Preparation method of carbon isotope labeled sulfur ylide salt

Abstract

The invention relates to a preparation method of a carbon isotope labeled sulfur ylide salt, which comprises the following steps: adding a main raw material 13CH3OH into a reaction container under the protection of nitrogen, slowly dropwise adding Tf2O at 0 DEG C, and continuously stirring the reaction liquid for 4 hours after dropwise adding; after the reaction is finished, firstly adding a halogenated alkane solvent for dilution, then adding alkali, continuously stirring for 20 minutes, and finally filtering with diatomite to obtain filtrate; and adding thioether into the filtrate, stirring for 12 hours at 40 DEG C, after the reaction is finished, evaporating to remove the solvent, washing white residues by using an ether solvent, and carrying out pumping treatment to obtain the white powdery sulfur ylide salt-13C. The method has the advantages of cheap raw materials, safe reaction, simple operation and high product yield.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis preparation chemistry, and in particular to a method for preparing a carbon isotope-labeled sulfur ylide salt. Background Art

[0002] Currently, we have developed 13 Preparation of CH3I 13 C-labeled sulfur ylide salt, which was then reacted with pinacol borate to prepare 13 C-labeled methylene diboron method (application number: 202211314514.5). However, from 13 Starting from CH3I, the cost of raw materials is relatively expensive, and one molecule 13 CH3OH 13 The C atom content is 13 5 times of CH3I, in other words, to get the same quality 13 C-labeled sulfur ylide salts require less mass 13 CH3OH greatly saves costs. At the same time, the reaction can be carried out on a large scale, and the operation is simple and safe.

[0003] Boron compounds play a very important role in organic synthesis. Boron can be used as a synthon to construct many drug molecules or drug molecules containing boron. 13 C-labeled compounds are widely used in biomedicine and can quickly provide doctors with information about the patient's condition. Considering the application prospects in this area, it is even more necessary to further address the shortcomings of the synthesis. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing a carbon isotope-labeled sulfur ylide salt with cheap raw materials, safe reaction and simple operation.

[0005] In order to solve the above problems, the present invention provides a method for preparing a carbon isotope labeled sulfur ylide salt, characterized in that: under nitrogen protection, a main raw material is added to a reaction container. 13 CH3OH, Tf2O was slowly added dropwise at 0 ℃. After the addition was completed, the reaction solution was stirred for 4 hours. After the reaction was completed, a halogenated alkane solvent was first added for dilution, and then a base was added for further stirring for 20 minutes, and finally filtered through diatomaceous earth to obtain a filtrate. Thioether was added to the filtrate, and stirred at 40 ℃ for 12 hours. After the reaction was completed, the solvent was first evaporated to remove the solvent, and then the white residue was washed with an ether solvent and dried to obtain a white powdery sulfur ylide salt- 13 C.

[0006] The main raw material 13The molar ratio of CH3OH to Tf2O is 1.0: 1.0-2.0 eq; the main raw material 13 The molar ratio of CH3OH to the base is 1.0: 1.0-3.0 eq; the main raw material 13 The molar ratio of CH3OH to the sulfide is 1.0: 1.0 to 3.0 eq.

[0007] The main raw material 13 The molar ratio of CH3OH to Tf2O is 1.0: 1.0-1.5 eq; the main raw material 13 The molar ratio of CH3OH to the base is 1.0: 1.5-2.5 eq; the main raw material 13 The molar ratio of CH3OH to the sulfide is 1.0: 1.5 to 2.5 eq.

[0008] The halogenated alkane solvent is dichloromethane or dichloroethane. 13 Calculated in terms of CH3OH, the dosage is 10-50 mL / g.

[0009] The base is one of NaH, KH or CaH2.

[0010] The sulfide is one of diphenyl sulfide, dibenzothiophene-based aryl sulfide or dimethyl sulfide-based alkyl sulfide.

[0011] The ether solvent is diethyl ether or methyl tert-butyl ether. 13 Calculated based on CH3OH, the dosage is 20-100 mL / g.

[0012] Compared with the prior art, the present invention has the following advantages: 1. The present invention selects commercially available 13 CH3OH and trifluoromethanesulfonic anhydride (Tf2O) were used as starting materials. 13 Preparation by reaction of CH3OH and Tf2O 13 CH3OTf is finally neutralized with alkali and then reacted with thioether to obtain 13 The whole reaction is carried out in a one-pot two-step form, which is simple and easy to operate.

[0013] 2. The raw materials of the present invention are relatively cheap 13 CH3OH as 13 C sources, of which Tf2O and sulfide are both cheap and easy to purchase in large quantities.

[0014] 3. The reaction conditions of the present invention are mild and safe, and the product yield is high.

