Process for the preparation of a pentafluorosulfonyl compound

Abstract

A method for preparing a pentafluorosulfenyl aryl compound is disclosed. The method comprises reacting an aryl thioate, aryl thiol, or diaryl disulfide with iodine pentafluoride in the presence or absence of one or more additives to form an aryl sulfenyl pentafluoride, wherein the additive is selected from the group consisting of a fluoride salt, a non-fluoride salt, and an unsaturated organic compound.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis, and relates to a method for synthesizing pentafluorosulfanyl aryl compounds. Background Art

[0002] Fluorine atoms play an important role in modern drug design and synthesis (Liu X, Xu C, Wang M, et al. Trifluoromethyltrimethylsilane: nucleophilic trifluoromethylation and beyond[J]. Chem Rev, 2015, 115(2):683-730.). According to statistics, 15% - 20% of modern drugs contain fluorine-containing groups (Hui R, Zhang S, Tan Z, et al. Research Progress of Trifluoromethylation with Sodium Trifluoromethanesulfinate[J]. Chin J Org Chem (Organic Chemistry), 2017, 37(12):3060-3075). The presence of fluorine-containing groups helps to increase the lipophilicity and metabolic stability of drug molecules (Yang B, Xu XH, Qing FL. Copper-mediated radical 1,2-bis(trifluoromethylation) of alkenes with sodium trifluoromethanesulfinate[J]. Org Lett, 2015, 17(8):1906-1909.), and also reduces the generation of drug resistance.

[0003] At the same time, pentafluorosulfanyl (-SF5) is one of the currently existing fluorine-containing functional groups with the strongest lipophilicity. Introducing this group into drugs can significantly change the liposolubility of drugs, improve the bioavailability and biofilm permeability properties of drugs. Currently, the traditional synthesis methods of pentafluorosulfanyl aryl compounds are mainly divided into two types. Among them, the direct fluorination method mostly requires the use of fluorine gas and various fluorine-containing metal reagents. The reaction conditions need to be strictly controlled anhydrous and anaerobic, which are relatively harsh, the post-treatment is cumbersome, and the purification is difficult. The indirect fluorination method requires the use of chlorine gas or cyanuric chloride配合fluorination reagents for synthesis. The synthesis steps are cumbersome, and the intermediates in the synthesis process are extremely unstable, which has a great impact on the yield. In summary, the existing routes are difficult to be scaled up for production applications, making it difficult to industrialize the production of this compound. The present invention provides a mild, low-cost method for preparing pentafluorosulfanyl aryl compounds suitable for industrial production. Summary of the Invention

[0004] The purpose of this invention is to provide a new and efficient method for preparing pentafluorothioaryl compounds. This synthetic method has the advantages of readily available and low-cost raw materials, no need for organometallic reagents in the reaction, and simple and economical preparation process.

[0005] To achieve the above objectives, this invention uses aryl thiols or diaryl disulfides as raw materials to prepare pentafluorothioaryl compounds with iodine pentafluoride in the presence of a fluorinating agent. The reaction equation is as follows: In equation (1), R 1 It is aryl; In equation (2), R 2 It is aryl; The synthesis process of the compound shown in formula (3) is as follows: the compound shown in formula () is dissolved in a solvent in the presence of a fluorinating agent, and then iodine pentafluoride is mixed and reacted to generate the compound shown in formula (3); The fluorinating agent is any one or a mixture of a fluorinated metal salt or a fluorinated organic salt containing a negatively charged fluoride ion; The solvent is any one of 1,2-dichloroethane, dichloromethane, acetonitrile, 1,4-dioxane, benzene, toluene, xylene, trifluorotoluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, and diethyl ether. In the reaction system, the molar ratio of the organic sulfur-containing compound, iodine pentafluoride, and fluorinating reagent shown in formulas (1) and (2) is 1:(1~10):(1~10). The reaction temperature is 10℃-90℃, and the reaction time is 0.5 h-72 h.

[0006] Compared with existing synthetic methods, the synthetic method for pentafluorothiolated aryl compounds described in this invention has the following advantages: (1) The reaction reagents used in this invention are easy to prepare. The pentafluorothioaryl compound is a key intermediate for introducing pentafluorothio groups into the molecule. Compared with the previous pentafluorothio group preparation methods, this method is inexpensive and conducive to industrial production. (2) The synthesis method of the present invention has high atom utilization rate and step economy, and the generated elemental iodine can be recovered and regenerated into iodine pentafluoride; (3) The operation is simple and safe, the conditions are mild, the reaction does not require transition metal catalysis, and it is green and environmentally friendly. Detailed Implementation

[0007] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0008] Example 1: In this example, pentafluorothioaryl compound 3a was synthesized by reacting arylthiol 1a with iodine pentafluoride. The reaction equation is as follows:

[0009] The synthesis steps were as follows: benzenethiol 1a (10 mmol, 1.1 g), potassium fluoride (60 mmol, 3.48 g), and 10 mL of acetonitrile were added to a 25 mL reaction tube equipped with a magnetic stirrer and stirred for 5 min. Iodine pentafluoride (15 mmol, 3.3 g) was then added. The reaction tube was fixed on a magnetic stirrer and reacted at 0 °C for 12 hours. After the reaction was completed, the target product 3a was obtained by separation and purification with a yield of 72.5%. The structure of 3a was identified by gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy.

