Synthesis method of phosphorous acid diester compound

Abstract

The invention relates to the technical field of organic synthesis, and particularly discloses a synthetic method of a phosphorous acid diester compound, which comprises the following steps: mixing sodium hypophosphite, an alcohol compound, pivaloyl chloride, a nickel catalyst and a solvent, stirring and reacting for 12-24 hours under the heating condition of 80-140 DEG C, so that the sodium hypophosphite is completely reacted and converted, and obtaining the phosphorous acid diester compound. And carrying out column chromatography separation on the reaction liquid to obtain the phosphorous acid diester compound. The raw materials are cheap, easy to obtain, non-toxic and easy to store; the method does not depend on PCl3 and is safer; reaction byproducts are sodium chloride and hydrogen which are easy to separate and remove, so that the problems of environmental pollution and the like are avoided, and the method is green, environment-friendly and relatively good in atom economy.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing a phosphite diester compound. Background Art

[0002] Phosphate esters and their derivatives are very important compounds. They are widely present in natural products, bioactive molecules, medicines, pesticides, ligands, materials, etc., and are important backbone molecules. Among the numerous organophosphate compounds and their derivatives, phosphite diesters [(RO)2P(O)H] are a major intermediate used in fine and industrial organophosphorus chemistry. The methods reported for phosphite diester compounds are shown in the figure below:

[0003] a)Synthesis of H-phonate diesters from photorus trichloride

[0004]

[0005] b)Synthesis of H-phphonate diesters from HPA.

[0006]

[0007] 1) The classic synthesis method is alcoholysis of phosphorus trichloride. Under the action of 3 equivalents of alcohol, three molecules of hydrogen chloride are removed between the alcohol and trivalent phosphorus chloride to form a triester of phosphite, and then the triester of phosphite is removed by one molecule of halogenated hydrocarbon under the action of one molecule of hydrogen chloride to obtain a diester of phosphite. This method is more common on an industrial scale, but the substrate phosphorus trichloride used is very sensitive to air and water and is highly toxic; and a large amount of operation and electricity are required in the production of phosphorus trichloride.

[0008] 2) Montchamp's research group developed a method for synthesizing phosphite diesters based on the oxidative coupling of hypophosphorous acid (H3PO2) and alcohols. The method needs to be divided into two stages. First, it starts with the esterification of H3PO2 and alcohol to generate hypophosphite (RO)2P(O)H, which is then oxidatively coupled with excess alcohol (3 equivalents) in the presence of a nickel catalyst (5 mol%) to obtain the final phosphite diester. This method is relatively new, but the substrate hypophosphorous acid used is also very sensitive to air and water and is toxic; the method needs to be carried out in two steps under argon conditions.

[0009] The above methods usually use substrates that are toxic and sensitive to air and water. Summary of the invention

[0010] The purpose of the present invention is to overcome the existing defects and provide a method for synthesizing a phosphite diester compound which is simple to operate, high in reaction efficiency and has wide applicability.

[0011] The purpose of the present invention is specifically achieved through the following technical solutions:

[0012] A method for synthesizing a phosphite diester compound comprises the following steps: mixing sodium hypophosphite, an alcohol compound, pivaloyl chloride, a nickel catalyst and a solvent, stirring and reacting for 12-24 hours under heating conditions to allow the sodium hypophosphite to react and convert completely, and then subjecting the reaction solution to column chromatography separation to obtain a phosphite diester compound. The reaction formula of the synthesis method is as follows:

[0013]

[0014] In the reaction formula, R is various alkyl groups.

[0015] Preferably, the molar ratio of the sodium hypophosphite, the alcohol compound, the pivaloyl chloride and the nickel catalyst is 1.0:2.0-4.0:2.0:0.05; and the reaction concentration of the sodium hypophosphite in the raw material mixture is 0.05-0.20 mol / L.

[0016] Further preferably, the molar ratio of the sodium hypophosphite, the alcohol compound, the pivaloyl chloride and the nickel catalyst is 1.0:4.0:2.0:0.05; and the reaction concentration of the sodium hypophosphite in the raw material mixture is 0.1 mol / L.

[0017] Preferably, the solvent is one of toluene, acetonitrile, ethylene dichloride or chlorobenzene; the nickel catalyst is one of nickel dichloride, nickel acetylacetonate, 1,3-bis(diphenylphosphinopropane)nickel dichloride or bis-(1,5-cyclooctadiene)nickel.