[0015] 4. The synthesis method of the present invention can be scaled up to tens of grams, which is suitable for medium-scale production. 13 C-labeled sulfur ylide salts provide a new idea. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The specific implementation modes of the present invention are further described in detail below in conjunction with the accompanying drawings.

[0017] Figure 1 Synthesized for the present invention 13 Chemical reaction process diagram of C-labeled sulfur ylide salt. DETAILED DESCRIPTION

[0018] like Figure 1 As shown, a method for preparing a carbon isotope labeled sulfur ylide salt is as follows: under nitrogen protection, a main raw material is added to a reaction vessel. 13 CH3OH, Tf2O was slowly added dropwise at 0 ℃. After the addition was completed, the reaction solution was stirred for 4 hours. After the reaction was completed, a halogenated alkane solvent was first added for dilution, and then a base was added for further stirring for 20 minutes, and finally filtered through diatomaceous earth to obtain a filtrate. Thioether was added to the filtrate, and stirred at 40 ℃ for 12 hours. After the reaction was completed, the solvent was first removed by a rotary evaporator, and then the white residue was washed with an ether solvent and dried with an oil pump to obtain a white powdery sulfur ylide salt- 13 C.

[0019] Among them: Main raw materials 13 The molar ratio of CH3OH to Tf2O is 1.0: 1.0 to 2.0 eq, preferably 1.0: 1.0 to 1.5 eq. Main raw material 13 The molar ratio of CH3OH to the base is 1.0: 1.0 to 3.0 eq, preferably 1.0: 1.5 to 2.5 eq. Main raw material 13 The molar ratio of CH3OH to thioether is 1.0: 1.0 to 3.0 eq, preferably 1.0: 1.5 to 2.5 eq.

[0020] The halogenated alkane solvent is dichloromethane or dichloroethane, preferably dichloromethane; 13 The amount used is 10-50 mL / g based on CH3OH, preferably 20-30 mL / g.

[0021] The base is one of NaH, KH or CaH2, preferably NaH.

[0022] The sulfide is one of diphenyl sulfide, dibenzothiophene-based aryl sulfide, and dimethyl sulfide-based alkyl sulfide, preferably diphenyl sulfide.

[0023] The ether solvent is diethyl ether or methyl tert-butyl ether, preferably diethyl ether;13 The amount used is 20-100 mL / g, preferably 40-60 mL / g, based on CH3OH.

[0024] Example 1 A method for preparing a carbon isotope labeled sulfur ylide salt: Under nitrogen protection, add 13 CH3OH (6.61 g, 200.0 mmol, 1.0 equiv.,>99atom%), Tf2O (56.42 g, 200.0 mmol, 1.0 equiv.) was slowly added dropwise at 0 ℃. After the addition was completed, the reaction solution was stirred for 4 hours. After the reaction was completed, dichloromethane (150 mL) was added for dilution, and then NaH (9.60 g, 400 mmol, without mineral oil; or 16.00 g, 400.0 mmol, containing 60% mineral oil, 2.0 equiv.) was added and stirred for 20 minutes. Finally, it was filtered through diatomaceous earth to obtain a filtrate. Diphenyl sulfide (74.52 g, 400.0 mmol, 2.0 equiv.) was added to the filtrate and heated at 40 ℃ and stirred for 12 hours. After the reaction was completed, the solvent was evaporated and then the white residue was washed with an ether solvent and dried to obtain the sulfur ylide salt in the form of a crystalline white powder. 13 C (62.52 g, yield 89%).

[0025] 1 (400 MHz, CDCl3) δ 7.97 – 7.89 (m, 4H), 7.73 – 7.60 (m, 6H), 3.69 (d, J = 147.6 Hz, 3H) ppm; 13 C NMR (101 MHz, CDCl3) δ 134.4, 131.4, 129.9, 125.8, 28.5 ppm. Example 2 A method for preparing a carbon isotope labeled sulfur ylide salt: Under nitrogen protection, add 13CH3OH (165.2 mg, 5.0 mmol, 1.0 equiv,>99atom%), Tf2O (1.41 g, 5.0 mmol, 1.0 equiv.) was slowly added dropwise at 0 ℃. After the addition was completed, the reaction solution was stirred for 4 hours. After the reaction was completed, dichloromethane (5 mL) was added for dilution, and KH (1.34 g, 10.0 mmol, containing 30% mineral oil, 2.0 equiv.) was added and stirred for 20 minutes. Finally, it was filtered through diatomaceous earth to obtain a filtrate. Diphenyl sulfide (1.86 g, 10.0 mmol, 2.0 equiv.) was added to the filtrate and stirred at 40 ℃ for 12 hours. After the reaction was completed, the solvent was evaporated and removed, and the white residue was washed with an ether solvent and dried to obtain a crystalline white powder of sulfur ylide salt- 13 C (1.23 g, yield 70 %).

