Preparation method of 1-benzyl-4-amino-4-piperidinecarboxylic acid
Compound II was prepared by using ammonium chloride, ammonia and trimethylcyanilane in 1-benzyl-4-amino-4-piperidinic acid synthesis, and the highly toxic substances and high-quality in the prior art were solved by hydrolysis reactions. The cost issue has achieved efficient and safe industrial production of 1-benzyl-4-amino-4-piperidinic acid.
Patent Information
- Application Number
- CN202411410221.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-10
- Publication Date
- 2025-01-03
AI Technical Summary
In the prior art, the synthesis method of 1-benzyl-4-amino-4-piperidinic acid has the problem of using highly toxic sodium cyanide, which is costly and complicated to operate, and it is difficult to meet the needs of industrial production.
Compound I was prepared in the presence of solvent with ammonium chloride, ammonium ammonia and trimethylcyanilane, and compound III was obtained by hydrolysis, avoiding the use of sodium cyanide, and using concentrated hydrochloric acid and sodium hydroxide to adjust the pH to achieve Efficient product purification.
This method avoids the use of highly toxic substances, is simple to operate, has high yield and purity, is suitable for industrial production, and avoids high-cost catalysts, which improves safety and environmental protection.
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Figure CN119241422A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of drug intermediate synthesis, and specifically relates to a method for preparing 1-benzyl-4-amino-4-piperidinic acid. Background Art
[0002] 1-Benzyl-4-amino-4-piperidinic acid (CAS: 39143-25-4) is a widely used pharmaceutical intermediate. It is used as an important structural fragment in many new drug development processes to optimize the activity of candidate drugs, especially in the synthesis of Difelikefalin and Capivasertib. The structure of Difelikefalin is as follows: , The structure of Capivasertib is as follows: , In the process of synthesizing Difelikefalin, the compound 4-(tert-butyloxycarbonylamino)-1-fluorenylmethoxycarbonylpiperidine-4-carboxylic acid is needed, and its structure is as follows: , This amino acid is a non-natural amino acid, and its synthesis route is as follows: , In the process of synthesizing Capivasertib, the compound 4-((tert-butoxycarbonyl)amino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid is needed, and its structure is as follows: , The synthetic route of the intermediate compound is as follows: .
[0003] In 2002, Jeffrey reported a two-step reaction to prepare compound III. The author used highly toxic sodium cyanide to prepare intermediate IV with a yield of 89%, and then hydrolyzed it with lithium hydroxide to synthesize compound III, with a hydrolysis yield of 66%. In 2023, patent CN115650903A used ammonium carbonate and trimethylsilyl cyanide to synthesize intermediate IV, and then prepared compound III with potassium hydroxide. In 2003, patent CN1122022C used zinc iodide as a catalyst for synthesis, which was expensive and costly. Advantages of this route: In the first step, trimethylsilyl cyanide and ammonium chloride were used to prepare compound II with a yield of 98%, and the purity reached 99%, avoiding the use of highly toxic sodium cyanide and potassium cyanide, which is safer, does not require the addition of catalysts in the experiment, and is more suitable for factory production. In the second step, concentrated hydrochloric acid is used to hydrolyze the cyanide group to obtain compound III with a yield of 96% and a purity of 99%. No other reagents or solvents are required, which saves costs and is more environmentally friendly.
[0004] In summary, as an important drug synthesis intermediate, 1-benzyl-4-amino-4-piperidinic acid will have a wider application space in the future. Therefore, it is very necessary to develop an efficient, cheap and simple industrial synthesis method. Summary of the invention
[0005] 1. Technical problems to be solved by the invention: The object of the present invention is to provide a method for preparing 1-benzyl-4-amino-4-piperidinic acid which has simple process, mild conditions, high efficiency and is suitable for industrial production, so as to solve the technical problems existing in the above-mentioned background technology.
[0006] 2. Technical solution: In order to solve the above technical problems, the technical solutions proposed by the present invention are as follows: A method for preparing 1-benzyl-4-amino-4-piperidinic acid, characterized in that it comprises the following steps: , Step 1: Compound I is used as a starting material to prepare Compound II in the presence of a solvent with ammonium chloride, ammonia water and trimethylsilyl cyanide; Step 2: Compound II undergoes hydrolysis to obtain compound III.
