Preparation method of 3-(tert-butyl diphenyl siloxy)-2, 2-difluoropropyl trifluoromethanesulfonate
Through the four-step reaction, 1,3-dihydroxyacetone, tert-butyldiphenyl chloride silane, trifluoromethanesulfonic anhydride and fluorination reagents were used to successfully solve the problems of fewer synthesis methods of 3-(tert-butyldiphenylsiloxy)-2,2-difluoropropyltrifluoromethanesulfonate in the prior art and expensive raw materials, achieving a high yield and easy operation synthesis process.
Patent Information
- Application Number
- CN202510055405.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-14
- Publication Date
- 2025-04-25
AI Technical Summary
In the existing literature, there are fewer synthesis methods for 3-(tert-butyldiphenylsiloxy)-2,2-difluoropropyltrifluoromethanesulfonate, and the starting materials are expensive, making it difficult to achieve a synthesis process that is easy to obtain raw materials, easy to operate, and easy to control reactions.
1,3-dihydroxyacetone, tert-butyldiphenyl chloride silane, trifluoromethanesulfonic anhydride and fluorinated reagent are used as raw materials. Through four steps of reaction: 1,3-dihydroxyacetone forms a ring with trimethyl borate, then reacts with tert-butyldiphenyl chloride silane, then reacts with trifluoromethanesulfonic anhydride and base, and finally undergoes fluorination reaction with the fluorinated reagent to form the target compound.
The synthesis method of 3-(tert-butyldiphenylsiloxy)-2,2-difluoropropyltrifluoromethanesulfonate with simple steps, simple and reliable processes and easy to industrially produce is realized. The operation is simple and stable, and the products are easy to separate at each step, with high yields and low raw material costs.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate. Background Art
[0002] 3-(tert-Butyldiphenylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate, English name: 3-((tert-Butyldiphenylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate, CAS: 160052-43-7, has a wide range of applications in pharmaceutical chemistry and organic synthesis, especially for the construction of biologically active compounds with pyrimidine ring skeletons.
[0003] Currently, there are few public reports on the synthesis of 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate, and the starting materials are expensive.
[0004] Therefore, it is necessary to develop a synthesis method with readily available raw materials, convenient operation, easy reaction control and appropriate overall yield. Summary of the invention
[0005] The purpose of the present invention is to provide a method for preparing 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate with simple steps, simple and reliable process, and easy industrial production. The process is divided into four steps. The first step is to cyclize 1,3-dihydroxyacetone and trimethyl orthoformate to generate intermediate 1; the second step is to substitute intermediate 1 and tert-butyldiphenylchlorosilane in an organic solvent to generate intermediate 2; the third step is to substitute intermediate 2, trifluoromethanesulfonic anhydride and base in an organic solvent to generate intermediate 3; the fourth step is to react intermediate 3 with a fluorination agent in an organic solvent to generate 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate. The technical scheme of the present invention is simple and stable to operate, the products of each step are easy to separate, the yield is high, and it is environmentally friendly, providing a new synthesis route for the compound.
[0006] The synthetic route of the preparation method of 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate of the present invention is as follows:
[0007]
[0008] In the first step, 1,3-dihydroxyacetone and trimethyl borate are heated in an organic solvent to react to generate intermediate 1.
[0009] Furthermore, in the above technical solution, the molar ratio of 1,3-dihydroxyacetone to trimethyl borate is 1:1 to 1.2.
[0010] Furthermore, in the above technical solution, the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or MTBE. Alternatively, the reaction can be directly carried out in trimethyl borate, in which case trimethyl borate serves as both a reactant and a reaction solvent.
[0011] In the second step, intermediate 1 is reacted with tert-butyldiphenylsilyl chloride in an organic solvent and in the presence of an organic base to generate intermediate 2.
[0012] Furthermore, in the above technical solution, the organic base is selected from triethylamine, diisopropylethylamine and pyridine.
[0013] Furthermore, in the above technical solution, the molar ratio of the intermediate 2 to tert-butyldiphenylchlorosilane is 1:1 to 1.3.
[0014] In the third step, intermediate 2 is reacted with trifluoromethanesulfonic anhydride in an organic solvent and in the presence of an organic base to generate intermediate 3.
[0015] Furthermore, in the above technical solution, the organic base is selected from triethylamine, diisopropylethylamine and pyridine.
[0016] Furthermore, in the above technical solution, the organic solvent is selected from a mixture of one or more of dichloromethane, chloroform, tetrahydrofuran, and methyltetrahydrofuran.
[0017] Furthermore, in the above technical solution, the molar ratio of the intermediate 1, trifluoromethanesulfonic anhydride and the organic base is 1:1-1.5:1-1.5.
[0018] In the fourth step, the intermediate 3 and a fluorination agent are subjected to a fluorination reaction in an organic solvent to generate 1-(3-pyrrolidinopropyl)-1,3-propylenediamine.
[0019] Furthermore, in the above technical solution, the fluorination agent is selected from BAST, MOST and DAST, etc.
