A method for synthesizing difluoroalkyl sulfide

Abstract

The present invention belongs to the technical field of organic synthesis, and in particular to a method for synthesizing difluoroalkyl sulfides. The following steps are included: a difluoroolefin, an electrophilic sulfiding agent, a nucleophilic agent and a solvent are uniformly mixed, and then a photosensitizer is added, and a light source is irradiated to obtain; the electrophilic sulfiding agent is N-(thioaryl)phthalimide. The method for preparing difluoroalkyl sulfides in the present invention is simple and easy to operate, has good regioselectivity, high yield, novel method, and environmentally friendly, and has good application prospects in catalytic chemistry, pharmaceutical industry and materials science.

Description

Technical Field

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

[0002] Due to the unique electronegativity, electronic effect and steric hindrance effect of fluorine atoms, organic fluorine chemistry reactions often show different characteristics and laws from conventional organic reactions, and therefore have unique academic research value; in addition, fluorine-containing organic compounds generally exhibit some unique physical and chemical properties, such as high physical and chemical stability, fluorocarbon phase and unique biological activity, which determines their wide application in materials, medicine, energy and other fields.

[0003] Among all fluorine-containing groups, difluoromethyl (a relatively special fluorine-containing group) has good metabolic stability, and its electron-withdrawing effect also affects the electronic properties, chemical properties and biological reactivity of the adjacent functional group R. 2 The hydrogen atom in H is weakly acidic and can form hydrogen bonds with the electron-rich system in biological macromolecules, which is beneficial to the binding of drugs to receptors, thereby improving the activity of drugs or lead compounds.

[0004] Organic sulfides are widely present in natural products, drugs and functional material molecules, and play an important role in chemistry, biology and materials science. Their green, efficient and selective synthesis is of great significance and is one of the research hotspots in organic synthetic chemistry. Therefore, the introduction of sulfur-containing groups into the parent molecule can further change the properties of difluoromethyl molecules, which may enhance the biological activity of related molecules and facilitate drug discovery. In addition, there are already some thiodifluoromethyl compounds on the market with good biological activity.

[0005] Chinese invention patent application CN202310618787.7 discloses a method for preparing a thioester derivative using C(sp 3 )-H bond donor as solvent, photosensitizer as catalyst, thioacid and C(sp 3 )-H bond donors to react to prepare thioester derivatives. The present invention develops a visible light-induced free radical relay catalysis strategy, in which unactivated C(sp 3 )-H bond and thioacid are directly converted into C(sp 3 )-S bonds without the need for additional hydrogen atom transfer reagents, complicated thiol radical precursor compounds, metals and additives.

[0006] Chinese invention patent application CN202310206112.1 discloses a method for preparing (Z)-α-fluorovinyl sulfide by ball milling, wherein the method uses geminal-difluoroolefin and thiol as substrate raw materials, sodium carbonate as base, and performs solvent-free ball milling at room temperature to prepare (Z)-α-fluorovinyl sulfide, and the method comprises the following steps: (1) uniformly mixing ball milling balls, geminal-difluoroolefin, thiol and sodium carbonate and adding them into a 2mL ball milling tube. (2) installing the ball milling tube obtained in step (1) on a hybrid ball mill, and obtaining a crude product after ball milling. (3) taking out the crude product described in step (2), separating and purifying by column chromatography. collecting the product solution, concentrating and drying under reduced pressure to obtain the target product.

[0007] There are few methods for simultaneously introducing sulfur-containing groups and difluoromethyl groups into organic compounds, and developing new methods to construct difluoroalkyl sulfides has become a challenging task. So far, there has been no reported method for synthesizing difluoroalkyl sulfides using visible light-induced harmonic difluoroolefins, N-(thioaryl)phthalimide as a sulfur electrophile, and water or alcohol as a nucleophile. Summary of the invention

[0008] Aiming at the disadvantage that difluoroalkyl sulfides are difficult to synthesize in the prior art, there is currently no method for synthesizing difluoroalkyl sulfides by using difluoroolefins, N-(thioaryl)phthalimide and a nucleophilic reagent. The present invention provides a method for synthesizing difluoroalkyl sulfides. The method has good regioselectivity, high yield, novelty, and environmental friendliness, and has good application prospects in catalytic chemistry, pharmaceutical industry and material science.