[0007] Furthermore, the specific operations of step one are: Add ammonium chloride and ammonia water into the reaction bottle and stir, and add trimethylsilyl cyanide and alcohol solution of N-benzylpiperidone dropwise at a controlled temperature. After the addition is complete, react. After the reaction is completed, add water and dichloromethane, separate the phases, dry the organic phase, and concentrate it for use in step 2.
[0008] Furthermore, in step 1, the temperature control range is 15-25°C, and the optimal temperature is 20°C.
[0009] Furthermore, in step 1, the molar ratio of compound I to trimethylsilyl cyanide is (1.0:1.05)-(1.0:1.25), and the optimal ratio is 1.0:1.05.
[0010] Furthermore, in step 1, the organic solvent alcohol is methanol, ethanol, isopropanol, and the optimal solvent is isopropanol.
[0011] Furthermore, the specific operations of step 2 are: Add compound II and dioxane to a reaction flask, add acid, stir at a suitable temperature to react, concentrate to dryness, add water to dissolve, adjust pH with sodium hydroxide, precipitate the product, filter and dry to obtain compound III.
[0012] Furthermore, in step 2, the molar ratio of compound II to acid is (1.0:10)-(1.0:25), and the optimal molar ratio is 1.0:20.
[0013] Furthermore, in step 2, the acid is concentrated hydrochloric acid or hydrobromic acid, and the optimal acid is concentrated hydrochloric acid.
[0014] Furthermore, in step 2, the suitable temperature is 80-120°C, and the most preferred reaction temperature is 110°C.
[0015] Furthermore, in step 2, the pH is 4-7, and the optimal pH is 6-7.
[0016] 3. Beneficial effects of the present invention: Compared with the prior art, the technical solution provided by the present invention has the following beneficial effects: The reaction of the invention avoids the use of highly toxic substances such as sodium cyanide and potassium cyanide, is safer, and is simple to operate. In addition, the reaction process has high yield and high purity, and the product purification is simple, which is very suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 is a synthetic flow chart of the present invention; Figure 2 It is the purity diagram of compound II; Figure 3 This is the purity diagram of compound III. DETAILED DESCRIPTION
[0018] To facilitate understanding of the present invention, the present invention will be described more comprehensively below with reference to the relevant drawings. Several embodiments of the present invention are shown in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thorough and comprehensive.
[0019] Example 1 Preparation of compound II: Under nitrogen protection, 36.7 g of ammonium chloride and 278 mL of ammonia water were added to the reaction bottle, 83 mL of trimethylsilyl cyanide was added dropwise at 20°C, and 100 g of N-benzyl piperidone in isopropanol solution was added dropwise. After the addition was completed, the mixture was stirred at 30°C for 16 h. 200 mL of water and 300 mL of DCM were added to the reaction bottle, stirred for 5 minutes, allowed to stand, separated, the organic phase was washed with 300 mL of brine, dried, and concentrated to obtain 112 g of compound II with a purity of 99.3% and a yield of 98.4%, which was used for the second step reaction.
[0020] 1 H NMR (400 MHz, DMSO) δ 7.31-7.22 (m, 5H), 3.47 (s, 2H), 2.73-2.69(m, 2H), 2.57 (s, 2H), 2.17-2.12 (m, 2H), 1.90-1.86 (m, 2H), 1.60-1.53 (m,2H). 13 C NMR (101 MHz, DMSO) δ 138.68, 129.24, 129.24, 128.64, 128.64, 127.39,124.76, 62.29, 50.05, 49.66, 49.66, 37.26, 37.26. MS m / z 216 (m + H + ).
[0021] Example 2 Preparation of compound II: Under nitrogen protection, 44 g of ammonium chloride and 334 mL of ammonia water were added to a reaction flask, 99 mL of trimethylsilyl cyanide was added dropwise at 20°C, and 120 g of N-benzylpiperidone ethanol solution was added dropwise. After the addition was completed, the mixture was stirred at 30°C for 16 h. 300 mL of water and 400 mL of DCM were added to the reaction flask, stirred for 5 minutes, allowed to stand, separated, the organic phase was washed with 400 mL of brine, dried, and concentrated to obtain 135 g of compound II for the second step reaction.
[0022] Example 3 Preparation of compound II: Under nitrogen protection, 18.3 g of ammonium chloride and 139 mL of ammonia water were added to the reaction flask, 35 mL of trimethylsilyl cyanide was added dropwise at 20°C, and 50 g of N-benzylpiperidone in isopropanol solution was added dropwise. After the addition was completed, the mixture was stirred at 30°C for 16 h. 100 mL of water and 200 mL of DCM were added to the reaction flask, stirred for 5 minutes, allowed to stand, separated, the organic phase was washed with 200 mL of brine, dried, and concentrated to obtain 55 g of compound II for the second step reaction.