[0020] Furthermore, in the above technical solution, the organic solvent is selected from a mixture of one or more of dichloromethane, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran and N,N-dimethylformamide.
[0021] Compared with the prior art, the present invention has the following significant advantages:
[0022] A. The comprehensive production yield of the present invention is much lower than that of the currently known process, and the synthesis process is more competitive in the market. The technical scheme of the present invention is simple and stable to operate, the products of each step are easy to separate, the yield is high, and it is environmentally friendly, providing a new synthesis route for the compound.
[0023] B. Using 1,3-dihydroxyacetone, tert-butyldiphenylsilyl chloride, trifluoromethanesulfonic anhydride and fluorination reagent as raw materials, the raw materials are cheap and easy to obtain, which reduces the cost of raw materials. In particular, 1,3-dihydroxyacetone is cyclized with trimethyl borate and then reacted with tert-butyldiphenylsilyl chloride to obtain a monosilane protected intermediate with high selectivity. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 The HPLC spectrum of 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate obtained in Example 1;
[0025] Figure 2 The HNMR spectrum of 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate obtained in Example 1; DETAILED DESCRIPTION
[0026] The present invention will be further described below in conjunction with specific embodiments. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.
[0027] Example 1
[0028] first step:
[0029] Under nitrogen protection, 1,3-dihydroxyacetone (0.5 g, 5.55 mmol) and trimethyl borate (0.63 g, 6.11 mmol) were added to 5 mL of tetrahydrofuran, heated under reflux and stirred for 6 hours. After the reaction was completed, the crude product was dried by spin drying and used directly in the next step.
[0030] Step 2:
[0031] The above crude product and pyridine (0.44 g, 5.55 mmol) were added to tetrahydrofuran (2.5 mL). Under nitrogen protection, tert-butyldiphenylsilyl chloride (1.53 g, 5.55 mmol) was added dropwise to a tetrahydrofuran (7 mL) solution at 5-10 ° C. The reaction solution was stirred at room temperature for 24 hours. After the reaction, sodium dihydrogen phosphate aqueous solution was used to quench the reaction, dichloromethane was extracted, dried over anhydrous sodium sulfate, and rotary evaporation was performed to obtain intermediate 2 (1.46 g, yield 80%). By nuclear magnetic resonance detection, it can be determined that the structure of intermediate 2 is correct, 1H NMR (CDCl3) δ7.73-7.36 (m, 10H), 4.60 (s, 2H), 4.32 (s, 2H), 1.11 (s, 9H).
[0032] Step 3:
[0033] Pyridine (0.36 g, 4.57 mmol) and trifluoromethanesulfonic anhydride (1.29 g, 4.57 mmol) were added to a dichloromethane (5 mL) solution of intermediate 2 (1 g, 3.04 mmol), and the reaction was stirred at 0-5°C for 2 hours. After the reaction was completed, water was added to dilute the organic phase, and the organic phase was washed with sodium bicarbonate aqueous solution and dried to obtain intermediate 3 (1.13 g, yield 81%). The structure of intermediate 3 was confirmed to be correct by nuclear magnetic resonance detection, 1HNMR (CDCI3) δ7.68-7.63 (m, 4H), 7.46-7.37 (m, 6H), 4.77 (s, 2H), 4.45 (s, 2H), 1.06 (s, 9H).
[0034] Step 4:
[0035] Under nitrogen protection, diethylaminosulfur trifluoride (0.53 g, 3.26 mmol) was added dropwise to a dichloromethane solution of intermediate 3 (1 g, 2.17 mmol), stirred at room temperature overnight, quenched with sodium bicarbonate aqueous solution after the reaction, extracted with dichloromethane and then dried, and then purified by silica gel column chromatography, eluted with petroleum ether as an eluent, and the solvent was decompressed and dried to obtain 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate (0.95 g, yield 90%). The final product structure was confirmed to be correct by nuclear magnetic resonance detection, 1H NMR (CDCI3) δ7.65-7.63 (m, 4H), 7.49-7.41 (m, 6H), 4.78-4.72 (t, 2H), 3.90-3.84 (t, 2H), 1.07 (s, 9H).
[0036] Example 2
[0037] first step:
[0038] Under nitrogen protection, 1,3-dihydroxyacetone (100 mg, 1.11 mmol) and trimethyl borate (138 mg, 1.33 mmol) were added to 2-methyltetrahydrofuran (3 mL), heated under reflux and stirred for 6 hours. After the reaction was completed, the crude product was dried by spin drying and used directly in the next step.