[0009] In order to achieve the above object, the specific technical solution adopted by the present invention is:

[0010] A method for synthesizing difluoroalkyl sulfide comprises the following steps:

[0011] The difluoroolefin, electrophilic sulfiding agent, nucleophilic agent and solvent are mixed evenly, and then a photosensitizer is added, light source is irradiated, reaction is carried out, concentration is carried out, and silica gel column chromatography is performed to separate the difluoroalkyl sulfide; the electrophilic sulfiding agent is N-(thioaryl)phthalimide.

[0012] Preferably, the structure of the difluoroolefin is as shown in formula (I), the structure of the electrophilic sulfurizing agent is as shown in formula (II), and the structure of the difluoroalkyl sulfide is as shown in formula (III); the general reaction formula is as follows:

[0013]

[0014] Wherein, R is an aryl group or an alkyl group, R 1 is an aryl group or an alkyl group, Ar is an aryl group, and NuH is a nucleophile.

[0015] More preferably, the R is phenyl (Ph) or Cl; 1 is a methyl group or a hydrogen group; the Ar is selected from any one of 4-methylphenyl, 3-methylphenyl, 4-methoxyphenyl and 4-bromophenyl; the nucleophile is methanol or water.

[0016] Preferably, the molar ratio of the nucleophile to the difluoroolefin is 1:3-20.

[0017] Preferably, the molar ratio of the electrophilic sulfurizing agent to the difluoroolefin is 1:1-2.

[0018] Preferably, the solvent is selected from one or more of acetonitrile, ethylene dichloride, toluene and tetrahydrofuran.

[0019] Preferably, the molar volume ratio of the difluoroolefin to the solvent is 0.05-0.15 mol:1L.

[0020] Preferably, the photosensitizer is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN).

[0021] Preferably, the molar ratio of the 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile to the difluoroolefin is 3-5:100.

[0022] Preferably, the light source is 445-455nm blue light, and the power of the light source is 20-40W.

[0023] Preferably, the reaction time is 10-14 hours and the reaction temperature is 20-50°C.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] (1) The present invention provides a green and sustainable one-pot method for preparing difluoroalkyl sulfides, which solves the disadvantage of the difficulty in synthesizing difluoroalkyl sulfides in the prior art and makes up for the new green, friendly and sustainable visible light-induced synthesis method;

[0026] (2) The method of the present invention is simple and easy to operate, has good regional selectivity, and the yield is about 60%. DETAILED DESCRIPTION

[0027] The technical solutions in the embodiments of the present invention are further clearly described. The described embodiments are only a part of the present invention and are used to explain the present invention but not to limit the present invention. Therefore, other embodiments obtained by other technicians in the field without creative work all belong to the protection scope of the present invention.

[0028] Example 1

[0029] 69.0 mg (0.3 mmol) of the difluoroolefin shown below, 96.9 mg (0.45 mmol) of the electrophilic sulfurizing agent, 48 mg (1.5 mmol) of methanol and solvent MeCN (3 mL) were added into a reaction tube with a stirring bar and mixed evenly. Subsequently, 8.0 mg of the photosensitizer 4CzIPN was added and stirred for 12 hours under a 30 W, 450 nm blue LED lamp. After the reaction was completed, the mixture was concentrated and separated by silica gel chromatography. The eluents were combined, concentrated and dried to obtain the target product with a yield of 70%.

[0030] The reaction formula is as follows:

[0031]

[0032] H NMR spectrum of target product: 1 H NMR (400 MHz, CDCl 3 )δ7.65-7.56(m,6H),7.49-7.41(m,4H),7.39-7.32(m,1H),7.1(d,2H),3.34(s,3H),2.32(s,3H),1.87(s,3H).