[0023] Example 4 Preparation of compound III: 20g of compound II and 140mL of dioxane were added to a reaction flask and stirred, and 155mL of concentrated hydrochloric acid was added to the reaction flask and stirred at 110°C for 16h. After the reaction, the reaction solution was spin-dried, dissolved in 140mL of water, extracted twice with 100mL of dichloromethane, and the combined aqueous phase was adjusted to pH 7 with 20% sodium hydroxide aqueous solution, filtered, and the solid was dried to obtain 21g, with a purity of 99.4% and a yield of 96.4%.
[0024] 1 H NMR (400 MHz, DMSO) δ 7.56-7.49 (m, 5H), 4.40 (s, 2H), 3.67-3.26(m, 4H), 2.45-2.41 (m, 2H), 2.20-2.01 (m, 2H). MS m / z 235 (m + H + ). The overall yield of 1-benzyl-4-amino-4-piperidinic acid prepared through the above steps is 94.8%, and the purity is greater than 99%.
[0025] The above fully illustrates that the present invention has good applicability, safety, high yield and purity, and is very suitable for industrial amplification. The examples only express a certain implementation mode of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention; it should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention; therefore, the protection scope of the patent of the present invention shall be based on the attached claims.
Claims
1. A method for preparing 1-benzyl-4-amino-4-piperidinic acid, characterized in that: The following steps are involved: Step 1: Using the compound N-benzylpiperidone as a starting material, and reacting with the compounds ammonium chloride, ammonia water, and trimethylsilyl cyanide in the presence of a solvent to synthesize the compound 4-amino-1-benzylpiperidine-4-carbonitrile; Step 2: The compound 4-amino-1-benzylpiperidine-4-carbonitrile is hydrolyzed in the presence of an acid to obtain the compound 1-benzyl-4-amino-4-piperidinic acid; The structure of 1-benzyl-4-amino-4-piperidinic acid is as follows: 。 2. The method for preparing 1-benzyl-4-amino-4-piperidinic acid according to claim 1, wherein The specific operation of step one is to add ammonium chloride and ammonia water into a reaction bottle and stir, heat to 15-25°C, then dropwise add trimethylsilyl cyanide and N-benzyl piperidone alcohol solution, and react at 20-30°C after the dropwise addition; after the reaction is completed, add water and dichloromethane, separate the phases, dry the organic phase, concentrate at 45°C, and use it directly in step two.
3. A method for preparing 1-benzyl-4-amino-4-piperidinic acid according to claim 2, characterized in that: The specific operation of step 2 is to add 4-amino-1-benzylpiperidine-4-carbonitrile and dioxane into the reaction bottle, add acid, heat and stir; after the reaction is completed, concentrate to dryness, add water to dissolve, adjust the pH with sodium hydroxide, precipitate the product, filter and dry.
4. A method for preparing 1-benzyl-4-amino-4-piperidinic acid according to claim 1, characterized in that: The molar ratio of N-benzyl piperidone to trimethylsilyl cyanide in step 1 is 1.0:(1.05-1.25).
5. The method for preparing 1-benzyl-4-amino-4-piperidinic acid according to claim 1, wherein: The reaction temperature in step 1 is 0-35°C.
6. The method for preparing 1-benzyl-4-amino-4-piperidinic acid according to claim 1, wherein: The solvent in step 1 is methanol, ethanol or isopropanol.
7. The method for preparing 1-benzyl-4-amino-4-piperidinic acid according to claim 1, characterized in that: In step 2, the molar ratio of the compound 4-amino-1-benzylpiperidine-4-carbonitrile to the acid is 1.0:(10-25).
8. The method for preparing 1-benzyl-4-amino-4-piperidinic acid according to claim 7, characterized in that: The acid in step 2 is concentrated hydrochloric acid or hydrobromic acid.
9. The method for preparing 1-benzyl-4-amino-4-piperidinic acid according to claim 1, characterized in that: The reaction temperature in step 2 is 80-120°C.
10. The method for preparing 1-benzyl-4-amino-4-piperidinic acid according to claim 3, characterized in that: The reaction pH in step 2 is 4-7.