[0039] Step 2:
[0040] The above crude product and triethylamine (146 mg, 1.44 mmol) were added to tetrahydrofuran (2.5 mL). Under nitrogen protection, tert-butyldiphenylsilyl chloride (396 mg, 1.44 mmol) was added dropwise to a tetrahydrofuran (2 mL) solution at 5-10°C. The reaction solution was stirred at room temperature for 24 hours. After the reaction was completed, the reaction was quenched with sodium dihydrogen phosphate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and rotary evaporated to obtain intermediate 2 (303 mg, yield 83%). Step 3:
[0041] Triethylamine (120 mg, 1.19 mmol) and trifluoromethanesulfonic anhydride (335 mg, 1.19 mmol) were added to a dichloromethane (5 mL) solution of intermediate 2 (300 mg, 0.91 mmol), and the reaction was stirred at 0-5°C for 2 hours. After the reaction was completed, water was added to dilute the organic phase, and the organic phase was washed with sodium bicarbonate aqueous solution and dried to obtain intermediate 3 (341 mg, yield 81%).
[0042] Step 4:
[0043] Under nitrogen protection, bis(2-methoxyethyl)aminosulfur trifluoride (243 mg, 1.1 mmol) was added dropwise to a solution of intermediate 3 (300 mg, 0.65 mmol) in 1,2-dichloroethane (5 mL), and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was quenched with aqueous sodium bicarbonate solution and extracted with dichloromethane and dried. The product was then purified by silica gel column chromatography. After elution with petroleum ether as the eluent, the solvent was dried under reduced pressure to obtain 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate (283 mg, yield 90%).
[0044] Example 3
[0045] first step:
[0046] Under nitrogen protection, 1,3-dihydroxyacetone (20 g, 222.03 mmol) and trimethyl borate (25.38 g, 244.23 mmol) were added to tetrahydrofuran, heated under reflux and stirred for 6 hours. After the reaction was completed, the crude product was dried by spin drying and used directly in the next reaction.
[0047] Step 2:
[0048] The above crude product and diisopropylethylamine (37.30 g, 288.64 mmol) were added to tetrahydrofuran (180 mL). Under nitrogen protection, tert-butyldiphenylsilyl chloride (79.34 g, 288.64 mmol) was added dropwise to a tetrahydrofuran (400 mL) solution at 5-10°C. The reaction solution was stirred at room temperature for 24 hours. After the reaction was completed, the reaction was quenched with sodium dihydrogen phosphate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and rotary evaporated to obtain intermediate 2 (59.80 g, yield 82%).
[0049] Step 3:
[0050] Diisopropylethylamine (25.54 g, 197.58 mmol) and trifluoromethanesulfonic anhydride (55.74 g, 197.58 mmol) were added to a solution of intermediate 2 (59 g, 179.62 mmol) in dichloromethane (300 mL), and the reaction was stirred at 0-5°C for 2 hours. After the reaction was completed, the mixture was diluted with water, and the organic phase was washed with aqueous sodium bicarbonate solution and dried to give intermediate 3 (69.48 g, yield 84%).
[0051] Step 4:
[0052] Under nitrogen protection, sulfur trifluoride morpholine (42 g, 240 mmol) was dropped into an acetonitrile solution of intermediate 3 (69 g, 149.82 mmol), and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was quenched with sodium bicarbonate aqueous solution, extracted with dichloromethane and dried, and then purified by silica gel column chromatography. After elution with petroleum ether as an eluent, the solvent was dried under reduced pressure to obtain 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate (65.8 g, yield 91%).
[0053] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.
Claims
1. A method for preparing 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate, characterized in that: The steps include: In the first step, 1,3-dihydroxyacetone and trimethyl borate are heated in an organic solvent to react to generate intermediate 1; In the second step, the intermediate 1 and tert-butyldiphenylsilyl chloride are reacted in an organic solvent and in the presence of an organic base to generate the intermediate 2; The third step is to react the intermediate 2 with trifluoromethanesulfonic anhydride in an organic solvent and in the presence of an organic base to generate the intermediate 3; In the fourth step, the intermediate 3 and a fluorination agent are subjected to a fluorination reaction in an organic solvent to generate 1-(3-pyrrolidinopropyl)-1,3-propylenediamine.
2. A method for preparing 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate according to claim 1, characterized in that: In the first step, the molar ratio of 1,3-dihydroxyacetone to trimethyl orthoformate is 1:1-1.
2.
3. A method for preparing 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate according to claim 1, characterized in that: In the second step, the molar ratio of the intermediate 2 to tert-butyldiphenylchlorosilane is 1:1-1.
3.
4. A method for preparing 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate according to claim 1, characterized in that: In the third step, the organic solvent is selected from a mixture of one or more of dichloromethane, chloroform, tetrahydrofuran, and methyltetrahydrofuran.
5. The method for preparing 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate according to claim 1, characterized in that: In the third step, the molar ratio of the intermediate 1, trifluoromethanesulfonic anhydride and the base is 1:1-1.5:1-1.
5.
6. The method for preparing 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate according to claim 1, characterized in that: In the fourth step, the fluorination agent is selected from BAST, MOST and DAST.
7. The method for preparing 3-(tert-butyldiphenylsilyloxy)-2,2-difluoropropyl trifluoromethanesulfonate according to claim 1, characterized in that: In the fourth step, the organic solvent is selected from a mixture of one or more of dichloromethane, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran and N,N-dimethylformamide.