A method for synthesizing tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate

Abstract

The present invention relates to a synthetic method for tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-formate, comprising the following synthetic route: the present invention has the advantage that when performing Witting reaction and boronation reaction, the reaction temperature is low, which helps to reduce the generation of by-products and improve the purity and yield of the product. Based on the synthetic route provided by the present invention, raw materials are more economical and easy to obtain, and expensive palladium-carbon catalysts are not used, which can significantly reduce costs; by accurately controlling the reaction conditions and molar ratio, the yield and purity of the target product are significantly improved; the raw materials and solvents used in the process are mostly environmentally friendly, and the reaction conditions are mild, the process is simple and feasible, and is suitable for the needs of large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediate preparation, and in particular to a method for synthesizing tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate. Background Art

[0002] Currently, tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate and related derivatives are important chemical intermediates. According to the document CN112384509A, pharmaceutical compositions containing them can be used to treat fibrotic diseases and other furin-mediated conditions. (Given the pharmaceutical application value of tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate, it is of great significance to develop a low-cost and high-yield method for preparing tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate.)

[0003] According to the literature European Journal of Organic Chemistry (2019), 2019 (33), 5624-5635., the synthesis of tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate mainly uses N-tert-butyloxycarbonyl-4-piperidone, bis[(pinacol)boryl]methane, tetramethylpiperidinium lithium, and palladium on carbon as raw materials, and tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate is obtained by pinacol and hydrogenation reduction. However, the price of bis[(pinacol)boryl]methane in the raw material is high, and the process requires the use of catalyst palladium on carbon, which is expensive, limiting the development of the industry.

[0004] According to the literature Organic Letters (2023), 25(8), 1268-1273., the synthesis of tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate mainly uses N-Boc-4-hydroxypiperidine, triphenylphosphine, bromine, imidazole, nickel bromide, cesium iodide, and iodomethylboronic acid pinacol ester as raw materials, and obtains tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate through bromination and coupling. However, the overall price of raw materials is relatively high, which is not conducive to industrial scale-up production.

[0005] According to the literature Journal of the American Chemical Society (2019), 141(23), 9391-9400., the synthesis of tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate can be prepared from N-Boc-4-hydroxypiperidine, methyltriphenylphosphonium bromide, Dess-Martin oxidant potassium tert-butoxide, nickel chloride, bipyraclostrobin, and sodium tert-butoxide. 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate is obtained through subtype methylation and coupling. The reaction yield is low and the material cost is high, which is not conducive to industrial scale-up production.

[0006] Based on the above research status, how to provide a high-yield and low-cost preparation method of tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate to solve the problems of low yield and high production cost of the above process has become a technical problem that needs to be solved urgently in the present invention. Summary of the Invention

[0007] The object of the present invention is to overcome the deficiencies in the prior art and provide a method for synthesizing tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate. When performing Witting reaction and borylation reaction, the reaction temperature is low, which helps to reduce the generation of by-products and improve the purity and yield of the product. Based on the synthesis path provided by the present invention, the raw materials are more economical and readily available, and no expensive palladium-carbon catalyst is used, which can significantly reduce costs. By precisely controlling the reaction conditions and molar ratio, the yield and purity of the target product are significantly improved. The raw materials and solvents used in the process are mostly environmentally friendly, and the reaction conditions are mild. The process is simple and feasible, and is suitable for the needs of large-scale industrial production.

[0008] The present invention is achieved through the following technical solutions: On the one hand, a method for synthesizing tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate is provided, comprising the following synthetic route:

[0009]

[0010] Furthermore, the compound of formula (I) is subjected to a witting reaction with a phosphine reagent and an organic base in a reaction solvent to obtain the compound of formula (II).

[0011] The above technical scheme provides the following specific synthesis steps: a phosphine reagent is added to a reaction solvent at 0°C, an organic base is added, and the mixture is stirred for 40 minutes. The compound represented by formula (I) dissolved in the reaction solvent is then added dropwise to the reaction system. After the addition is complete, the mixture is stirred at room temperature for 18 hours. TLC confirms the reaction is complete. The reaction solution is quenched with saturated ammonium chloride, followed by the addition of water and ethyl acetate. The mixture is then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to spin drying. The mixture is then purified by column chromatography to yield the compound represented by formula (II).

[0012] Furthermore, the phosphine reagent is selected from any one of methyltriphenylphosphine bromide and methyltriphenylphosphine iodide; the molar ratio of the phosphine reagent to the compound represented by formula (I) is (1.1-2):1; preferably 2:1.

