealed, stirred at room temperature for 15 minutes, and then placed in a magnetic stirrer at 110°C and stirred for 16 hours. After the reaction was complete, 1 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous Na2SO4, and spin-dried. Finally, the product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a colorless liquid (170 mg, yield 88%).

[0083] 1H NMR (400MHz, CDCl3) δ8.00(d,J=8.3Hz,2H),7.53(d,J=8.2Hz,2H),5.74(dd,J=37.8,4.4Hz,1H ),4.92(td,J=10.9,4.4Hz,1H),4.77(dp,J=7.8,6.2Hz,2H),2.91(dd,J=21.7,19.2Hz,2H),2. 16–2.10(m,1H),1.96(td,J=7.0,2.7Hz,1H),1.73(dq,J=15.4,3.4Hz,2H),1.62–1.48(m,2H), 1.34(t,J=5.7Hz,12H),1.20–1.03(m,2H),0.92(dd,J=6.8,4.7Hz,6H),0.79(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ165.80,137.51,129.74,129.23,128.28,128.26,128.20,128.18,109.12,109.04,109.01,108.94,74.77,71. 42,71.35,47.24,40.95,34.30,33.94,33.66,32.52,32.24,31.44,26.46,24.09,24.05,23.94,23.89,23.59,22.08,20.79,16.51. 19 F NMR (376MHz, CDCl3) δ-92.59 (d, J=5.2Hz). 31 P NMR (162MHz, CDCl3) δ19.86 (d, J = 4.8Hz). HRMS (ESI) m / z: [M+H] + Calculate for C 26 H 41 FO5P483.2670; found:483.2679.

[0084] Example 9

[0085] A method for synthesizing β-fluoroallyl phosphine, synthesis of diisopropyl (Z)-2-fluoro-3-((8R, 9S, 13S, 14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)allyl)phosphonate

[0086]

[0087] 8R, 9S, 13S, 14S)-3-(2,2-difluorocyclopropyl)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthrene-17-one (132.0 mg, 0.4 mmol), diisopropyl phosphite (76.4 mg, 0.46 mmol), allylpalladium chloride (21.8 mg, 0.06 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46.3 mg, 0.08 mmol) and potassium phosphate (168.8 mg, 0.8 mmol) were added to a 25 mL pressure-resistant reaction tube, and the tube was evacuated and filled with argon. Subsequently, 4 ml of 1,4-dioxane was added, the tube was sealed, stirred at room temperature for 15 minutes, and then placed in a magnetic stirrer at 110°C and stirred for 14 hours. After the reaction was complete, 1 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous Na2SO4, and spin-dried. Finally, the product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a colorless liquid (160 mg, yield 84%).

[0088] 1 H NMR (400MHz, CDCl3) δ7.28–7.18(m,3H),5.61(dd,J=38.6,4.5Hz,1H),4.76(dp,J=7.9,6.1Hz,2H),2.93–2.81(m,4H),2.51(dd,J=18.8,8. 7Hz,1H),2.45–2.39(m,1H),2.29(td,J=10.9,4.2Hz,1H),2.21–1.94(m,5H),1.63–1.48(m,5H),1.34(dd,J=6.2,3.4Hz,12H),0.91(s,3H). 13 C NMR (101MHz, CDCl3) δ138.91,136.52,130.79,129.08,129.01,126.02,125.95,125.48,109.39,109.31,109.21,71.25,71.18,50. 48,48.01,44.44,38.11,35.90,33.80,33.51,32.38,32.10,31.59,29.42,26.51,25.66,24.14,24.11,24.02,23.97,21.61,13.87. 19 F NMR (376MHz, CDCl3) δ-96.96 (d, J=5.3Hz). 31P NMR (162MHz, CDCl3) δ20.47 (d, J = 5.3Hz). HRMS (ESI) m / z: [M+H] + Calculate for C 27 H 39 FO4P477.2565; found:477.2568.

[0089] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any technician familiar with the profession, without departing from the scope of the technical solution of the present invention, according to the technical essence of the present invention, any simple modification, equivalent replacement and improvement made to the above embodiment still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for synthesizing β-fluoroallyl phosphine, characterized in that: β-fluoroallyl phosphine compounds can be obtained by reacting 1,1-difluorocyclopropane compounds and phosphite or diaryl phosphine oxide as reactants under the action of a palladium catalyst, a phosphine ligand, a base and a solvent. The specific steps are as follows: The first step: adding 1,1-difluorocyclopropane compounds and phosphites or diarylphosphine oxide compounds to a reaction tube, and then adding a palladium catalyst, a phosphine ligand, and a base in sequence; exhausting the air in the reaction vessel and replacing it with an inert gas, then adding a solvent, sealing, stirring at room temperature for 15 minutes, and then heating to 90-120°C for reaction, and the reaction time is 12-16 hours; Step 2: Use thin layer chromatography to detect the progress of the reaction, and wait until the reaction raw materials disappear completely; cool the reaction system, add 1 mL of water to quench, extract 3 times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, spin dry, and then separate by column chromatography to obtain β-fluoroallyl phosphine compounds; The reaction formula is as follows: ； In the formula, R 1 , R 2 and R 3 is aryl, heteroaryl or alkyl; The palladium catalyst is palladium acetate, palladium chloride, diacetonitrile palladium dichloride, palladium trifluoroacetate, ditriphenylphosphine palladium dichloride, allyl palladium chloride or tetrakistriphenylphosphine palladium; The phosphine ligand is a triphenylphosphine ligand compound, a trialkylphosphine ligand compound, a bidentate phosphine ligand, a Buchwald ligand or a carbene ligand; The base is cesium carbonate, potassium carbonate, potassium tert-butoxide, potassium phosphate, sodium phosphate or lithium tert-butoxide; The solvent is dioxane, acetonitrile, toluene, ethylene glycol dimethyl ether, tetrahydrofuran or 1,2-dichloroethane.

2. The method for synthesizing β-fluoroallyl phosphine according to claim 1, characterized in that: The 1,1-difluorocyclopropane compound is 2-(2,2-difluorocyclopropyl)naphthalene, 4-(2,2-difluorocyclopropyl)-N,N-dimethylaniline, 1-(2,2-difluorocyclopropyl)-2-methoxybenzene, (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl-4-(2,2-difluorocyclopropyl)benzoate or (8R, 9S, 13S, 14S)-3-(2,2-difluorocyclopropyl)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthrene-17-one; the phosphite is diisopropyl phosphite or ethyl phenylphosphonate; and the diaryl phosphine oxide is bis(p-methoxyphenyl)phosphine oxide.

3. The method for synthesizing β-fluoroallyl phosphine according to claim 1, characterized in that: In the first step, the reaction is carried out by stirring with a magnetic stirrer at 500-700 rpm for 12-16 hours; in the second step, the mobile phase eluent used in the column chromatography is a volume ratio of petroleum ether to ethyl acetate of 2:1-1:

2.

4. The method for synthesizing β-fluoroallyl phosphine according to claim 1, characterized in that: The molar ratio of the palladium catalyst to the phosphine ligand is 1:2; the molar ratio of the palladium catalyst to the 1,1-difluorocyclopropane compound is 1:10; the molar ratio of the base to the 1,1-difluorocyclopropane compound is 3:1; the concentration of the 1,1-difluorocyclopropane compound in the mixed solution containing the solvent is 0.1 mol / L; the molar ratio of the 1,1-difluorocyclopropane compound to the phosphite or diaryl phosphine oxide is 1:1.15.

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