[0018] More preferably, the solvent is toluene; and the nickel catalyst is 1,3-bis(diphenylphosphinopropane)nickel dichloride.

[0019] Preferably, the stirring reaction is carried out in an air atmosphere; the temperature of the stirring reaction is 100°C.

[0020] Preferably, during the column chromatography separation, the eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to ethyl acetate is 4:1-1:2.

[0021] Preferably, the alcohol compound includes but is not limited to 3-pentanol, n-butanol, isobutanol, isopropanol, cyclohexanol, adamantane alcohol, benzyl alcohol, neopentyl alcohol, phenylethyl alcohol, phenylpropanol, 3-chloro-1-propanol, 1-phenyl-2-propanol, 4-penten-1-ol, 4-pentyn-1-ol, 1-naphthalenemethanol, xanthene-9-methanol, fluorenemethanol, N-(3-hydroxypropyl)phthalimide, ibuprofen impurity P, naproxol, D-menthol, L-borneol, methyl-2,3-O-isopropylidene-beta-D-furanosidoside, methyl 2,3,4-tri-O-methyl-β-D-pyranoglucoside,

[0022] 1,2,3,4,4A,4B,5,6,10,10A-Decahydro-1,4A-dimethyl-7-isopropyl-1-phenanthrenol, cholesterol.

[0023] Compared with the prior art, the present invention has the following advantages:

[0024] The raw materials of the synthesis method of the present invention are cheap, easily available, non-toxic and easy to store; it does not rely on PCl3 and is safer; the byproducts of the reaction are sodium chloride and hydrogen that are easy to separate and remove, there is no problem of environmental pollution, it is green and environmentally friendly and has good atom economy. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Above the horizontal line is the reaction formula for the synthesis reaction of the phosphorous acid diester compound, below the horizontal line is the structural formula of the compound synthesized in Examples 1-26, and below the structural formula is the compound number and yield. DETAILED DESCRIPTION

[0026] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0027] Unless otherwise specified, the raw materials in the embodiments of the present invention were purchased through commercial channels, and the sources of some of the raw materials are as follows: sodium hypophosphite, alcohol compounds, pivaloyl chloride, and nickel catalyst were directly purchased from common reagent companies such as Anage and Bidex without purification.

[0028] Example 1

[0029] In the reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of 3-pentanol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 63%. 1H NMR (400MHz, CDCl3) δ7.79 (s, 0.5H), 6.07 (s, 0.5H), 4.52–4.13 (m, 2H), 1.67 (dd, J = 12.9, 6.5Hz, 8H), 0.96 (t, J = 7.4Hz, 12H). 13 C NMR (101MHz, CDCl3) δ80.70 (d, J = 6.5Hz), 27.90 (d, J = 3.8Hz), 27.63 (d, J = 4.3Hz), 9.57 (s), 9.38 (s). 31 P NMR (162 MHz, CDCl3) δ 6.31 (s).

[0030] The product structure is as follows:

[0031]

[0032] Example 2

[0033] In the reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of n-butanol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 64%. 1 H NMR (400MHz, CDCl3) δ7.68(s,0.5H),5.95(s,0.5H),4.09(dt,J=13.6,4.1Hz,4H),1.84–1.54(m,4H),1.54–1.33(m,4H),0.95(t,J=7.4Hz,6H). 13 C NMR (101MHz, CDCl3) δ65.45 (d, J = 6.0Hz), 32.34 (d, J = 6.2Hz), 18.68 (s), 13.51 (s). 31 P NMR (162 MHz, CDCl3) δ 7.80 (s).

[0034] The product structure is as follows:

[0035]

[0036] Example 3

[0037] In the reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of isobutyl alcohol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100° C. and an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 62%. 1 H NMR (400MHz, CDCl3) δ7.70 (s, 0.5H), 5.96 (s, 0.5H), 3.89–3.81 (m, 4H), 1.97 (dp, J = 13.3, 6.6Hz, 2H), 0.95 (t, J = 7.0Hz, 12H). 13 C NMR (101MHz, CDCl3) δ71.62 (d, J = 6.3Hz), 29.14 (d, J = 6.4Hz), 18.66 (d, J = 2.2Hz). 31 PNMR (162MHz,CDCl3)δ8.02(s).

