A method for preparing thiophosphine (phosphine) ester substituted benzofluorene compound

Abstract

The invention discloses a method for preparing a thiophosphine (phosphorus) ester substituted benzofluorene compound, wherein the method is to use a 1,6-diynol compound as shown in formula (I) as a raw material, add an organic solvent to fully dissolve under room temperature, and then add a P(O)-SH compound, react for 1-10 hours at 80°C, and after the reaction is completed, the reaction product is separated and purified by silica gel column chromatography to obtain a thiophosphine (phosphorus) ester substituted benzofluorene compound as shown in formula (II). The raw materials of the present invention are simple and easy to obtain, the conditions are mild, the operation is simple, the substrate applicability is good, the yield is good, etc.; in addition, the prepared target product thiophosphine (phosphorus) ester substituted benzofluorene compound has potential application value in the fields of organic synthesis, pharmacy, materials science, and the like, and has a chemical synthesis method with good promotion and application prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing a thiophosphine (phosphine) ester substituted benzofluorene compound. Background Art

[0002] Contains (RO)2P(O)SC(SP 2 ) bond structure, can be used as pharmaceutical intermediates, pesticides, bactericides, curing accelerators, antistatic agents and a cholinesterase inhibitor in medicine. In terms of functional materials, it can be used as a surfactant, optoelectronic material, and phosphorus-containing flame retardant. Similarly, thiophosphate compounds play an important role in the field of organic synthesis as synthetic intermediates.

[0003] In addition, benzofluorene compounds are a very important class of carbon ring skeletons in polycyclic aromatic hydrocarbons. This type of skeleton is the core structural unit of many natural metabolites and anti-tumor antibiotic families. It has excellent biological and pharmacological activities and has broad applications and development prospects in the medical field. For example, Kinamycin D is a natural diazo compound isolated from Streptomyces protease, which has anti-tumor properties and antibiotic activity against Gram-positive bacterial organisms; Kinobscurinone is a key intermediate for the synthesis of quinonemycin drugs; Stealthin C series compounds are a class of natural products isolated from S. murayamaensis culture. In addition, due to its novel rigid structure and large π conjugated system, it has unique photoelectric properties, making the synthesis and application of benzofluorene compounds always a research hotspot in the intersection of chemistry and materials, chemistry and biology, etc. Although there are many methods for constructing benzofluorene compounds, they are mainly carried out under transition metal, high temperature or strong oxidant conditions, and there are few reports on the synthesis of benzofluorene skeleton compounds without metal catalysts or strong oxidants, especially for the construction of thiophosphine (phospho)ester substituted benzofluorene compounds.

[0004] Based on the wide application of thiophosphate compounds and benzofluorene compounds in organic synthesis, medicinal chemistry and material science, it is very important and challenging to develop a metal-free, atom-economical, efficient and green synthetic strategy to construct thiophosphate (phospho)ester-substituted benzofluorene compounds. Summary of the invention

[0005] The present invention uses 1,6-diynol compounds as substrates to promote the synthesis of thiophosphine (phosphate) ester substituted benzofluorene compounds in the next step in the presence of P(O)-SH compounds, and aims to provide a preparation method for thiophosphine (phosphate) ester substituted benzofluorene compounds, which has easy-to-obtain raw materials, mild conditions, no metal, atom economy, high efficiency, greenness and good application prospects.

[0006] The technical solution adopted by the present invention is as follows:

[0007] A method for synthesizing a thiophosphine (phosphate) ester substituted benzofluorene compound as shown in formula (II), wherein the method comprises taking a 1,6-diynol compound as shown in formula (I) as a raw material, adding an organic solvent to fully dissolve the compound at room temperature, then adding a P(O)-SH-containing compound, heating the reaction for 1-10 hours, and after the reaction is completed, separating and purifying the reaction product to obtain a thiophosphine (phosphate) ester substituted benzofluorene compound as shown in formula (II);

[0008] The chemical structures of the 1,6-diynol compound represented by formula (I) and the thiophosphine (phosphine) ester substituted benzofluorene compound represented by formula (II) are shown below:

[0009]

[0010] Among them, R in formula (I) and formula (II) 1 R is a strong electron donating group. 2 is aryl or alkyl, R 3 ~R 6 Each is independently one of H, CH3, X (X is one of F, Cl, Br), OCH3 and the like, R 7 It is an aromatic group.