[0033] NMR carbon spectrum: 13 C NMR (100 MHz, CDCl 3 )δ141.0,140.5,139.8,136.7,136.4,130.4(t),129.5,128.7,128.6,127.4,127.2,126.6,122.7,82.9(t),51.2,21.2,19.1.

[0034] High resolution mass spectrometry: ESI (m / z):calcd for C 23 H 22 F 2 NaOS[M+Na] + :407.1250;found:407.1249.

[0035] Example 2

[0036] 56.4 mg (0.3 mmol) of the difluoroolefin shown below, 96.9 mg (0.45 mmol) of the electrophilic sulfurizing agent, 48 mg (1.5 mmol) of methanol and solvent MeCN (3 mL) were added to a reaction tube with a stirring bar and mixed evenly. Subsequently, 8.0 mg of the photosensitizer 4CzIPN was added and stirred for 12 hours under a 30 W 450 nm blue LED lamp. After the reaction was completed, the mixture was concentrated and separated by silica gel chromatography. The eluents were combined, concentrated and dried to obtain the target product with a yield of 62%.

[0037] The reaction formula is as follows:

[0038]

[0039] H NMR spectrum of target product: 1 H NMR (400 MHz, CDCl 3 )δ7.42(t,4H),7.38-7.32(m,2H),7.11(d,2H),3.28(s,3H),2.32(s,3H),1.81(s,3H).

[0040] NMR carbon spectrum: 13 C NMR (100 MHz, CDCl 3 )δ140.2,136.7,136.1,134.4,130.1(t,),129.6,129.6,128.1,122.5,82.7,51.2,21.2,19.0.

[0041] High resolution mass spectrometry ESI (m / z):calcd for C 17 H 18 CIF 2 OS[M+H] + :343.0727,found:343.0730.

[0042] Example 3

[0043] 64.8 mg (0.3 mmol) of the difluoroolefin shown below, 96.9 mg (0.45 mmol) of the electrophilic sulfurizing agent, 48 mg (1.5 mmol) of methanol and solvent MeCN (3 mL) were added into a reaction tube with a stirring bar and mixed evenly. Subsequently, 8.0 mg of the photosensitizer 4CzIPN was added and stirred for 12 hours under a 30 W 450 nm blue LED lamp. After the reaction was completed, the mixture was concentrated and separated by silica gel chromatography to obtain the target product with a yield of 60%.

[0044] The reaction formula is as follows:

[0045]

[0046] H NMR spectrum of target product: 1 H NMR (400 MHz, CDCl 3 )δ7.65-7.58(m,4H),7.50-7.41(m,6H),7.39-7.32(m,1H),7.15(d,2H),4.56(dd,1H),3.43(s,3H),2.34(s,3H).

[0047] NMR carbon spectrum: 13C NMR (100 MHz, CDCl 3 )δ141.9,140.5,140.0,136.6,132.6,129.7,129.0,128.7,128.1(d),127.5,127.1,127.0,122.5,84.9(d),58.1,21.2.

[0048] High resolution mass spectrometry ESI (m / z):calcd for C 22 H 20 F 2 NaOS[M+Na] + :393.1093,found:393.1110.

[0049] Example 4

[0050] 69.0 mg (0.3 mmol) of the difluoroolefin shown below, 161.4 mg (0.6 mmol) of the electrophilic sulfiding agent, 96 mg (3 mmol) of methanol and solvent THF (6 mL) were added into a reaction tube with a stirring bar and mixed evenly. Subsequently, 8.0 mg of the photosensitizer 4CzIPN was added and stirred for 12 hours under a 30 W 450 nm blue LED lamp. After the reaction was completed, the mixture was concentrated and separated by silica gel chromatography to obtain the target product with a yield of 62%.

[0051] The reaction formula is as follows:

[0052]

[0053] H NMR spectrum of target product: 1 H NMR (400 MHz, CDCl 3 )δ7.65-7.56(m,6H),7.48-7.41(m,2H),7.41-7.32(m,3H),7.25-7.15(m,2H),3.35(s,3H),2.30(s,3H),1.88(s,3H).