[0038] The product structure is as follows:

[0039]

[0040] Example 4

[0041] In a reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of isopropanol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100° C. and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 64%. 1 H NMR (400MHz, CDCl3) δ7.72 (s, 0.5H), 6.00 (s, 0.5H), 4.91–4.49 (m, 2H), 1.38 (dd, J = 6.1, 2.0Hz, 12H). 13 C NMR (101MHz, CDCl3) δ70.76 (d, J = 5.7Hz), 23.79 (dd, J = 19.6, 4.5Hz). 31 PNMR (162MHz,CDCl3)δ4.30(s).

[0042] The product structure is as follows:

[0043]

[0044] Example 5

[0045] In the reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of cyclohexanol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1, with a yield of 82%. 1 H NMR(400MHz, CDCl3)δ7.76(s,0.5H),6.04(s,0.5H),4.68–4.34(m,2H),2.07–1 .87(m,4H),1.86–1.70(m,4H),1.56(tt,J=16.2,4.9Hz,6H),1.46–1.14(m,6H). 13 C NMR (101MHz, CDCl3) δ75.67 (d, J = 5.9Hz), 33.65 (dd, J = 20.2, 4.1Hz), 25.09 (s), 23.54 (s). 31 P NMR (162 MHz, CDCl3) δ 4.47 (s).

[0046] The product structure is as follows:

[0047]

[0048] Example 6

[0049] In a reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of adamantane alcohol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 56%. 1 H NMR (400MHz, CDCl3) δ7.90 (s, 0.5H), 6.20 (s, 0.5H), 2.18 (s, 7H), 2.10 (d, J = 2.3Hz, 13H), 1.64 (s, 14H). 13 C NMR (101MHz, CDCl3) δ82.32 (d, J = 7.7Hz), 44.06 (d, J = 4.5Hz), 35.78 (s), 31.08 (s). 31PNMR (162MHz,CDCl3)δ-4.04(s).

[0050] The product structure is as follows:

[0051]

[0052] Example 7

[0053] In the reactor, 0.20 mmol sodium hypophosphite and 2 ml toluene were added, followed by 0.80 mmol benzyl alcohol, 0.40 mmol pivaloyl chloride and 0.01 mmol 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, and 3 g of a phosphite diester compound was obtained. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1, and the yield was 63%. 1 H NMR (400MHz, CDCl3) δ7.81 (s, 0.5H), 7.46–7.24 (m, 10H), 6.04 (s, 0.5H), 5.28–4.91 (m, 4H). 13 CNMR(101MHz,CDCl3)δ142.94(d,J=8.8Hz),141.42(s),127.99(d,J=2.5Hz),127.20( d,J=2.3Hz), 125.02(s), 120.08(d,J=4.6Hz), 67.04(d,J=6.2Hz), 47.99(d,J=6.8Hz). 31 PNMR (162MHz,CDCl3)δ7.74(s).

[0054] The product structure is as follows:

[0055]

[0056] Example 8

[0057] In the reactor, 0.20 mmol sodium hypophosphite and 2 ml toluene were added, followed by 0.80 mmol neopentyl alcohol, 0.40 mmol pivaloyl chloride and 0.01 mmol 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 76%. 1 H NMR (400MHz, CDCl3) δ7.70 (s, 0.5H), 5.97 (s, 0.5H), 3.74 (t, J = 6.7Hz, 4H), 0.96 (s, 18H).13 CNMR (101MHz, CDCl3) δ74.96 (d, J = 6.7Hz), 32.15 (d, J = 6.9Hz), 26.04 (s). 31 P NMR (162 MHz, CDCl3) δ 8.44 (s).

[0058] The product structure is as follows:

[0059]

[0060] Example 9

[0061] In a reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of phenylethanol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100° C. and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 84%. 1 H NMR (400MHz, CDCl3) δ7.49 (s, 0.5H), 7.37–7.14 (m, 10H), 5.74 (s, 0.5H), 4.18 (dtd, J = 13.7, 6.9, 5.3Hz, 4H), 2.94 (t, J = 6.9Hz, 4H). 13 C NMR (101MHz, CDCl3) δ136.97 (s), 129.01 (s), 128.61 (s), 126.85 (s), 66.02 (d, J = 6.2Hz), 36.87 (d, J = 6.1Hz). 31 P NMR (162 MHz, CDCl3) δ7.66 (s).

