Preparation method of N-substituent-2, 2-dimethyl-3-cyano piperidine
High-purity N-substituent-2,2 was successfully prepared by adding diethyl cyanomethyl phosphate with acetone under the action of alkali, and through multiple reactions including reducing amination, chlorination and cyclization. -dimethyl-3-cyanopiperidine solves the problems of incomplete reactions and low product purity in the preparation method in the prior art.
Patent Information
- Application Number
- CN202411654122.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-19
- Publication Date
- 2025-02-25
AI Technical Summary
In the prior art, the preparation method of N-substituent-2,2-dimethyl-3-cyanopiperidine has problems such as incomplete reaction, many by-products, and low product purity.
Diethyl cyanomethyl phosphate was used as the starting material, and the addition reaction was carried out with acetone under the action of alkali. Then, through reduction amination, chlorination, cyclization and substitution reaction, N- is synthesized by amino substituent protection. Substituent-2,2-dimethyl-3-cyanopiperidine.
It has achieved efficient and high purity preparation of N-substituent-2,2-dimethyl-3-cyanopiperidine. The reaction operation is simple and reliable, with high yield and is suitable for large-scale production.
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Figure CN119504565A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of fine chemicals and organic synthesis, and in particular to a method for preparing N-substituted-2,2-dimethyl-3-cyanopiperidine. Background Art
[0002] Piperidine compounds have a wide range of application values in the fields of medicine, pesticides and veterinary drugs. N-substituted-2,2-dimethyl-3-cyanopiperidine is one of the most important chemical intermediates. Currently, there are very few reports on the synthesis of N-substituted-2,2-dimethyl-3-cyanopiperidine, and the relevant preparation methods often have problems such as incomplete reaction, many by-products, and low product purity. Therefore, it is of great significance to develop a method for preparing N-substituted-2,2-dimethyl-3-cyanopiperidine with high efficiency and high purity. Summary of the invention
[0003] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for preparing N-substituted-2,2-dimethyl-3-cyanopiperidine, which uses diethyl cyanomethyl phosphate as a starting material, reacts with acetone under the action of a base, and then undergoes a reduction amination reaction, a chlorination reaction, a cyclization, and an amino substituent protection to synthesize N-substituted-2,2-dimethyl-3-cyanopiperidine. Various raw materials and reagents are cheap and readily available, the reaction operation is simple and reliable, the yield is high, and large-scale production can be carried out.
[0004] The present invention is achieved through the following technical scheme: On the one hand, a method for preparing N-substituted-2,2-dimethyl-3-cyanopiperidine is provided, wherein diethyl cyanomethyl phosphate is used as a starting material, and acetone is reacted with cyanomethyl phosphate in the presence of a base, and then subjected to addition reaction, reductive amination reaction, chlorination reaction, cyclization and substitution reaction in sequence to obtain the N-substituted-2,2-dimethyl-3-cyanopiperidine; wherein the general structural formula of the N-substituted-2,2-dimethyl-3-cyanopiperidine is as follows:
[0005]
[0006] Where: R 1 It is any one of Boc, Cbz, Bn, Tos, PMB, and Alloc; -N is a nitrogen group, and -CN is a cyano group.
[0007] Further, the method comprises the following reaction formula:
[0008]
[0009] The specific reaction steps are as follows:
[0010] S1. dissolving the compound represented by formula (I) in an organic solvent, and subjecting it to an addition reaction with acetone in the presence of a base to obtain a compound represented by formula (II);
[0011] S2, subjecting the obtained compound represented by formula (II) and the compound represented by formula (III) to reductive amination reaction to obtain a compound represented by formula (IV);
[0012] S3, dissolving the obtained compound represented by formula (IV) in an organic solvent, and subjecting it to chlorination reaction with a chlorinating agent to obtain a compound represented by formula (V);
[0013] S4, cyclizing the obtained compound represented by formula (V) under the action of a base to obtain a compound represented by formula (VI);
[0014] S5. Dissolve the obtained compound represented by formula (VI) in an organic solvent, add a substituent and a base, and carry out a substitution reaction to obtain a compound represented by formula (VII).