[0054] NMR carbon spectrum: 13 C NMR (100 MHz, CDCl 3 )δ141.1,140.5,138.5,137.2,136.3,133.6,130.5(t),130.3,128.7,128.6,128.5,127.4,127.1,126.6,126.1,83.0(t),51.2,21.1,19.1.

[0055] HRMS MALDI(m / z):calcd for C 23 H22 F 2 NaOS[M+Na] + :407.1250,found:407.1254.

[0056] Example 5

[0057] 69.0 mg (0.3 mmol) of the following difluoroolefin, 85.5 mg (0.3 mmol) of an electrophilic sulfurizing agent, 108 mg (6 mmol) of H 2 O and toluene (2 mL) were added into a reaction tube with a stirring bar and mixed evenly. Subsequently, 11.6 mg of photosensitizer 4CzIPN was added and stirred for 10 hours under a 40 W 455 nm blue LED lamp. After the reaction was completed, the mixture was concentrated and separated by silica gel chromatography to obtain the target product with a yield of 65%.

[0058] The reaction formula is as follows:

[0059]

[0060] H NMR spectrum of target product: 1 H NMR (400 MHz, CDCl 3 )δ7.66-7.56(m,6H),7.52-7.42(m,4H),7.35(m,1H),6.90-6.82(m,2H),3.77(s,3H),3.34(s,3H),1.88(s,3H).

[0061] NMR carbon spectrum: 13 C NMR (100 MHz, CDCl 3 )δ160.9,141.0,140.5,138.5,136.4,130.3(t),128.6,128.6,127.4,127.1,126.6,116.7,114.3,82.9(t),55.2,51.2,19.1.

[0062] HRMS MALDI(m / z):calcd for C 23 H 22 F 2 NaO 2 S[M+Na] + :423.1199,found:423.1198.

[0063] Example 6

[0064] 69.0 mg (0.3 mmol) of the difluoroolefin shown below, 149.8 mg (0.45 mmol) of the electrophilic sulfurizing agent, 48 mg (1.5 mmol) of methanol and solvent MeCN (3 mL) were added into a reaction tube with a stirring bar and mixed evenly. Subsequently, 10.0 mg of the photosensitizer 4CzIPN was added and stirred for 12 hours under a 30 W 450 nm blue LED lamp. After the reaction was completed, the mixture was concentrated and separated by silica gel chromatography to obtain the target product with a yield of 63%.

[0065] The reaction formula is as follows:

[0066]

[0067] H NMR spectrum of target product: 1 H NMR (400 MHz, CDCl 3 )δ7.65-7.54(m,6H),7.48-7.39(m,6H),7.39-7.32(m,1H),3.33(s,3H),1.86(s,3H).

[0068] NMR carbon spectrum: 13 C NMR (100 MHz, CDCl 3 )δ141.2,140.4,138.0,136.1,131.9,130.3(t),128.7,128.6,127.5,127.1,126.7,125.6,124.4,82.9(t),51.2,19.0.

[0069] HRMS MALDI(m / z):calcd for C 22 H 20 F 2 OS[M+H] + :449.0380,found:449.0390.

[0070] Example 7

[0071] 69.0 mg (0.3 mmol) of the difluoroolefin shown below, 96.9 mg (0.45 mmol) of the electrophilic sulfurizing agent, 28.8 mg (0.9 mmol) of methanol and solvent MeCN (3 mL) were added into a reaction tube with a stirring bar and mixed evenly. Subsequently, 7.1 mg of the photosensitizer 4CzIPN was added and stirred for 14 hours under a 20 W 445 nm blue LED lamp. After the reaction was completed, the mixture was concentrated and separated by silica gel chromatography to obtain the target product with a yield of 60%.

[0072] The reaction formula is as follows:

[0073]

[0074] H NMR spectrum of target product: 1 H NMR (400 MHz, CDCl 3 )δ7.67(d,2H),7.66-7.59(m,4H),7.48-7.40(m,4H),7.39-7.32(m,1H),7.13(d,2H),2.61(s,1H),2.33(s,3H),1.82(s,3H).