[0011] The reaction formula of the reaction is as follows:

[0012]

[0013]

[0014] Wherein, the organic solvent is one of the following: 1,2-dichloroethane, acetonitrile, nitromethane, dichloromethane, tetrahydrofuran. The mass of the organic solvent is 10-30 times the mass of the 1,6-diynol compound.

[0015] In the present invention, the molar ratio of the 1,6-diynol compound to the P(O)-SH compound is 1:2.0 to 3.0. More preferably, the molar ratio of the 1,6-diynol compound to the P(O)-SH compound is 1:2.5.

[0016] During the reaction of the present invention, TCL is used to track the reaction progress time, and the reaction time is 1-10 hours, and different substrates require different reaction times.

[0017] Further preferably, the reaction heating temperature of the method is 80°C.

[0018] The separation and purification described in the present invention can be carried out by the following steps: adding a saturated sodium bicarbonate solution to the reaction solution, then adding ethyl acetate, stirring thoroughly and then standing to separate the layers; extracting the separated water layer with ethyl acetate, combining the ethyl acetate extract with the separated organic layer, washing them with saturated brine and drying them with anhydrous sodium sulfate; evaporating the ethyl acetate solvent, and then subjecting the mixture to silica gel column chromatography to obtain a thiophosphine (phospho)ester substituted benzofluorene compound.

[0019] Compared with the prior art, the present invention has the following beneficial effects: (1) a new synthetic strategy is provided to construct a thiophosphine (phosphate) ester substituted benzofluorene compound; (2) the reaction of the present invention does not require a metal catalyst, an additional acid promoter, and the conditions are mild; (3) the method of the present invention is not only highly atom-economical, but also easy to operate and has a wide range of substrate applicability, thereby obtaining a thiophosphine (phosphate) ester substituted benzofluorene compound; (4) the present invention does not require a metal catalyst, does not involve additional acid, the raw materials are simple and easy to obtain, and the yield is good.

[0020] In summary, the present invention has the advantages of cheap and readily available reagents, no need for catalysts, mild reaction conditions, simple process operation, high efficiency, and less green pollution. It is a method for synthesizing thiophosphine (phospho)ester substituted benzofluorene compounds with good promotion and application prospects. DETAILED DESCRIPTION

[0021] The present invention is further described in detail by the following examples, but the protection scope of the present invention is not limited thereto.

[0022] Example 1: Preparation of thiophosphonate (phosphate) ester substituted benzofluorene compound 1. The chemical structure of thiophosphonate (phosphate) ester substituted benzofluorene compound 1 is shown below:

[0023]

[0024] Representative implementation process: 1,6-diynol compound I-1 (67.6 mg, 0.2 mmol) and 2 ml of dry nitromethane were added to the reaction bottle at room temperature, and then diethyl thiophosphate (0.5 mmol) was added to the reaction bottle, and then the reaction was placed at 80°C for 5 hours. TLC was used to track the progress of the reaction. After the reaction was completed, the reaction solution was added with a saturated sodium bicarbonate solution, and then ethyl acetate was added. After sufficient stirring, the reaction solution was allowed to stand for stratification; the separated water layer was extracted with ethyl acetate, and the ethyl acetate extract was combined with the separated organic layer, and then washed with saturated brine and dried over anhydrous sodium sulfate; the ethyl acetate solvent was evaporated, and then the thiophosphine (phosphorus) ester substituted benzofluorene compound 1 (78.1 mg, 80%) was obtained.