[0015] Furthermore, in step S1, the molar ratio of acetone to the compound represented by formula (I) is 1.1-1.5:1.
[0016] Furthermore, the base is any one of sodium bis(trimethylsilyl)amide, NaH, sodium carbonate, and triethylamine; the molar ratio of the added amount of the base to the compound represented by formula (I), formula (V), and formula (VI) is (1.1-1.5):1.
[0017] Furthermore, in step S2, the molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:(1.1-1.5).
[0018] Furthermore, in step S3, the chlorinating agent is one of thionyl chloride and phosphorus oxychloride; the molar ratio of the added amount of the chlorinating agent to the compound represented by formula (IV) is (1.1-1.5):1.
[0019] Furthermore, the ratio of the amount of the organic solvent added to the amount of the compound represented by formula (I), formula (IV), formula (V), and formula (VI) is 5-15 mL: 1 g.
[0020] Furthermore, the organic solvent is any one of tetrahydrofuran, dichloromethane and methanol.
[0021] Furthermore, in step S5, the molar ratio of the amount of the substituent added to the compound represented by formula (VI) is (1.1-1.5):1.
[0022] Further, the method comprises the following reaction formula:
[0023]
[0024] The specific reaction steps are as follows:
[0025] S1. Add the compound represented by formula (I) to tetrahydrofuran, replace nitrogen, then cool to 0-10°C, add alkali dropwise during stirring, raise the temperature to 20-30°C and stir for 0.5-1h after the addition is complete, then add acetone dropwise, stir for 12h after the addition is complete, detect the reaction by TLC, concentrate the reaction solution, then extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, spin dry, and perform column chromatography to obtain the compound represented by formula (II);
[0026] S2, adding the compound represented by formula (II) and the compound represented by formula (III) to a reaction bottle in sequence, heating to 80-100° C. and stirring for 48-72 hours, and detecting by TLC that the compound represented by formula (II) has reacted completely, then concentrating under reduced pressure to remove excess compound represented by formula (III), and then performing column chromatography to obtain the compound represented by formula (IV);
[0027] S3, adding the compound represented by formula (IV) to dichloromethane, then cooling to 0-10°C, adding a chlorinating agent dropwise, heating to room temperature and stirring for 1 hour after the addition is completed, then heating to 40°C and stirring for 12 hours, and TLC detection shows that the reaction is complete. After the reaction solution is cooled, the reaction solution is poured into methyl tert-butyl ether, the solid is precipitated, filtered, and dried to obtain the compound represented by formula (V);
[0028] S4, adding the compound represented by (V) to tetrahydrofuran, replacing nitrogen, cooling to below -60°C, then adding alkali dropwise, warming to room temperature after the addition is completed, stirring for 5 hours, and detecting the reaction is complete by TLC, concentrating the reaction solution, and then extracting with ethyl acetate, drying over anhydrous sodium sulfate, spin-drying, and then dissolving in methyl tert-butyl ether, and then passing hydrochloric acid gas, stirring at room temperature for 1 hour, solid precipitates, filtering, and drying to obtain the compound represented by formula (VI);
[0029] S5. Dissolve the compound represented by (VI) in a solvent, add a substituent and a base, stir at room temperature for 12-24 hours, monitor the reaction completion by GC, cool to 0-5°C, slowly add HCl, separate the layers, extract the aqueous phase twice with EA, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography to obtain the compound represented by formula (VII).
[0030] Beneficial Effects
[0031] The invention uses diethyl cyanomethyl phosphate as a starting material, carries out addition reaction with acetone under the action of a base, and then undergoes reduction amination reaction, chlorination reaction, cyclization, and amino substituent protection to synthesize N-substituted-2,2-dimethyl-3-cyanopiperidine; wherein various raw materials and reagents are cheap and easily available, the reaction operation is simple and reliable, the yield is high, and large-scale production can be carried out. BRIEF DESCRIPTION OF THE DRAWINGS
[0032] Figure 1This is the 1H NMR spectrum of 2,2-dimethylpiperidine-3-carbonitrile hydrochloride. DETAILED DESCRIPTION
[0033] 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.
[0034] 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.
[0035] 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.