[0075] NMR carbon spectrum: 13 C NMR (100 MHz, CDCl 3 )δ140.9,140.5,140.0,139.0,136.6,130.9(t),129.7,128.7,127.4,127.1,126.8,126.7,122.4,77.8(t),24.6,21.2.

[0076] HRMS MALDI(m / z):calcd for C 22 H 21 F 2 OS[M+H] + :371.1274,found:371.1287.

[0077] Effect test

[0078] The chemical reagents used in the experiment were purchased directly from reagent companies such as Aladdin, Jiuding, and McLean.

[0079] Using osimertinib as a control, the MTT colorimetric method was used to study the effects of the target products in Examples 2, 3 and 6 on the growth of Hep-G2 liver cancer cells. It was found that the products in Examples 2 and 6 had a significant inhibitory effect on Hep-G2 liver cancer cells (the half-maximal inhibitory concentrations were 28.40 μM and 29.65 μM, respectively).

[0080] The specific steps are as follows:

[0081] Take the logarithmically growing cells, digest them and pipette to evenly distribute the cells, then count the cells and dilute them to 6×10 3(cell / mL), evenly add 100μL cell suspension to the 96-well plate (36 wells at the edge are not added), place it in the incubator, and after 12 hours of cell attachment, administer the drug; no drug is added to the negative control group. The drug is set at 5 concentrations (90μM, 30μM, 10μM, 3.3μM, 1.1μM) and 3 replicates are set. After the drug is administered, continue to incubate in the incubator for 48 hours. After the incubation is completed, discard the stock solution, add 10μL of MTT solution (5mg / mL) and 90μL of blank culture medium, continue to culture for 4 hours, then discard the stock solution, add 100μL DMSO solution to dissolve, shake on a shaker for 15 minutes, and use an enzyme reader to measure the absorbance value of each well at a wavelength of 490nm. Finally, the cell survival rate is calculated using the following formula, and the test results are shown in Table 1.

[0082] Survival rate = (OD test sample - OD blank) / (OD negative control - OD blank) × 100%

[0083] Table 1 Cytotoxicity test results

[0084] Compound No. IC50(μM) Osimertinib 5.23 Example 1 Product 55.26 Example 2 Product 28.40 Example 3 Product 30.61 Example 4 Product ＞100 Example 5 Product ＞100 Example 6 Product 29.65 Example 7 Product ＞100

[0085] The above detailed description is a specific description of one feasible embodiment of the present invention. The embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing difluoroalkyl sulfide, characterized in that: The following steps are involved: A difluoroolefin, an electrophilic sulfurizing agent, a nucleophilic agent and a solvent are mixed, and then a photosensitizer is added, and the mixture is irradiated with a light source and reacted to obtain the product; the electrophilic sulfurizing agent is N-(thioaryl)phthalimide; The structure of the difluoroolefin is shown in formula (I), the structure of the electrophilic sulfurizing agent is shown in formula (II), and the structure of the difluoroalkyl sulfide is shown in formula (III); the general reaction formula is as follows: ； Wherein, R is phenyl or Cl, R 1 is a methyl group or a hydrogen group, Ar is an aromatic group, NuH is a nucleophile, and the nucleophile is methanol or water; The molar ratio of the difluoroolefin to the nucleophile is 1:3-20; The molar ratio of the difluoroolefin to the electrophilic sulfurizing agent is 1:1-2; The solvent is selected from one or more of acetonitrile, ethylene dichloride, toluene and tetrahydrofuran; The molar volume ratio of the difluoroolefin to the solvent is 0.05-0.15 mol:1L; The photosensitizer is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile; the molar ratio of the 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile to the difluoroolefin is 3-5:100; The light source is 445-455nm blue light.

2. The synthesis method according to claim 1, characterized in that The Ar is selected from any one of 4-methylphenyl, 3-methylphenyl, 4-methoxyphenyl and 4-bromophenyl.

3. The synthesis method according to claim 1, characterized in that The power of the light source is 20-40W; the reaction time is 10-14h.

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