Synthesis method of 4-((4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane-2-yl) methyl) piperidine-1-tert-butyl formate

Abstract

The invention relates to a synthetic method of 4-((4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane-2-yl) methyl) piperidine-1-tert-butyl formate, which comprises the following synthetic route: # imgabs0 #. The synthetic method has the advantages that when Witting reaction and boronation reaction are carried out, the reaction temperature is lower, the generation of by-products is reduced, and the purity and yield of the product are improved. Based on the synthesis route provided by the invention, the raw materials are more economical and easy to obtain, an expensive palladium-carbon catalyst is not used, and the cost can be remarkably reduced; the yield and the purity of the target product are remarkably improved by accurately controlling the reaction conditions and the molar ratio; the raw materials and solvents used in the process are mostly environment-friendly, the reaction conditions are mild, the process is simple and feasible, and the method is suitable for the requirements of large-scale industrial production.

Description

Technical Field

[0001] The 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] At present, 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, a pharmaceutical composition containing it can be used to treat fibrotic diseases and other furin-mediated diseases. In view of the application value of tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate in medicine, it is of great significance to develop a method for preparing tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate with low cost and high yield.

[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 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 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 tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate is obtained by bromination and coupling. However, the overall price of raw materials is 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. The tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate is obtained by 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 the present invention urgently needs to solve. 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 route provided by the present invention, the raw materials are more economical and easy to obtain, and no expensive palladium-carbon catalyst is used, which can significantly reduce the cost; 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 it is suitable for the needs of large-scale industrial production.

[0008] The present invention is achieved by the following technical scheme: 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 synthesis path:

[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 a compound of formula (II).

[0011] According to the above technical scheme, the specific synthesis steps are as follows: under 0°C, add the phosphine reagent to the reaction solvent, add the organic base and stir for 40 minutes, then drop the compound shown in formula (I) dissolved in the reaction solvent into the reaction system, stir at room temperature for 18 hours after the dropwise addition, and the reaction is complete when detected by TLC. The reaction solution is quenched with saturated ammonium chloride, and then water and ethyl acetate are added, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and column chromatographed to obtain the compound shown in 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 temperature for reacting the phosphine reagent and the organic base in the reaction solvent is 0°C-5°C, and the reaction time is 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] Through 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 uses a phosphine reagent and an organic base to promote the Witting reaction by precisely controlling the reaction conditions and molar ratio, and the reaction conditions are mild and the yield is high;

[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 It 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 solution 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 used to limit the present invention.

[0030] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. The experimental methods without specific conditions in the following examples are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, all percentages, ratios, proportions or 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] The first step: at 0°C, add 969g of methyl triphenylphosphonium bromide to 1L THF, then add 456g of potassium tert-butoxide, stir for 40min, then drop 100g of the compound shown in formula (I) dissolved in 100mL THF into the reaction system, stir at room temperature for 18h after the dropwise addition, and the reaction is complete by TLC detection. The reaction solution is quenched with saturated ammonium chloride, then water and ethyl acetate are added, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and column chromatography to obtain 97g of the compound shown in formula (II), with a yield of 98%. In this embodiment, the molar ratio of the compound shown in formula (I), methyl triphenylphosphonium bromide, and potassium tert-butoxide is 1:2:3.

[0034] Step 2: Under 0°C, 97g of the compound shown in formula (II) was dissolved in 0.97L THF, and then 85g of borane tetrahydrofuran was slowly added to the reaction system. After stirring for 3h, the raw material disappeared by TLC detection, and then 116g of pinacol was slowly added. After the addition was completed, the temperature was raised to 70°C and refluxed for 2h. The reaction was complete by TLC detection. Then, the reaction solution was 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 155g of the compound shown in formula (II), with a yield of 97%. In this embodiment, the molar ratio of the compound shown in formula (II), borane tetrahydrofuran, and pinacol is 1:2:2.

[0035] Embodiment 2:

[0036] The first step: at 0 ° C, 533g of methyl triphenylphosphine bromide was added to 1L THF, and then 228g of potassium tert-butoxide was added. After stirring for 40min, 100g of the compound shown in formula (I) dissolved in 100mL THF was added dropwise to the reaction system. After the addition was complete, it 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, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and column chromatography to obtain 93g of the compound shown in formula (II), with a yield of 94%. Wherein, in this embodiment, the molar ratio of the compound shown in formula (I), methyl triphenylphosphine bromide, and potassium tert-butoxide is 1:1.1:1.5.