[0036] Example 1: A method for preparing N-Boc-2,2-dimethyl-3-cyanopiperidine
[0037]
[0038] S1. Add 100g of the compound shown in formula (I) to 1000mL of tetrahydrofuran, replace nitrogen, then cool to below 10°C, add 847mL of sodium bis(trimethylsilyl)amide dropwise during stirring, warm to 25°C and stir for 1h after the addition, then add 49g of acetone dropwise, stir for 12h after the addition, and the reaction is complete by TLC detection. The reaction solution is concentrated, then extracted with ethyl acetate, dried with anhydrous sodium sulfate, spin-dried, and column chromatographed to obtain 40g of the compound shown in formula (II). In this embodiment, the molar ratio of the compound shown in formula (I), sodium bis(trimethylsilyl)amide, and acetone is 1:1.5:1.5.
[0039] S2, 40g of the compound represented by formula (II) and 86g of the compound represented by formula (III) were added to the reaction bottle in sequence, the temperature was raised to 100°C and stirred for 72h, TLC detected that the compound represented by formula (II) was completely reacted, and then the excess of the compound represented by formula (III) was removed by vacuum concentration, and then column chromatography was performed to obtain 71g of the compound represented by formula (IV). In this embodiment, the molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:1.5.
[0040] S3, add 71g of the compound shown in formula (IV) to 710mL of dichloromethane, then cool to 10 ° C, add 81g of thionyl chloride, warm to room temperature and stir for 1h after the addition, then warm to 40 ° C and stir for 12h, TLC detection reaction is complete, after the reaction solution is cooled, pour the reaction solution into methyl tert-butyl ether, precipitate solid, filter, and dry to obtain 95g of the compound shown in formula (V). Wherein, in this embodiment, the molar ratio of the compound shown in formula (IV) to thionyl chloride is 1:1.5.
[0041] S4, 95g of the compound shown in (V) is added to 950mL of tetrahydrofuran, nitrogen is replaced, and the temperature is lowered to below -60 ° C, then 142mL of bis (trimethylsilyl) sodium amide is added dropwise, and the temperature is raised to room temperature after the addition is completed, and stirred for 5h, and the TLC detection reaction is complete, and the reaction solution is concentrated, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then dissolved in 100mL of methyl tert-butyl ether, and then hydrochloric acid gas is passed through, and stirred for 1h at room temperature, solid is precipitated, filtered, and dried to obtain 75g of the compound shown in formula (VI). Wherein, in this embodiment, the molar ratio of the compound shown in formula (V) and bis (trimethylsilyl) sodium amide is 1:1.5.
[0042] S5, dissolve 75g of the compound shown in (VI) in 750mL N,N-dimethylformamide, add 141g of Boc anhydride, 65g of triethylamine, stir at room temperature for 12-24h, monitor the reaction completely by GC, cool to 5°C, slowly add HCl, separate the liquids, extract the aqueous phase with EA twice, wash the organic phase with saturated brine once, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography to obtain 96g of the compound shown in formula (VII). Wherein, in this embodiment, the molar ratio of the compound shown in formula (VI), Boc anhydride, and triethylamine is 1:1.5:1.5.
[0043] Example 2: A method for preparing N-Boc-2,2-dimethyl-3-cyanopiperidine
[0044]
[0045] S1. Add 100g of the compound shown in formula (I) to 1000mL of tetrahydrofuran, replace nitrogen, then cool to below 10°C, add 621mL of sodium bis(trimethylsilyl)amide dropwise during stirring, warm to 25°C and stir for 1h after the addition, then add 36g of acetone dropwise, stir for 12h after the addition, TLC detection shows that the reaction is complete, the reaction solution is concentrated, then extracted with ethyl acetate, dried with anhydrous sodium sulfate, spin-dried, column chromatography, and 38g of the compound shown in formula (II) is obtained. Wherein, in this embodiment, the molar ratio of the compound shown in formula (I), sodium bis(trimethylsilyl)amide, and acetone is 1:1.1:1.1.