[0013] Furthermore, the organic base is selected from any one of potassium tert-butoxide and sodium bis(trimethylsilyl)amide; the molar ratio of the organic base to the compound represented by formula (I) is (1.5-3):1; preferably 3:1.

[0014] Furthermore, the phosphine reagent and the organic base are reacted in a reaction solvent at a temperature of 0°C-5°C and a reaction time of 0.5h-1h; after adding the compound represented by formula (I), the reaction temperature is 20-30°C and the reaction time is 12h-24h.

[0015] Furthermore, the compound represented by formula (II) is subjected to borylation reaction with borane tetrahydrofuran in a reaction solvent, and then subjected to coupling reaction with pinacol to obtain the compound represented by formula (III).

[0016] According to the above technical scheme, the specific synthesis steps are as follows: at 0°C, the compound represented by formula (II) is dissolved in a reaction solvent, and then borane tetrahydrofuran is slowly added dropwise to the reaction system. After stirring for 3 hours, TLC detection shows that the raw material disappears, and then pinacol is slowly added dropwise. After the addition is completed, the temperature is raised to 70°C and refluxed for 2 hours. TLC detection shows that the reaction is complete, and then the reaction solution is concentrated and water is added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain the compound represented by formula (III).

[0017] Furthermore, the molar ratio of the borane tetrahydrofuran to the compound represented by formula (II) is (1.2-2):1; preferably 2:1.

[0018] Furthermore, the molar ratio of pinacol to the compound represented by formula (II) is (1.2-2):1, preferably 2:1.

[0019] Preferably, the reaction solvent is one of THF and DMF, and the usage ratio of the reaction solvent to the compound represented by formula (I) and the compound represented by formula (II) is (5-20) mL:1 g.

[0020] Furthermore, the compound of formula (II) and borane tetrahydrofuran are reacted in a reaction solvent at a temperature of 0°C-5°C and a reaction time of 2h-5h; after adding the compound represented by formula (II), the reaction is carried out at a temperature of 60-80°C and a reaction time of 1h-3h.

[0021] Beneficial effects

[0022] ① The present invention promotes the Witting reaction by precisely controlling the reaction conditions and molar ratio using a phosphine reagent and an organic base, which has mild reaction conditions and high yield;

[0023] ② When carrying out Witting reaction and borylation reaction, the reaction temperature is low, which helps to reduce the formation of by-products and improve the purity and yield of the product.

[0024] ③ Through the borylation reaction of borane-tetrahydrofuran and the coupling reaction of pinacol, the yield and purity of the target product were significantly improved under the conditions of precise control of reaction conditions and molar ratio;

[0025] ④ Most of the raw materials and solvents used in the process are environmentally friendly, the reaction conditions are mild, the process is simple and feasible, and it is suitable for the needs of large-scale industrial production.

[0026] ⑤ Based on the synthesis route provided by the present invention, the raw materials are more economical and readily available, and no expensive palladium-carbon catalyst is used, which can significantly reduce costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is the 1HNMR spectrum of tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate;

[0028] Figure 2 This is the GC spectrum of tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate. DETAILED DESCRIPTION

[0029] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0030] All other embodiments obtained by persons of ordinary skill in the art based on the embodiments herein without inventive effort are intended to fall within the scope of protection of the present invention. Experimental methods in the following examples, where specific conditions are not specified, were generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise indicated, all percentages, ratios, proportions, and parts are by weight.

[0031] Unless otherwise specified, the reagents and raw materials used in the examples and comparative examples of the present invention can be obtained through commercial channels.

[0032] Example 1

[0033] Step 1: At 0°C, 969g of methyltriphenylphosphonium bromide was added to 1L of THF, followed by 456g of potassium tert-butoxide. After stirring for 40 minutes, 100g of the compound represented by formula (I) dissolved in 100mL of THF was added dropwise to the reaction system. After complete addition, the mixture was stirred at room temperature for 18 hours. TLC confirmed the reaction was complete. The reaction solution was quenched with saturated ammonium chloride, followed by addition of water and ethyl acetate. The mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and dried by spin drying. Column chromatography yielded 97g of the compound represented by formula (II) in a 98% yield. In this embodiment, the molar ratio of the compound represented by formula (I), methyltriphenylphosphonium bromide, and potassium tert-butoxide was 1:2:3.