[0062] The product structure is as follows:

[0063]

[0064] Example 10

[0065] In the reactor, 0.20 mmol sodium hypophosphite and 2 ml toluene were added, followed by 0.80 mmol phenylpropanol, 0.40 mmol pivaloyl chloride and 0.01 mmol 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 1:1, with a yield of 83%. 1H NMR (400MHz, CDCl3) δ7.69 (s, 0.5H), 7.29 (t, J = 7.3Hz, 4H), 7.19 (t, J = 8.7Hz, 6H), 5.96(s,0.5H),4.08(qd,J=6.5,1.4Hz,4H),2.85–2.49(m,4H),2.15–1.86(m,4H). 13 C NMR (101MHz, CDCl3) δ140.75 (s), 128.50 (d, J = 7.5Hz), 126.17 (s), 64.93 (d, J = 5.9Hz), 31.96 (d, J = 6.5Hz), 31.67 (s). 31 P NMR (162 MHz, CDCl3) δ7.91 (s).

[0066] The product structure is as follows:

[0067]

[0068] Embodiment 11

[0069] In a reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of 3-chloro-1-propanol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100° C. and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 70%. 1 H NMR (400MHz, CDCl3) δ7.74 (s, 0.5H), 5.99 (s, 0.5H), 4.27 (dd, J = 13.5, 6.0Hz, 4H), 3.68 (t, J = 6.2Hz, 4H), 2.15 (p, J = 6.0Hz, 4H). 13 C NMR (101MHz, CDCl3) δ62.24 (d, J = 5.6Hz), 40.50 (s), 32.94 (d, J = 6.7Hz). 31 PNMR (162MHz,CDCl3)δ8.03(s).

[0070] The product structure is as follows:

[0071]

[0072] Example 12

[0073] In the reactor, 0.20 mmol sodium hypophosphite and 2 ml toluene were added, followed by 0.80 mmol 1-phenyl-2-propanol, 0.40 mmol pivaloyl chloride and 0.01 mmol 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, and the phosphite diester compound 31 was obtained. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 1:1, and the yield was 60%. 1 HNMR(400MHz, CDCl3)δ7.42(d,J=6.9Hz,0.1H),7.32–7.11(m,10H),7.06(s,0.15H),5.47(t ,J=75.0Hz,0.5H),4.85–4.47(m,2H),3.12–2.52(m,4H),1.28(ddd,J=16.5,8.3,3.5Hz,6H). 13 C NMR(101MHz, CDCl3)δ137.09(dd,J=7.6,6.0Hz),129.81–129.41(m),128.84–128.24(m),126. 77(d,J=5.4Hz),76.78–71.87(m),43.96(dd,J=5.1,2.3Hz),21.74(ddd,J=12.9,8.7,3.1Hz). 31 PNMR (162MHz, CDCl3) δ5.52 (t, J = 105.3Hz).

[0074] The product structure is as follows:

[0075]

[0076] Embodiment 13

[0077] In a reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of 4-penten-1-ol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 62%. 1HNMR (400MHz, CDCl3) δ7.68 (s, 0.5H), 5.95 (s, 0.5H), 5.80 (ddt, J = 16.9, 10.1, 6.7Hz, 2H), 5.05 (dd ,J=25.3,6.0Hz,4H),4.09(dd,J=13.6,6.8Hz,4H),2.17(dd,J=14.3,7.0Hz,4H),1.88–1.72(m,4H). 13 C NMR (101MHz, CDCl3) δ137.03 (s), 115.68 (s), 65.01 (d, J = 5.9Hz), 29.63–29.44 (m). 31 P NMR (162 MHz, CDCl3) δ7.81 (s).

[0078] The product structure is as follows:

[0079]

[0080] Embodiment 14

[0081] In a reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of 4-pentyn-1-ol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100° C. and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 70%. 1 HNMR (400MHz, CDCl3) δ7.72 (s, 0.5H), 5.98 (s, 0.5H), 4.21 (dd, J = 13.9, 6.2H z,4H),2.35(td,J=6.9,2.5Hz,4H),1.99(t,J=2.5Hz,2H),1.95–1.86(m,4H). 13 C NMR (101MHz, CDCl3) δ82.51 (s), 69.41 (s), 64.03 (d, J = 5.7Hz), 29.05 (d, J = 6.7Hz), 14.72 (s). 31 PNMR (162MHz,CDCl3)δ7.98(s).