[0010] The NMR data for compound 3a are as follows: 1 H NMR (600 MHz, Chloroform-d): δ 7.77-7.74 (m,2H, aromatic), 7.60- 7.40 (m, 3H, aromatic); (600 MHz, Chloroform-d): δ85.20-84.13 (m, 1F, SF5), 62.91 (d, 4F, SF5).

[0011] Example 2: In this example, pentafluorothioaryl compound 3b was synthesized by reacting diaryl disulfide 1b with iodine pentafluoride. The reaction equation is as follows:

[0012] The synthesis steps were as follows: Diaryl disulfide 1a (10 mmol, 2.2 g), potassium fluoride (120 mmol, 6.97 g), and 20 mL of acetonitrile were added to a 50 mL reaction tube equipped with a magnetic stirrer and stirred for 5 min. Iodine pentafluoride (30 mmol, 6.7 g) was then added. The reaction tube was fixed on a magnetic stirrer and reacted at 0 °C for 12 hours. After the reaction was completed, the target product 3b was obtained by separation and purification with a yield of 74.7%. The structure of 3b was identified by gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy.

[0013] The NMR data for compound 3b are as follows: 1¹H NMR (600 MHz, Chloroform-d): δ 7.77–7.74 (m, 2H, aromatic), 7.60–7.40 (m, 3H, aromatic); (600 MHz, Chloroform-d): δ 85.20–84.13 (m, 1F, SF5), 62.91 (d, 4F, SF5). The NMR data for compound 3b are as follows: 1 H NMR (600MHz, Chloroform-d): δ 7.77-7.74 (m, 2H, aromatic), 7.60- 7.40 (m, 3H, aromatic); (600 MHz, Chloroform-d): δ 85.20-84.13 (m, 1F, SF5), 62.91 (d, 4F,SF5).

[0014] Example 3: In this example, pentafluorothioaryl compound 3c is synthesized by reacting arylthiol 1c with iodine pentafluoride. The reaction equation is as follows:

[0015] The synthesis steps were as follows: 10 mmol (1.55 g) of benzenethiol 1c, 60 mmol (3.48 g) of potassium fluoride, and 10 mL of acetonitrile were added to a 25 mL reaction tube equipped with a magnetic stirrer. The mixture was stirred for 5 min, and then 15 mmol (3.3 g) of iodine pentafluoride was added. The reaction tube was then fixed on a magnetic stirrer and reacted at 0 °C for 12 hours. After the reaction was completed, the target product 3c was obtained by separation and purification with a yield of 82.3%. The structure of 3c was identified by gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy.

[0016] The NMR data for compound 3c are as follows: 1 H NMR (600 MHz, Chloroform-d): δ 8.36-8.30 (m, 2H, aromatic), 7.99-7.95 (m, 2H, aromatic); 19 F NMR (600 MHz, Chloroform-d): δ82.32-80.69 (m, 1F, SF5), 62.76 (d, 4F, SF5).

[0017] Example 4: In this example, pentafluorothioaryl compound 3d was synthesized by reacting diaryl disulfide 1d with iodine pentafluoride. The reaction equation is as follows:

[0018] The synthesis steps were as follows: Diaryl disulfide 1d (10 mmol, 3.1 g), potassium fluoride (120 mmol, 6.97 g), and 20 mL of acetonitrile were added to a 50 mL reaction tube equipped with a magnetic stirrer. The mixture was stirred for 5 min, and then iodine pentafluoride (30 mmol, 6.7 g) was added. The reaction tube was fixed on a magnetic stirrer and reacted at 0 °C for 12 hours. After the reaction was completed, the target product 3d was obtained by separation and purification with a yield of 87.2%. The structure of 3d was identified by gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy.

[0019] The NMR data for compound 3d are as follows: 1 H NMR (600 MHz, Chloroform-d): δ 8.36-8.30 (m, 2H, aromatic), 7.99-7.95 (m, 2H, aromatic); 19 F NMR (600 MHz, Chloroform-d): δ82.32-80.69 (m, 1F, SF5), 62.76 (d, 4F, SF5).

[0020] Example 5: In this example, pentafluorothioaryl compound 3e is synthesized by reacting arylthiol 1e with iodine pentafluoride. The reaction equation is as follows:

[0021] The synthesis steps were as follows: 10 mmol (1.55 g) of benzenethiol 1e, 60 mmol (3.48 g) of potassium fluoride, and 10 mL of acetonitrile were added to a 25 mL reaction tube equipped with a magnetic stirrer. The mixture was stirred for 5 min, and then 15 mmol (3.3 g) of iodine pentafluoride was added. The reaction tube was then fixed on a magnetic stirrer and reacted at 0 °C for 12 hours. After the reaction was completed, the target product 3e was obtained by separation and purification with a yield of 64.3%. The structure of 3e was identified by gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy.