[0034] Step 2: Under 0°C conditions, 97g of the compound represented by formula (II) was dissolved in 0.97L THF, and then 85g of borane tetrahydrofuran was slowly added dropwise to the reaction system. After stirring for 3h, TLC detection showed that the raw material disappeared, and then 116g of pinacol was slowly added dropwise. After the addition was completed, the temperature was raised to 70°C and refluxed for 2h. TLC detection showed that the reaction was complete. The reaction solution was then concentrated and water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and column chromatography to obtain 155g of the compound represented by formula (II) with a yield of 97%. In this embodiment, the molar ratio of the compound represented by formula (II), borane tetrahydrofuran, and pinacol was 1:2:2.

[0035] Example 2:

[0036] The first step: at 0 ° C, 533g of methyl triphenyl phosphonium bromide was added to 1L THF, and then 228g of potassium tert-butoxide was added. After stirring for 40min, 100g of compound shown in formula (I) dissolved in 100mL THF was added dropwise to the reaction system. After completion of the addition, the mixture was stirred at room temperature for 18h. The reaction was detected by TLC. The reaction solution was quenched with saturated ammonium chloride, then concentrated and added with water and ethyl acetate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 93g of compound shown in formula (II). The yield was 94%. In this embodiment, the molar ratio of compound shown in formula (I), methyl triphenyl phosphonium bromide, and potassium tert-butoxide was 1:1.1:1.5.

[0037] Step 2: At 0°C, 93g of the compound represented by formula (II) was dissolved in 0.93L THF, and then 45g of borane tetrahydrofuran was slowly added dropwise to the reaction system. After stirring for 3h, TLC detection showed that the raw material disappeared, and then 61g of pinacol was slowly added dropwise. After the addition was completed, the temperature was raised to 70°C and refluxed for 2h. TLC detection showed that the reaction was complete. The reaction solution was then concentrated and water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 140g of the compound represented by formula (II) in a yield of 91%. In this embodiment, the molar ratio of the compound represented by formula (II), borane tetrahydrofuran, and pinacol was 1:1.1:1.1.

[0038] Example 3:

[0039] Step 1: At 0°C, 969g of methyltriphenylphosphine bromide was added to 1L of THF, followed by 7.46g of sodium bis(trimethylsilyl)amide. After stirring for 40 minutes, 100g of the compound represented by formula (I) dissolved in 100mL of THF was added dropwise to the reaction system. After complete addition, the mixture was stirred at room temperature for 18 hours. TLC confirmed the reaction was complete. The reaction solution was quenched with saturated ammonium chloride, followed by addition of water and ethyl acetate. The mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and dried by spin drying. Column chromatography yielded 93g of the compound represented by formula (II) in a 94% yield. In this embodiment, the molar ratio of the compound represented by formula (I), methyltriphenylphosphine bromide, and sodium bis(trimethylsilyl)amide was 1:2:3.

[0040] Step 2: Under 0°C conditions, 97g of the compound represented by formula (II) was dissolved in 0.97L THF, and then 45g of borane tetrahydrofuran was slowly added dropwise to the reaction system. After stirring for 3h, TLC detection showed that the raw material disappeared, and then 111g of pinacol was slowly added dropwise. After the addition was completed, the temperature was raised to 70°C and refluxed for 2h. TLC detection showed that the reaction was complete. The reaction solution was then concentrated and water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and column chromatography to obtain 146g of the compound represented by formula (II), with a yield of 95%. Wherein, in this embodiment, the molar ratio of the compound represented by formula (II), borane tetrahydrofuran, and pinacol was 1:1.1:2.

[0041] Example 4:

[0042] Step 1: At 0°C, 1097g of methyltriphenylphosphine iodide was added to 1L of THF, followed by 746g of sodium bis(trimethylsilyl)amide. After stirring for 40 minutes, 100g of the compound represented by formula (I) dissolved in 100mL of THF was added dropwise to the reaction system. After complete addition, the mixture was stirred at room temperature for 12 hours. TLC confirmed the reaction was complete. The reaction solution was quenched with saturated ammonium chloride, followed by addition of water and ethyl acetate. The mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and dried by spin drying. Column chromatography yielded 92g of the compound represented by formula (II) in a 93% yield. In this example, the molar ratio of the compound represented by formula (I), methyltriphenylphosphine iodide, and sodium bis(trimethylsilyl)amide was 1:2:3.

[0043] Step 2: At 0°C, 92g of the compound represented by formula (II) was dissolved in 0.92L THF, and then 80g of borane tetrahydrofuran was slowly added dropwise to the reaction system. After stirring for 3h, TLC detection showed that the raw material disappeared, and then 60g of pinacol was slowly added dropwise. After the addition was completed, the temperature was raised to 70°C and refluxed for 2h. TLC detection showed that the reaction was complete. The reaction solution was then concentrated and water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and column chromatography to obtain 143g of the compound represented by formula (II) with a yield of 94%. In this embodiment, the molar ratio of the compound represented by formula (II), borane tetrahydrofuran, and pinacol was 1:2:1.1.