[0046] S2, 38g of the compound represented by formula (II) and 60g of the compound represented by formula (III) were added to the reaction bottle in sequence, the temperature was raised to 100°C and stirred for 72h, TLC detected that the compound represented by formula (II) was completely reacted, and then the excess compound represented by formula (III) was removed by vacuum concentration, and then column chromatography was performed to obtain 63g of the compound represented by formula (IV). In this embodiment, the molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:1.1.
[0047] S3, add 63g of the compound shown in formula (IV) to 630mL of dichloromethane, then cool to 10 ° C, add 53g of thionyl chloride, warm to room temperature and stir for 1h after the addition, then warm to 40 ° C and stir for 12h, TLC detection reaction is complete, the reaction solution is cooled, the reaction solution is poured into methyl tert-butyl ether, solid is precipitated, filtered, and dried to obtain 81g of the compound shown in formula (V). Wherein, in this embodiment, the molar ratio of the compound shown in formula (IV) to thionyl chloride is 1:1.1.
[0048] S4, add 81g compound shown in (V) to 810mL tetrahydrofuran, replace nitrogen, cool to below -60 ℃, then drip 89mL bis (trimethylsilyl) sodium amide, warm to room temperature after dripping, stir 5h, TLC detection reaction is complete, reaction solution is concentrated, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, then dissolved in 100mL methyl tert-butyl ether, then pass into hydrochloric acid gas, stir 1h at room temperature, solid is precipitated, filter, dry to obtain 62g compound shown in formula (VI). Wherein, in this embodiment, the ratio of the molar amount of compound shown in formula (V) and bis (trimethylsilyl) sodium amide is 1:1.1.
[0049] S5, dissolve 62g of the compound shown in (VI) in 620mL N,N-dimethylformamide, add 85g of Boc anhydride, 40g of triethylamine, stir at room temperature for 124h, monitor the reaction completely by GC, cool to 5°C, slowly add HCl, separate the liquids, extract the aqueous phase with EA twice, wash the organic phase with saturated brine once, dry with anhydrous sodium sulfate, concentrate under reduced pressure, column chromatography, and obtain 75g of the compound shown in formula (VII). Wherein, in this embodiment, the molar ratio of the compound shown in formula (VI), Boc anhydride, and triethylamine is 1:1.1:1.1.
[0050] Example 3: A method for preparing N-Boc-2,2-dimethyl-3-cyanopiperidine
[0051]
[0052] S1. Add 100g of the compound shown in formula (I) to 1000mL of tetrahydrofuran, replace nitrogen, then cool to below 10°C, add 56g of sodium hydrogen dropwise during stirring, heat to 25°C and stir for 1h after the addition, then add 49g of acetone dropwise, stir for 12h after the addition, TLC detection shows that the reaction is complete, the reaction solution is concentrated, then extracted with ethyl acetate, dried with anhydrous sodium sulfate, spin-dried, column chromatography, and 37g of the compound shown in formula (II) is obtained. Wherein, in this embodiment, the molar ratio of the compound shown in formula (I), sodium hydrogen, and acetone is 1:1.5:1.5.
[0053] S2, 37g of the compound represented by formula (II) and 79g of the compound represented by formula (II) were added to the reaction bottle in sequence, the temperature was raised to 100°C and stirred for 72h, TLC detected that the compound represented by formula (II) was completely reacted, and then the excess of the compound represented by formula (III) was removed by vacuum concentration, and then column chromatography was performed to obtain 65g of the compound represented by formula (IV). In this embodiment, the molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:1.5.
[0054] S3, add 65g of the compound shown in formula (IV) to 650mL of dichloromethane, then cool to 10 ° C, add 95g of phosphorus oxychloride, warm to room temperature and stir for 1h after the addition, then warm to 40 ° C and stir for 12h, TLC detection reaction is complete, after the reaction solution is cooled, pour the reaction solution into methyl tert-butyl ether, precipitate solid, filter, and dry to obtain 83g of the compound shown in formula (V). Wherein, in this embodiment, the molar ratio of the compound shown in formula (IV) to phosphorus oxychloride is 1:1.5.