[0082] The product structure is as follows:

[0083]

[0084] Embodiment 15

[0085] In the reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of 1-naphthalenemethanol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 1:1, with a yield of 31%. 1 H NMR (400MHz, CDCl3) δ7.95 (dd, J=6.1, 3.4Hz, 2H), 7.88–7.80 (m, 4.5H), 7.50 (dq,J=6.5,3.3Hz,4H),7.45–7.32(m,4H),6.04(s,0.5H),5.66–5.23(m,4H). 13 C NMR (101MHz, CDCl3) δ133.71 (s), 131.27 (s), 131.06 (d, J = 6.0Hz), 129.86 (s), 128.7 6(s),127.45(s),126.85(s),126.17(s),125.25(s),123.44(s),65.83(d,J=5.9Hz). 31 PNMR (162MHz,CDCl3)δ7.87(s).

[0086] The product structure is as follows:

[0087]

[0088] Example 16

[0089] In the reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of xanthene-9-methanol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1, with a yield of 81%. 1 H NMR (400MHz, CDCl3) δ7.26–7.15(m,8H),7.14(s,0.5H),7.13–6.97(m,8H),5.36(s,0.5H),4.12(t,J=6.0Hz,2H),3.99–3.79(m,4H). 13C NMR (101MHz, CDCl3) δ152.20 (d, J = 5.3Hz), 129.32 (d, J = 2.8Hz), 128.72 (d, J = 2.3Hz), 123. 37 (s), 120.46 (d, J = 0.8Hz), 116.63 (d, J = 1.8Hz), 70.17 (d, J = 6.7Hz), 39.88 (d, J = 6.5Hz). 31 P NMR (162 MHz, CDCl3) δ7.86 (s).

[0090] The product structure is as follows:

[0091]

[0092] Embodiment 17

[0093] In the reactor, 0.20 mmol sodium hypophosphite and 2 ml toluene were added, followed by 0.80 mmol fluorenylmethanol, 0.40 mmol pivaloyl chloride and 0.01 mmol 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 89%. 1 H NMR (400MHz, CDCl3) δ7.74–7.66(m,4H),7.54(s,0.5H),7.52(d,J=7.5Hz,2H),7.47(d,J=7.5Hz,2H),7. 36(dt,J=17.6,7.4Hz,4H),7.31–7.17(m,4H),5.78(s,0.5H),4.35–4.17(m,4H),4.10(t,J=6.4Hz,2H). 13 C NMR (101MHz, CDCl3) δ142.92 (d, J = 9.0Hz), 141.40 (s), 127.99 (d, J = 2.5Hz), 127.20 (d , J=2.3Hz), 125.02(s), 120.08(d,J=4.6Hz), 67.04(d,J=6.2Hz), 47.97(d,J=6.8Hz). 31 PNMR (162MHz,CDCl3)δ7.80(s).

[0094] The product structure is as follows:

[0095]

[0096] Embodiment 18

[0097] In the reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of N-(3-hydroxypropyl)phthalimide, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 67%. 1 H NMR (400MHz, CDCl3) δ7.86–7.79(m,4H),7.76(s,0.5H),7.75–7.68(m,4H),6. 00(s,0.5H),4.29–4.07(m,4H),3.83(t,J=6.8Hz,4H),2.10(p,J=6.5Hz,4H). 13 C NMR (101MHz, CDCl3) δ168.21 (s), 134.02 (s), 131.96 (s), 123.26 (s), 63.10 (d, J = 5.7Hz), 34.52 (s), 29.40 (d, J = 6.9Hz). 31 P NMR (162 MHz, CDCl3) δ 8.13 (s).

[0098] The product structure is as follows:

[0099]

[0100] Embodiment 19

[0101] In the reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of ibuprofen impurity P, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1, with a yield of 74%. 1 HNMR(400MHz, CDCl3)δ7.41(t,J=21.2Hz,0.5H),7.20–6.89(m,8H),5.66(t,J=20.6Hz,0.5H),4.20–3.84(m,4H),3.1 8–2.90(m,2H),2.44(dd,J=7.2,1.8Hz,4H),1.84(dp,J=13.4,6.7Hz,2H),1.31–1.25(m,6H),0.90(d,J=6.6Hz,12H).13 C NMR (101MHz, CDCl3) δ140.33 (d, J = 1.6Hz), 139.48 (d, J = 2.2Hz), 129.31 (s), 127.10 (d, J = 1.4Hz ),72.29–69.97(m),45.04(s),40.67–39.10(m),30.25(s),22.43(s),17.63(dd,J=7.6,2.2Hz). 31 PNMR (162MHz, CDCl3) δ7.82 (t, J=34.8Hz).