[0044] Example 5:

[0045] At 0°C, 969g of methyltriphenylphosphonium bromide was added to 1L of DMF, followed by 456g of potassium tert-butoxide. After stirring for 40 minutes, 100g of the compound represented by formula (I) dissolved in 100mL of THF was added dropwise to the reaction system. After complete addition, the mixture was stirred at room temperature for 12 hours. TLC confirmed the reaction was complete. The reaction solution was quenched with saturated ammonium chloride, followed by addition of water and ethyl acetate. The mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried. The mixture was then purified by column chromatography to obtain 91g of the compound represented by formula (II) in a 92% yield. In this example, the reaction solvent was DMF.

[0046] Effect embodiment

[0047] The tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate prepared in Examples 1 to 5 was subjected to nuclear magnetic resonance analysis. The resulting nuclear magnetic resonance 1HNMR spectrum is shown as follows: Figure 1 As shown. Figure 1 It can be seen that the present invention successfully prepared the target product tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate.

[0048] The yield and purity (purity test using gas chromatography) of tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate prepared in Examples 1 to 5 were analyzed. The results are shown in Table 1. The GC spectrum of the tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate product prepared in Example 1 is shown in Table 1. Figure 2 shown.

[0049] Table 1

[0050]

[0051]

[0052] Depend on Figure 2As can be seen from the data in Table 1, the preparation method of tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate provided by the present invention is as follows: Compound (I) is subjected to a witting reaction with a phosphine reagent and an organic base in a reaction solvent to obtain compound (II); the compound represented by formula (II) is subjected to a borylation reaction with borane tetrahydrofuran in a reaction solvent, and then subjected to a coupling reaction with pinacol to obtain the compound represented by formula (III). Based on the synthesis route provided by the present invention, the raw materials are more economical and easily available, and no expensive palladium-carbon catalyst is used, which can significantly reduce costs; by precisely controlling the reaction conditions and molar ratio, the yield and purity of the target product are significantly improved; the raw materials and solvents used in the process are mostly environmentally friendly, and the reaction conditions are mild, the process is simple and feasible, and it is suitable for the needs of large-scale industrial production.

[0053] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate, comprising the following synthetic route: ； Wherein, the compound of formula (I) is subjected to a witting reaction with a phosphine reagent and an organic base in a reaction solvent to obtain the compound of formula (II); The compound represented by formula (II) undergoes borylation reaction with borane tetrahydrofuran in a reaction solvent, and then undergoes coupling reaction with pinacol to obtain the compound represented by formula (III); The temperature of the reaction between the compound of formula (II) and borane tetrahydrofuran in a reaction solvent is 0°C-5°C, and the reaction time is 2h-5h; after the compound of formula (II) is added, the reaction temperature is 60-80°C, and the reaction time is 1h-3h.

2. The method for synthesizing tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate according to claim 1, wherein The phosphine reagent is selected from any one of methyltriphenylphosphine bromide and methyltriphenylphosphine iodide; the molar ratio of the phosphine reagent to the compound represented by formula (I) is (1.1-2):

1.

3. The method for synthesizing tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate according to claim 1, wherein The organic base is selected from any one of potassium tert-butoxide and sodium bis(trimethylsilyl)amide; the molar ratio of the organic base to the compound represented by formula (I) is (1.5-3):

1.

4. The method for synthesizing tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate according to any one of claims 1 to 3, characterized in that: The phosphine reagent and the organic base are reacted in a reaction solvent at a temperature of 0°C-5°C and a reaction time of 0.5h-1h. After the compound represented by formula (I) is added, the reaction is carried out at a temperature of 20-30°C and a reaction time of 12h-24h.

5. The method for synthesizing tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate according to claim 1, wherein The molar ratio of the borane tetrahydrofuran to the compound represented by formula (II) is (1.2-2):

1.

6. The method for synthesizing tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate according to claim 1, wherein The molar ratio of the pinacol to the compound represented by formula (II) is (1.2-2):

1.

7. The method for synthesizing tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate according to claim 1, wherein The reaction solvent is one of THF and DMF, and the usage ratio of the reaction solvent to the compound represented by formula (I) and the compound represented by formula (II) is (5-20) mL:1 g.

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