[0055] S4, add 83g of the compound shown in (V) to 830mL of tetrahydrofuran, replace nitrogen, cool to below -60 ° C, then drop 23g of sodium hydroxide, warm to room temperature after the addition is completed, stir for 5h, TLC detection reaction is complete, the reaction solution is concentrated, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, then dissolved in 100mL of methyl tert-butyl ether, then passed through hydrochloric acid gas, stirred at room temperature for 1h, solid precipitation, filtered, and dried to obtain 61g of the compound shown in formula (VI). Wherein, in this embodiment, the molar ratio of the compound shown in formula (V) to sodium hydroxide is 1:1.5.
[0056] S5, dissolve 61g of the compound shown in (VI) in 610ml of tetrahydrofuran, add 115g of Boc anhydride, 56g of sodium carbonate, stir at room temperature for 24h, monitor the reaction completely by GC, cool to 5°C, slowly add HCl, separate the liquids, extract the aqueous phase with EA twice, wash the organic phase with saturated brine once, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography to obtain 77g of the compound shown in formula (VII). Wherein, in this embodiment, the molar ratio of the compound shown in formula (VI), Boc anhydride, and sodium carbonate is 1:1.5:1.5.
[0057] Example 4: A method for preparing N-Cbz-2,2-dimethyl-3-cyanopiperidine
[0058]
[0059] This embodiment provides a method for preparing N-Cbz-2,2-dimethyl-3-cyanopiperidine. The difference between this embodiment and embodiment 1 is that in the step of preparing the compound shown in formula (VII), 100g of the compound shown in (VI) is dissolved in 1000mL of N,N-dimethylformamide, and then 92g of benzyl chloroformate and 87g of triethylamine are added, stirred at room temperature for 24h, and the reaction is complete after GC monitoring, cooled to 5°C, HCl is slowly added, the liquid is separated, the aqueous phase is extracted twice with EA, the organic phase is washed once with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography is performed to obtain 142g of the compound shown in formula (VII). In this embodiment, the molar ratio of the compound shown in formula (VI), benzyl chloroformate, and triethylamine is 1:1.5:1.5.
[0060] Example 5: A method for preparing N-Bn-2,2-dimethyl-3-cyanopiperidine
[0061]
[0062] This embodiment provides a method for preparing N-Bn-2,2-dimethyl-3-cyanopiperidine. The difference between this embodiment and embodiment 1 is that in the step of preparing the compound shown in formula (VII), 100g of the compound shown in (VI) is dissolved in 750mL N,N-dimethylformamide, and then 147g of benzyl bromide and 87g of triethylamine are added, stirred at room temperature for 24h, and the reaction is complete after GC monitoring, cooled to 5°C, HCl is slowly added, the liquid is separated, the aqueous phase is extracted twice with EA, the organic phase is washed once with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography is performed to obtain 118g of the compound shown in formula (VII). Wherein, in this embodiment, the molar ratio of the compound shown in formula (VI), benzyl bromide, and triethylamine is 1:1.5:1.5.
[0063] Example 6: A method for preparing N-Tos-3-cyano-2,2-dimethylpiperidine
[0064]
[0065] This embodiment provides a method for preparing N-Tos-2,2-dimethyl-3-cyanopiperidine. The difference between this embodiment and embodiment 1 is that in the step of preparing the compound shown in formula (VII), 100g of the compound shown in (VI) is dissolved in 1000mL of N,N-dimethylformamide, and then 164g of toluenesulfonyl chloride and 87g of triethylamine are added, stirred at room temperature for 24h, and the reaction is complete after GC monitoring, cooled to 5°C, HCl is slowly added, the liquid is separated, the aqueous phase is extracted twice with EA, the organic phase is washed once with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography is performed to obtain 156g of the compound shown in formula (VII). Wherein, in this embodiment, the molar ratio of the compound shown in formula (VI), toluenesulfonyl chloride, and triethylamine is 1:1.5:1.5.