[0102] The product structure is as follows:

[0103]

[0104] Embodiment 20

[0105] In the reactor, 0.20 mmol sodium hypophosphite and 2 ml toluene were added, followed by 0.80 mmol naphthoyl chloride, 0.40 mmol pivaloyl chloride and 0.01 mmol 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ7.64(d,J=8.6Hz,4H),7.50(d,J=6.5Hz,2H),7.42(s,0.5H),7.21(ddd,J=8.1,4.3,1.6Hz,2H),7.12(dd,J=8.9,2.4Hz,2H),7 .07(t,J=2.7Hz,2H),5.66(s,0.5H),4.06(tt,J=9.4,4.8Hz,4H),3.88(t ,J=4.7Hz,6H),3.13(td,J=14.2,7.0Hz,2H),1.29(dd,J=9.6,7.0Hz,6H). 13 C NMR(101MHz, CDCl3)δ157.53(s),137.43(s),133.61(s),129.18(s),128.95(d,J=1.4Hz),127.13(s),126.14( s), 125.84 (s), 119.01 (s), 105.56 (s), 70.31 (d, J = 6.5Hz), 55.33 (s), 40.29 (d, J = 6.3Hz), 17.65 (d, J = 12.8Hz). 31P NMR (162 MHz, CDCl3) δ7.82 (s).

[0106] The product structure is as follows:

[0107]

[0108] Embodiment 21

[0109] In the reactor, 0.20 mmol sodium hypophosphite and 2 ml toluene were added, followed by 0.80 mmol menthol, 0.40 mmol pivaloyl chloride and 0.01 mmol 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1, with a yield of 66%. 1 H NMR (400MHz, CDCl3) δ7.77(s,0.5H),6.05(s,0.5H),4.36–4.02(m,2H),2.33–1.99(m,4H),1.75–1.61(m,4H),1.46(dddd,J=14.8,9.0,6.2,3. 0Hz,2H),1.36(t,J=11.4Hz,2H),1.29–1.15(m,2H),1.03(ddd,J=26.0,12.8,5.1Hz,4H),0.92(d,J=6.7Hz,12H),0.81(dd,J=7.0,1.6Hz,6H). 13 C NMR (101MHz, CDCl3) δ77.89(d,J=6.7Hz),77.74(d,J=6.5Hz),48.31(dd,J=6.4,3.0Hz),43.41(s),42.87(s),33.94(d,J=2.8H z), 31.55 (d, J = 3.3Hz), 25.84 (s), 25.51 (s), 22.86 (d, J = 8.3Hz), 21.90 (d, J = 2.2Hz), 20.88 (d, J = 1.3Hz), 15.69 (d, J = 2.0Hz). 31 PNMR (162MHz,CDCl3)δ5.45(s).

[0110] The product structure is as follows:

[0111]

[0112] Embodiment 22

[0113] In the reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of L-borneol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 1:1, with a yield of 52%. 1 H NMR (400MHz, CDCl3) δ7.71 (s, 0.5H), 5.99 (d, J = 4.1Hz, 0.5H), 4.65 (t, J = 8.5Hz, 2H), 2.44–2.25 (m,2H),2.01–1.85(m,2H),1.81–1.64(m,4H),1.27(dt,J=13.1,6.4Hz,6H),0.93–0.77(m,18H). 13 C NMR (101MHz, CDCl3) δ82.33 (dd, J = 12.1, 6.6Hz), 49.66 (d, J = 5.6Hz), 47.64 (d, J = 3.4Hz), 44.90 (d, J = 2.0Hz ),37.47–37.26(m),37.10(s),29.20–27.30(m),26.47(d,J=5.5Hz),19.92(s),18.75(s),14.24–12.18(m). 31 P NMR (162MHz, CDCl3) δ15.92–-13.87(m).