[0025] 1H NMR (400MHz, CDCl3): δppm 1.24(t,J=7.2Hz,6H),3.72(s,3H),4.10-4.22(m,4H),4.42(d,J=2.8Hz,2H),6.41(d,J=7.6Hz,1H),6.87(d,J=2 .4Hz,1H),7.04(t,J=7.6Hz,1H),7.24-7.30(m,2H),7.41-7.43(m,2H),7.55-7.66(m,4H),8.61(d,J=9.2Hz,1H). 13 C NMR (100 MHz, CDCl3): 16.1 (d, J C-P =6.8Hz),38.2,55.1,64.4(d,J C-P =7.2Hz),105.8,117.6(d,J C-P =8.4Hz),118.1,123.7,124.8,126.5,127.3,127.5,128.0,129.3,129.6(d,J C-P =3.1Hz),129.7,134.7(d,J C-P =4.1Hz),135.1(d,J C-P =2.4Hz),138.2(d,J C-P =3.6Hz),138.5,141.2,144.0,147.4(d,J C-P =6.2Hz),157.4. 31 P NMR (162MHz, CDCl3): δppm 22.89.HRMS (ESI, m / z): calcd for C 28 H 27 O4PS:M+H=491.1441; found:491.1433.

[0026] Example 2: Preparation of thiophosphonate (phosphate) ester substituted benzofluorene compound 2. The chemical structure of thiophosphonate (phosphate) ester substituted benzofluorene compound 2 is shown below:

[0027]

[0028] Representative implementation process: 1,6-diynol compound I-2 (73.6 mg, 0.2 mmol) and 2 ml of dry nitromethane were added to the reaction bottle at room temperature, and then diethyl thiophosphate (0.5 mmol) was added to the reaction bottle, and then the reaction was placed at 80°C for 1 hour, and the reaction progress was tracked by TLC. The separation and purification steps were the same as in Example 1, and the thiophosphine (phosphine) ester substituted benzofluorene compound 2 (65.5 mg, 63%) was obtained.

[0029] 1 H NMR (400MHz, CDCl3): δppm 1.24(t,J=6.8Hz,6H),3.76(s,3H),4.01(s,3H),4.08-4.24(m,4H),4.43(d,J=2.8Hz,2H),6.54(d,J=8.0Hz,1H),6.93(s,1H),7.08 (t,J=7.6Hz,1H),7.18(d,J=8.4Hz,2H),7.29(d,J=7.6Hz,2H),7.34(d,J=8.0Hz,2H),7.57(d,J=7.2Hz,1H),8.61(d,J=9.2Hz,1H). 13 C NMR (100 MHz, CDCl3): 16.1 (d, J C-P =6.5Hz),38.3,55.2,55.4,64.5(d,J C-P =7.1Hz),106.0,114.7,118.1,123.8,124.9,126.5,127.3,127.6,129.8,130.7,130.9,134.5,135.6,138.7,141.4,144.0,147.5(d,J C-P =6.2Hz),157.5,159.4. 31 P NMR (162MHz, CDCl3): δppm 21.81.HRMS (ESI, m / z): calcd for C 29 H 29 O5PS:M+H=521.1546; found:521.1544.

[0030] Example 3: Preparation of thiophosphonate (phosphate) ester substituted benzofluorene compound 3. The chemical structure of thiophosphonate (phosphate) ester substituted benzofluorene compound 3 is shown below:

[0031]

[0032] Representative implementation process: 1,6-diynol compound I-3 (73.2 mg, 0.2 mmol) and 2 ml of dry nitromethane were added to the reaction bottle at room temperature, and then diethyl thiophosphate (0.5 mmol) was added to the reaction bottle, and then the reaction was placed at 80°C for 3 hours, and the reaction progress was tracked by TLC. The separation and purification steps were the same as in Example 1, and thiophosphine (phosphine) ester substituted benzofluorene compound 3 (88.1 mg, 85%) was obtained.

[0033] 1 H NMR (400MHz, CDCl3): δppm 1.19(t,J=7.2Hz,6H),2.41(s,6H),3.73(s,3H),4.04-4.17(m,4H),4.39(d,J=3.2Hz,2H),6.47(d,J=7.6Hz,1H),6.92(d,J= 2.4Hz,1H),6.99(s,2H),7.04(t,J=7.2Hz,1H),7.19(s,1H),7.24-7.26(m,2H),7.53(d,J=7.2Hz,1H),8.58(d,J=9.2Hz,1H). 13 C NMR (100 MHz, CDCl3): 16.1 (d, J C-P =6.5Hz),21.4,38.3,55.3,64.5(d,J C-P =7.2Hz),106.4,117.3(d,J C-P =6.7Hz),117.8,123.9,124.4(d,J C-P =8.5Hz),124.8,126.5,127.3,127.5,129.5,129.7,135.2,138.2,138.3,138.7,141.4,144.0,147.5(d,J C-P =5.8Hz),157.4. 31 P NMR (162MHz, CDCl3): δppm 22.25.HRMS (ESI, m / z): calcd for C 30 H 31 O4PS:M+H=519.1759; found:519.1757.