[0026] 1 (400 MHz, CDCl3) δ 7.97 – 7.89 (m, 4H), 7.73 – 7.60 (m, 6H), 3.69 (d, J = 147.6 Hz, 3H) ppm; 13 C NMR (101 MHz, CDCl3) δ 134.4, 131.4, 129.9, 125.8, 28.5 ppm. Example 3 A method for preparing a carbon isotope labeled sulfur ylide salt: Under nitrogen protection, add 13 CH3OH (165.2 mg, 5.0 mmol, 1.0 equiv,>99atom%), Tf2O (1.41 g, 5.0 mmol, 1.0 equiv.) was slowly added dropwise at 0 ℃. After the addition was completed, the reaction solution was stirred for 4 hours. After the reaction was completed, dichloromethane (5 mL) was added for dilution, and CaH2 (0.42 g, 10.0mmol, 2.0 equiv.) was added and stirred for 20 minutes. Finally, it was filtered through diatomaceous earth to obtain a filtrate. Diphenyl sulfide (1.86 g, 10.0 mmol, 2.0equiv.) was added to the filtrate and stirred at 40 ℃ for 12 hours. After the reaction was completed, the solvent was evaporated and removed, and the white residue was washed with an ether solvent and dried to obtain a crystalline white powder of sulfur ylide salt- 13 C (1.30 g, yield 75%).

[0027] 1(400 MHz, CDCl3) δ 7.97 – 7.89 (m, 4H), 7.73 – 7.60 (m, 6H), 3.69 (d, J = 147.6 Hz, 3H) ppm; 13 C NMR (101 MHz, CDCl3) δ 134.4, 131.4, 129.9, 125.8, 28.5 ppm. It should be understood that the technical solution of the present invention is not limited to the above specific implementation cases. 11 C. 12 C. 14 Sulfur ylide salts labeled with carbon isotopes such as C can also be prepared by this scheme. Any technical variations made according to the technical scheme of the present invention without departing from the scope of protection of the present invention and the claims shall fall within the scope of protection of the present invention.

Claims

1. A method for preparing a carbon isotope-labeled sulfur ylide salt, characterized in that: Under nitrogen protection, add the main raw material into the reaction vessel 13 CH3OH, Tf2O was slowly added dropwise at 0 ℃. After the addition was completed, the reaction solution was stirred for 4 hours. After the reaction was completed, a halogenated alkane solvent was first added for dilution, and then a base was added for further stirring for 20 minutes, and finally filtered through diatomaceous earth to obtain a filtrate. Thioether was added to the filtrate, and stirred at 40 ℃ for 12 hours. After the reaction was completed, the solvent was first evaporated to remove the solvent, and then the white residue was washed with an ether solvent and dried to obtain a white powdery sulfur ylide salt- 13 C.

2. The method for preparing a carbon isotope-labeled sulfur ylide salt according to claim 1, characterized in that: The main raw material 13 The molar ratio of CH3OH to Tf2O is 1.0: 1.0-2.0 eq; the main raw material 13 The molar ratio of CH3OH to the base is 1.0: 1.0-3.0 eq; the main raw material 13 The molar ratio of CH3OH to the sulfide is 1.0: 1.0 to 3.0 eq.

3. The method for preparing a carbon isotope-labeled sulfur ylide salt according to claim 2, characterized in that: The main raw material 13 The molar ratio of CH3OH to Tf2O is 1.0: 1.0-1.5 eq; the main raw material 13 The molar ratio of CH3OH to the base is 1.0: 1.5-2.5 eq; the main raw material 13 The molar ratio of CH3OH to the thioether is 1.0: 1.5 to 2.5 eq.

4. The method for preparing a carbon isotope-labeled sulfur ylide salt according to claim 1, characterized in that: The halogenated alkane solvent is dichloromethane or dichloroethane. 13 Calculated in terms of CH3OH, the dosage is 10-50 mL / g.

5. The method for preparing a carbon isotope labeled sulfur ylide salt according to claim 1, characterized in that: The base is one of NaH, KH or CaH2.

6. The method for preparing a carbon isotope labeled sulfur ylide salt according to claim 1, characterized in that: The sulfide is one of diphenyl sulfide, dibenzothiophene-based aryl sulfide or dimethyl sulfide-based alkyl sulfide.

7. The method for preparing a carbon isotope labeled sulfur ylide salt according to claim 1, characterized in that: The ether solvent is diethyl ether or methyl tert-butyl ether. 13 Calculated based on CH3OH, the dosage is 20-100 mL / g.

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