[0114] The product structure is as follows:

[0115]

[0116] Embodiment 23

[0117] In a reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of methyl-2,3-O-isopropylidene-beta-D-furanosyl glycoside, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 1:2, with a yield of 72%. 1H NMR(400MHz, CDCl3)δ7.79(s,0.5H),6.00(s,0.5H),4.96(s,2H),4.70(s,2H),4.68–4.54(m,2 H),4.35(t,J=6.9Hz,2H),4.07(dd,J=17.5,9.3Hz,4H),3.32(s,6H),1.46(s,6H),1.30(s,6H). 13 C NMR(101MHz, CDCl3)δ112.61(s),109.34(d,J=7.4Hz),85.91–82.96(m),81.30(d ,J=7.2Hz),65.46(dd,J=26.4,6.2Hz),55.08(d,J=3.4Hz),26.34(s),24.86(s). 31 PNMR (162MHz,CDCl3)δ7.67(s).

[0118] The product structure is as follows:

[0119]

[0120] Embodiment 24

[0121] In a reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of methyl 2,3,4-tri-O-methyl-β-D-pyranoglucoside, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 1:2, with a yield of 64%. 1 H NMR(400MHz, CDCl3)δ7.87(s,0.5H),6.08(s,0.5H),4.83(s,2H),4.44–4.17(m,4H),3.66(s,2H) ,3.63(s,6H),3.57(d,J=2.7Hz,6H),3.56–3.49(m,8H),3.40(t,J=8.9Hz,6H),3.24–3.07(m,4H). 13C NMR (101MHz, CDCl3) δ97.47(d,J=6.5Hz),83.37(d,J=2.6Hz),81.68(d,J=10.5Hz),79.09(s),78.84(s),69.35(dd ,J=14.5,5.5Hz),64.53(dd,J=8.4,5.9Hz),60.93(s),60.65(d,J=8.3Hz),59.09(d,J=3.7Hz),55.38(d,J=3.3Hz). 31 PNMR (162MHz,CDCl3)δ9.57(s).

[0122] The product structure is as follows:

[0123]

[0124] Embodiment 25

[0125] In a reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of 1,2,3,4,4A,4B,5,6,10,10A-decahydro-1,4A-dimethyl-7-isopropyl-1-phenanthrenol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100° C. and an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 47%. 1 HNMR (400MHz, CDCl3) δ7.63 (s, 0.5H), 5.89 (s, 0.5H), 5.77 (d, J = 4.6Hz, 2H), 5.39 (s, 2H), 3.79(ddd,J=20.2,9.8,6.4Hz,2H),3.62–3.47(m,2H),2.22(dt,J=13.6,6.7Hz,2H),2.02( dd,J=23.9,17.0Hz,8H),1.92–1.74(m,6H),1.55(ddd,J=20.5,10.7,4.6Hz,8H),1.47–1.3 3(m,6H),1.29–1.13(m,4H),1.03–0.98(m,12H),0.93–0.89(m,6H),0.82(d,J=3.0Hz,6H). 13C NMR (101MHz, CDCl3) δ145.25(d,J=10.4Hz), 135.44(d,J=4.9Hz), 122.40(d,J=4.4Hz), 120.61( d,J=6.6Hz),73.41(dd,J=30.8,6.8Hz),50.76(d,J=8.4Hz),43.59(s),43.16(s),38.67(s),37. 09(d,J=6.5Hz),35.87(d,J=2.9Hz),34.89(s),34.66(d,J=1.2Hz),27.52(s),23.73(d,J=9.1Hz ), 22.66 (s), 21.15 (d, J = 57.5Hz), 20.86 (s), 18.01 (s), 17.40 (d, J = 9.8Hz), 14.18 (d, J = 5.3Hz). 31 P NMR (162 MHz, CDCl3) δ 8.26 (s).

[0126] The product structure is as follows:

[0127]