[0037] Step 2: Under 0°C, 93g of the compound shown in formula (II) was dissolved in 0.93L THF, and then 45g of borane tetrahydrofuran was slowly added to the reaction system. After stirring for 3h, the raw material disappeared by TLC detection, and then 61g of pinacol was slowly added. After the addition was completed, the temperature was raised to 70°C and refluxed for 2h. The reaction was complete by TLC detection. Then, the reaction solution was 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 shown in formula (II), with a yield of 91%. In this embodiment, the molar ratio of the compound shown in formula (II), borane tetrahydrofuran, and pinacol was 1:1.1:1.1.

[0038] Embodiment 3:

[0039] The first step: at 0°C, add 969g of methyl triphenylphosphine bromide to 1L THF, then add 7.46g of sodium bis(trimethylsilyl)amide, stir for 40min, then drop 100g of the compound shown in formula (I) dissolved in 100mL THF into the reaction system, stir at room temperature for 18h after the addition, and the reaction is complete by TLC detection. The reaction solution is quenched with saturated ammonium chloride, then water and ethyl acetate are added, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and column chromatographed to obtain 93g of the compound shown in formula (II), with a yield of 94%. In this embodiment, the molar ratio of the compound shown in formula (I), methyl triphenylphosphine bromide, and sodium bis(trimethylsilyl)amide is 1:2:3.

[0040] Step 2: Under 0°C, 97g of the compound shown in formula (II) was dissolved in 0.97L THF, and then 45g of borane tetrahydrofuran was slowly added to the reaction system. After stirring for 3h, the raw material disappeared by TLC detection, and then 111g of pinacol was slowly added. After the addition was completed, the temperature was raised to 70°C and refluxed for 2h. The reaction was complete by TLC detection. Then, the reaction solution was 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 146g of the compound shown in formula (II), with a yield of 95%. In this embodiment, the molar ratio of the compound shown in formula (II), borane tetrahydrofuran, and pinacol is 1:1.1:2.

[0041] Embodiment 4:

[0042] The first step: at 0°C, add 1097g of methyl triphenylphosphine iodide to 1L THF, then add 746g of sodium bis(trimethylsilyl)amide, stir for 40min, then drop 100g of the compound shown in formula (I) dissolved in 100mL THF into the reaction system, stir at room temperature for 12h after the addition, and the reaction is complete by TLC detection. The reaction solution is quenched with saturated ammonium chloride, then water and ethyl acetate are added, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, column chromatography, and 92g of the compound shown in formula (II) is obtained, with a yield of 93%. Wherein, in this embodiment, the molar ratio of the compound shown in formula (I), methyl triphenylphosphine iodide, and sodium bis(trimethylsilyl)amide is 1:2:3.

[0043] Step 2: Under 0°C, 92g of the compound shown in formula (II) was dissolved in 0.92L THF, and then 80g of borane tetrahydrofuran was slowly added to the reaction system. After stirring for 3h, the raw material disappeared by TLC detection, and then 60g of pinacol was slowly added. After the addition was completed, the temperature was raised to 70°C and refluxed for 2h. The reaction was complete by TLC detection. Then, the reaction solution was 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 143g of the compound shown in formula (II), with a yield of 94%. In this embodiment, the molar ratio of the compound shown in formula (II), borane tetrahydrofuran, and pinacol is 1:2:1.1.

[0044] Embodiment 5:

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

[0046] Effect Example

[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 obtained nuclear magnetic resonance 1HNMR spectrum is 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. Among them, 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 as follows 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 shown in 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 a compound shown in formula (III). Based on the synthesis route provided by the present invention, the raw materials are more economical and easy to obtain, 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, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments or to 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 protection scope 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:

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, characterized in that: The compound of formula (I) is reacted with a phosphine reagent and an organic base in a reaction solvent to obtain a compound of formula (II).

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 2, characterized in that: 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.

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 claim 2, characterized in that: 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.

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 any one of claims 2 to 4, characterized in that: The temperature for reacting the phosphine reagent and the organic base in the reaction solvent is 0°C-5°C, and the reaction time is 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.

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 2, characterized in that: 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).

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 6, characterized in that: The molar ratio of the borane tetrahydrofuran to the compound represented by formula (II) is (1.2-2):

1.

8. 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 6, characterized in that: The molar ratio of the pinacol to the compound represented by formula (II) is (1.2-2):

1.

9. 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 2 or 6, characterized in that: 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.

10. 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 6, characterized in that: The temperature for reacting 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 adding the compound represented by formula (II), the reaction temperature is 60-80°C, and the reaction time is 1h-3h.

Images