[0066] Example 7: A method for preparing N-PMB-2,2-dimethyl-3-cyanopiperidine
[0067]
[0068] This embodiment provides a method for preparing N-PMB-2,2-dimethyl-3-cyanopiperidine. The difference between this embodiment and embodiment 1 is that in the step of preparing the compound shown in formula (VII), 100g of the compound shown in (VI) is dissolved in 1000mL of N,N-dimethylformamide, and then 173g of p-methoxybenzyl bromide and 87g of triethylamine are added, stirred at room temperature for 24h, and the reaction is complete after GC monitoring, cooled to 5°C, HCl is slowly added, the liquid is separated, the aqueous phase is extracted twice with EA, the organic phase is washed once with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography is performed to obtain 136g of the compound shown in formula (VII). Wherein, in this embodiment, the molar ratio of the compound shown in formula (VI), p-methoxybenzyl bromide, and triethylamine is 1:1.5:1.5.
[0069] Example 8: A method for preparing N-Alloc-2,2-dimethyl-3-cyanopiperidine
[0070]
[0071] This embodiment provides a method for preparing N-Alloc-2,2-dimethyl-3-cyanopiperidine. The difference between this embodiment and embodiment 1 is that in the step of preparing the compound shown in formula (VII), 100g of the compound shown in (VI) is dissolved in 1000mL N, N-dimethylformamide, and then 78g of allyl chloroformate and 87g of triethylamine are added, and stirred at room temperature for 24h. The reaction is complete after GC monitoring, and the temperature is lowered to 5°C, HCl is slowly added, and the liquid is separated. The aqueous phase is extracted twice with EA, and the organic phase is washed once with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography is performed to obtain 112g of the compound shown in formula V. In this embodiment, the molar ratio of the compound shown in formula (VI), allyl chloroformate, and triethylamine is 1:1.5:1.5.
[0072] Effect Example
[0073] The 2,2-dimethylpiperidine-3-carbonitrile hydrochloride prepared in Examples 1 to 3 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 2,2-dimethylpiperidine-3-carbonitrile hydrochloride, and the nuclear magnetic purity is greater than 95%. In the last step of the reaction of Examples 1 to 8, the type of substituent is changed to prepare N-substituted-2,2-dimethyl-3-cyanopiperidine; among them, according to the yield analysis, Example 1 is the best example, and the type and addition equivalent of the reaction materials in each step of Example 1 are the best.
[0074] Table 1:
[0075]
[0076]
[0077] Depend on Figure 1 As can be seen from the data in Table 1, the preparation method of N-substituted-2,2-dimethyl-3-cyanopiperidine provided by the present invention uses diethyl cyanomethylphosphate as a starting material, reacts with acetone under the action of a base, and then undergoes a reductive amination reaction, a chlorination reaction, a cyclization, and an amino substituent protection to synthesize N-substituted-2,2-dimethyl-3-cyanopiperidine; wherein various raw materials and reagents are cheap and easily available, the reaction operation is simple and reliable, the yield is high, and large-scale production can be carried out.
[0078] 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 preparing N-substituted-2,2-dimethyl-3-cyanopiperidine, which is prepared by using diethyl cyanomethylphosphonate as a starting material and reacting it with acetone in the presence of a base, and then sequentially undergoing addition reaction, reductive amination reaction, chlorination reaction, cyclization and substitution reaction; wherein: The general structural formula of the N-substituted-2,2-dimethyl-3-cyanopiperidine is as follows: In the formula: R1 is any one of Boc, Cbz, Bn, Tos, PMB, Alloc; -N is a nitrogen group, and -CN is a cyano group.
2. The method for preparing N-substituted-2,2-dimethyl-3-cyanopiperidine according to claim 1, characterized in that: The method includes the following reaction formula: The specific reaction steps are as follows: S1. dissolving the compound represented by formula (I) in an organic solvent, and subjecting it to an addition reaction with acetone in the presence of a base to obtain a compound represented by formula (II); S2, subjecting the obtained compound represented by formula (II) and the compound represented by formula (III) to reductive amination reaction to obtain a compound represented by formula (IV); S3, dissolving the obtained compound represented by formula (IV) in an organic solvent, and subjecting it to chlorination reaction with a chlorinating agent to obtain a compound represented by formula (V); S4, cyclizing the obtained compound represented by formula (V) under the action of a base to obtain a compound represented by formula (VI); S5. Dissolve the obtained compound represented by formula (VI) in an organic solvent, add a substituent and a base, and carry out a substitution reaction to obtain a compound represented by formula (VII).