[0034] Example 4: Preparation of thiophosphonate (phosphate) ester substituted benzofluorene compound 4. The chemical structure of thiophosphonate (phosphate) ester substituted benzofluorene compound 4 is shown below:

[0035]

[0036] Representative implementation process: At room temperature, 1,6-diynol compound I-4 (74.4 mg, 0.2 mmol) and 2 ml of dry nitromethane were added to the reaction bottle in sequence, and then diethyl thiophosphate (0.5 mmol) was added to the reaction bottle, and then the reaction was placed at 80°C for 10 hours, and the reaction progress was tracked by TLC. The separation and purification steps were the same as in Example 1, and the thiophosphinothioate (phosphothioate) ester substituted benzofluorene compound 4 (77.6 mg, 74%).

[0037] 1 H NMR (400MHz, CDCl3): δppm 1.22(t,J=7.2Hz,6H),3.72(s,3H),4.07–4.19(m,4H),4.39(d,J=2.8Hz,2H),6.46(d,J=8.0Hz,1H),6.77(d,J=2.0Hz,1H),7.06 (t,J=7.2Hz,1H),7.24-7.27(m,2H),7.35(d,J=8.4Hz,2H),7.55(d,J=7.6Hz,1H),7.60(d,J=8.4Hz,2H),8.59(d,J=9.2Hz,1H). 13 C NMR (100 MHz, CDCl3): 16.1 (d, J C-P =6.8Hz),38.3,55.3,64.5(d,J C-P =7.2Hz),105.6,118.2,123.6,125.0,126.6,127.6,127.7,129.7,131.4,133.2(d,J C-P =3.8Hz),134.1,135.0,137.2,138.4(d,J C-P =3.6Hz),141.0,144.2,147.4(d,J C-P =6.3Hz),157.7. 31 P NMR (162MHz, CDCl3): δppm 21.70. HRMS (ESI, m / z): calcdfor C 28 H 26 ClO4PS:M+H=525.1051; found:525.1042.

Claims

1. A preparation method for a thiophosphate-substituted benzofluorene compound, wherein the preparation steps are as follows: step 1, using a 1,6-diynol compound as a raw material, adding an organic solvent to fully dissolve the compound at room temperature, and then adding diethyl thiophosphate; step 2, heating the reaction for 1-10 hours; step 3, after the reaction is completed, separating and purifying the reaction product to obtain a thiophosphate-substituted benzofluorene compound; in, The 1,6-diynol compound is a compound represented by any one of the following formulas (I-1) to (I-4): , , and , The chemical structure of the phosphorothioate-substituted benzofluorene compound is shown in the following formula 1-4: , , and , The organic solvent in step 1 is one of the following: acetonitrile, nitromethane, The heating temperature in step 2 is 80°C.

2. The preparation method according to claim 1, characterized in that: The molar ratio of the 1,6-diynol compound and diethyl thiophosphate described in step 1 is 1:2.0-3.

0.

3. The preparation method according to claim 2, characterized in that: The molar ratio of the 1,6-diynol compound and diethyl thiophosphate described in step 1 is 1:2.

5.

4. The preparation method according to claim 1, characterized in that: The mass of the organic solvent in step 1 is 10-30 times the mass of the 1,6-diynol compound.

5. The preparation method according to claim 1, characterized in that: The separation and purification steps described in step three are: adding a saturated sodium bicarbonate solution to the reaction solution, then adding ethyl acetate, stirring thoroughly and standing to separate the layers; extracting the separated aqueous layer with ethyl acetate, combining the ethyl acetate extract with the separated organic layer, washing with saturated brine and drying with anhydrous sodium sulfate; evaporating the ethyl acetate solvent, and then obtaining a thiophosphate-substituted benzofluorene compound by silica gel column chromatography.

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