[0022] The NMR data for compound 3e are as follows: 1 H NMR (600 MHz, Chloroform-d): δ 7.91 (t, 1H, aromatic), 7.72-7.64 (m, 2H, aromatic), 7.35 (t, 1H, aromatic); 19 F NMR (600MHz, Chloroform-d): δ 83.55-82.47 (m, 1F, SF5), 63.13 (d, 4F, SF5).

[0023] Example 6: In this example, pentafluorothioaryl compound 3f is synthesized by reacting diaryl disulfide 1f with iodine pentafluoride. The reaction equation is as follows:

[0024] The synthesis steps were as follows: Diaryl disulfide 1f (10 mmol, 3.1 g), potassium fluoride (120 mmol, 6.97 g), and 20 mL of acetonitrile were added to a 50 mL reaction tube equipped with a magnetic stirrer. The mixture was stirred for 5 min, and then iodine pentafluoride (30 mmol, 6.7 g) was added. The reaction tube was fixed on a magnetic stirrer and reacted at 0 °C for 12 hours. After the reaction was completed, the target product 3f was obtained by separation and purification with a yield of 65.2%. The structure of 3f was identified by gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy.

[0025] The NMR data for compound 3f are as follows: 1 H NMR (600 MHz, Chloroform-d): δ 7.91 (t, 1H, aromatic), 7.72-7.64 (m, 2H, aromatic), 7.35 (t, 1H, aromatic); 19 F NMR (600MHz, Chloroform-d): δ 83.55-82.47 (m, 1F, SF5), 63.13 (d, 4F, SF5).

[0026] Example 7: In this example, 3g of pentafluorothioaryl compound was synthesized by reacting 1g of diaryl disulfide with iodine pentafluoride. The reaction equation is as follows:

[0027] The synthesis steps were as follows: 1 g (10 mmol, 3.74 g) of diaryl disulfide, 120 mmol, 6.97 g of potassium fluoride, and 20 mL of acetonitrile were added to a 50 mL reaction tube equipped with a magnetic stirrer. The mixture was stirred for 5 min, and then iodine pentafluoride (30 mmol, 6.7 g) was added. The reaction tube was fixed on a magnetic stirrer and reacted at 0 °C for 12 hours. After the reaction was completed, the product was separated and purified to obtain 3 g of the target product, with a yield of 74.4%. The structure of the 3 g product was identified using gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy.

[0028] The NMR data for compound 3g are as follows: 1 H NMR (600 MHz, Chloroform-d): 7.63 (s, 4H, aromatic); 19F NMR (600 MHz, Chloroform-d): 5 84.13-82.53 (m, IF, SF), 63.11 (d, 4F, SF4).

[0029] Example 8: In this example, pentafluorothioaryl compounds were synthesized by reacting diaryl disulfide with iodine pentafluoride for 1 hour and 3 hours. The reaction equation is as follows:

[0030] The synthesis steps were as follows: Diaryl disulfide 1h (10 mmol, 4.7 g), potassium fluoride (120 mmol, 6.97 g), and 20 mL of acetonitrile were added to a 50 mL reaction tube equipped with a magnetic stirrer. The mixture was stirred for 5 min, and then iodine pentafluoride (30 mmol, 6.7 g) was added. The reaction tube was fixed on a magnetic stirrer and reacted at 0 °C for 12 hours. After the reaction was completed, the target product 3h was separated and purified to obtain a yield of 59.7%. The structure of 3h was identified using gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy.

[0031] The NMR data for compound 3h are as follows: 1 H NMR (600 MHz, Chloroform-d): δ 7.63 (d, 2H, aromatic), 7.24 (d, 2H, aromatic); 19 F NMR (600 MHz, Chloroform-d): δ 86.55-84.96 (m, 1F, SF5), 63.26 (d, 4F, SF5).

Claims

1. A method for synthesizing a pentafluorothio-aryl compound, characterized in that: Pentafluorothioaryl compounds are prepared by reacting aryl thiols or diaryl disulfides with iodine pentafluoride in the presence of a fluorinating agent: The reaction equation is: In equation (1), R 1 It is aryl; In equation (2), R 2 It is aryl; The synthesis process of the compound shown in formula (3) is as follows: the compound shown in formula () is dissolved in a solvent in the presence of a fluorinating agent, and then iodine pentafluoride is mixed and reacted to generate the compound shown in formula (3); The fluorinating agent is any one or a mixture of a fluorinated metal salt or a fluorinated organic salt containing a negatively charged fluoride ion; The solvent is any one of 1,2-dichloroethane, dichloromethane, acetonitrile, 1,4-dioxane, benzene, toluene, xylene, trifluorotoluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, and diethyl ether. In the reaction system, the molar ratio of the organic sulfur-containing compound, iodine pentafluoride, and fluorinating reagent shown in formulas (1) and (2) is 1:(1~10):(1~10). The reaction temperature is 10℃-90℃, and the reaction time is 0.5 h-72 h.

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