3. The method for preparing N-substituted-2,2-dimethyl-3-cyanopiperidine according to claim 2, characterized in that: In step S1, the molar ratio of acetone to the compound represented by formula (I) is 1.1-1.5:
1.
4. The method for preparing N-substituted-2,2-dimethyl-3-cyanopiperidine according to claim 2, characterized in that: The base is any one of sodium bis(trimethylsilyl)amide, NaH, sodium carbonate, and triethylamine; the molar ratio of the added amount of the base to the compound represented by formula (I), formula (V), and formula (VI) is (1.1-1.5):
1.
5. The method for preparing N-substituted-2,2-dimethyl-3-cyanopiperidine according to claim 2, characterized in that: In step S2, the molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:(1.1-1.5).
6. The method for preparing N-substituted-2,2-dimethyl-3-cyanopiperidine according to claim 2, characterized in that: In step S3, the chlorinating agent is one of thionyl chloride and phosphorus oxychloride; the molar ratio of the added amount of the chlorinating agent to the compound represented by formula (IV) is (1.1-1.5):
1.
7. The method for preparing N-substituted-2,2-dimethyl-3-cyanopiperidine according to claim 2, characterized in that: The ratio of the amount of the organic solvent added to the amount of the compound represented by formula (I), formula (IV), formula (V), and formula (VI) is 5-15 mL: 1 g.
8. The method for preparing N-substituted-2,2-dimethyl-3-cyanopiperidine according to claim 7, characterized in that: The organic solvent is any one of tetrahydrofuran, dichloromethane and methanol.
9. The method for preparing N-substituted-2,2-dimethyl-3-cyanopiperidine according to claim 2, characterized in that: In step S5, the molar ratio of the amount of the substituent added to the compound represented by formula (VI) is (1.1-1.5):
1.
10. The method for preparing N-substituted-2,2-dimethyl-3-cyanopiperidine according to claim 2, characterized in that: The method includes the following reaction formula: The specific reaction steps are as follows: S1. Add the compound represented by formula (I) to tetrahydrofuran, replace nitrogen, then cool to 0-10°C, add alkali dropwise during stirring, raise the temperature to 20-30°C and stir for 0.5-1h after the addition is complete, then add acetone dropwise, stir for 12h after the addition is complete, detect the reaction by TLC, concentrate the reaction solution, then extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, spin dry, and perform column chromatography to obtain the compound represented by formula (II); S2, adding the compound represented by formula (II) and the compound represented by formula (III) to a reaction bottle in sequence, heating to 80-100° C. and stirring for 48-72 hours, and detecting by TLC that the compound represented by formula (II) has reacted completely, then concentrating under reduced pressure to remove excess compound represented by formula (III), and then performing column chromatography to obtain the compound represented by formula (IV); S3, adding the compound represented by formula (IV) to dichloromethane, then cooling to 0-10°C, adding a chlorinating agent dropwise, heating to room temperature and stirring for 1 hour after the addition is completed, then heating to 40°C and stirring for 12 hours, and TLC detection shows that the reaction is complete. After the reaction solution is cooled, the reaction solution is poured into methyl tert-butyl ether, the solid is precipitated, filtered, and dried to obtain the compound represented by formula (V); S4, adding the compound represented by (V) to tetrahydrofuran, replacing nitrogen, cooling to below -60°C, then adding alkali dropwise, warming to room temperature after the addition is completed, stirring for 5 hours, and detecting the reaction is complete by TLC, concentrating the reaction solution, and then extracting with ethyl acetate, drying over anhydrous sodium sulfate, spin-drying, and then dissolving in methyl tert-butyl ether, and then passing hydrochloric acid gas, stirring at room temperature for 1 hour, solid precipitates, filtering, and drying to obtain the compound represented by formula (VI); S5. Dissolve the compound represented by (VI) in a solvent, add a substituent and a base, stir at room temperature for 12-24 hours, monitor the reaction completion by GC, cool to 0-5°C, slowly add HCl, separate the layers, extract the aqueous phase twice with EA, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography to obtain the compound represented by formula (VII).