[0128] Embodiment 26

[0129] In the reactor, 0.20 mmol of sodium hypophosphite and 2 ml of toluene were added, followed by 0.80 mmol of cholesterol, 0.40 mmol of pivaloyl chloride and 0.01 mmol of 1,3-bis(diphenylphosphinopropane)nickel dichloride. After stirring in an oil bath at 100°C and in an air atmosphere for 12 hours, the reaction solution was directly chromatographed on a silica gel column using an eluent, the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, with a yield of 67%. 1 H NMR (400MHz, CDCl3) δ7.76 (s, 0.5H), 6.04 (s, 0.5H), 5.38 (d, J = 3.4Hz, 2H), 4.47–4.20(m,2H),2.56–2.33(m,4H),2.00(dd,J=18.7,9.5Hz,6H),1.93–1. 70(m,6H),1.65–1.41(m,12H),1.44–1.23(m,12H),1.21–1.03(m,12H),1.03 (d,J=11.5Hz,10H),0.91(d,J=6.5Hz,6H),0.89–0.84(m,12H),0.67(s,6H). 13CNMR(101MHz, CDCl3)δ139.27(d,J=3.7Hz),123.14(s),56.67(s),56.14(s),49.98(s), 42.31(s),40.25(dd,J=16.6,4.4Hz),39.70(s),39.52(s),36.92(s),36.43(s),36.19(s) ),35.79(s),31.86(d,J=5.9Hz),29.95(dd,J=18.5,4.0Hz),28.23(s),28.01(s),27.08( s),24.28(s),23.84(s),22.83(s),22.58(s),21.04(s),19.27(s),18.72(s),11.86(s). 31 PNMR (162MHz,CDCl3)δ4.41(s).

[0130] The product structure is as follows:

[0131]

[0132] The raw materials for the synthesis reaction in the embodiment are cheap, readily available, non-toxic and easy to store, and do not require PCl3, which is safer; the reaction by-products are sodium chloride and hydrogen that are easy to separate and remove, have little impact on the environment, and have good atom economy.

[0133] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a phosphite diester compound, characterized in that: The following steps are involved: Sodium hypophosphite, alcohol compound, pivaloyl chloride, nickel catalyst and solvent are mixed, and stirred for reaction at 80-140° C. for 12-24 hours to complete the reaction conversion of sodium hypophosphite, and then the reaction solution is separated by column chromatography to obtain a phosphite diester compound.

2. The method for synthesizing a phosphite diester compound according to claim 1, characterized in that: The molar ratio of the sodium hypophosphite, the alcohol compound, the pivaloyl chloride and the nickel catalyst is 1.0:2.0-4.0:2.0:0.05; the reaction concentration of the sodium hypophosphite in the raw material mixture is 0.05-0.20 mol / L.

3. The method for synthesizing a phosphite diester compound according to claim 2, characterized in that: The molar ratio of the sodium hypophosphite, the alcohol compound, the pivaloyl chloride and the nickel catalyst is 1.0:4.0:2.0:0.05; the reaction concentration of the sodium hypophosphite in the raw material mixture is 0.1 mol / L.

4. The method for synthesizing a phosphite diester compound according to claim 1, characterized in that: The solvent is one of toluene, acetonitrile, ethylene dichloride or chlorobenzene; the nickel catalyst is one of nickel dichloride, nickel acetylacetonate, 1,3-bis(diphenylphosphinopropane)nickel dichloride or bis-(1,5-cyclooctadiene)nickel.

5. The method for synthesizing a phosphite diester compound according to claim 4, characterized in that: The solvent is toluene; the nickel catalyst is 1,3-bis(diphenylphosphinopropane)nickel dichloride.

6. The method for synthesizing a phosphite diester compound according to claim 1, characterized in that: The stirring reaction is carried out under air atmosphere; the temperature of the stirring reaction is 100°C.

7. The method for synthesizing a phosphite diester compound according to claim 1, characterized in that: During the column chromatography separation, the eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to ethyl acetate is 4:1-1:

2.

8. The method for synthesizing a phosphite diester compound according to claim 1, characterized in that: The alcohol compounds include, but are not limited to, 3-pentanol, n-butanol, isobutanol, isopropanol, cyclohexanol, adamantane alcohol, benzyl alcohol, neopentyl alcohol, phenylethyl alcohol, phenylpropanol, 3-chloro-1-propanol, 1-phenyl-2-propanol, 4-penten-1-ol, 4-pentyn-1-ol, 1-naphthalenemethanol, xanthene-9-methanol, fluorenemethanol, N-(3-hydroxypropyl)phthalimide, ibuprofen impurity P, naproxol, D-menthol, L-borneol, methyl-2,3-O-isopropylidene-beta-D-furanosidoside, methyl 2,3,4-tri-O-methyl-β-D-pyranoglucoside, 1,2,3,4,4A,4B,5,6,10,10A-decahydro-1,4A-dimethyl-7-isopropyl-1-phenanthrenol, and cholesterol.

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