Synthesis method of (2R, 4S)-N-BOC-4-hydroxypiperidine-2-methyl formate

Abstract

The invention relates to the field of organic synthesis, in particular to a synthetic method of (2R, 4S)-N-BOC-4-hydroxypiperidine-2-methyl formate. The synthesis method of (2R, 4S)-N-BOC-4-hydroxypiperidine-2-methyl formate comprises the following steps: mixing a material A, a material B, potassium carbonate, sodium iodide and a solvent, and reacting to obtain a material C; mixing the material C, the material D, triethylamine and a solvent, and reacting to obtain a material E; mixing the material E, ammonia water and a solvent, and reacting to obtain a material F; and mixing the material F, di-tert-butyl dicarbonate, a palladium carbon catalyst and a solvent, and carrying out a reaction to obtain the (2R, 4S)-N-BOC-4-hydroxypiperidine-2-methyl formate. The process route is easy to operate and has no special dangerous reaction. Reaction materials are cheap and easy to obtain, and the prepared product is high in purity.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more specifically, to a method for synthesizing methyl (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylate. Background Technology

[0002] (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylate (CAS: 321744-26-7) is an important pharmaceutical intermediate. This intermediate has three reaction sites (hydroxyl, ester, and amino groups) and can dock with various molecular fragments. For example, the core fragment of the new drug glasgibril is this intermediate fragment. For the separation of isomers, chiral columns or expensive resolving agents are currently available on the market. Separation is inconvenient and costly. Summary of the Invention

[0003] In view of this, the present invention aims to provide a method for synthesizing (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester. The synthetic route of the present invention reveals that the two isomers in the third step of this route have significantly different polarities and can be easily separated by column chromatography, thereby obtaining the desired configurational intermediate material F. Therefore, the chiral separation of the intermediate can be easily achieved.

[0004] To solve the above-mentioned technical problems, this application is implemented as follows: This invention provides a method for synthesizing methyl (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylate, comprising the following steps: (1) Material A, material B, potassium carbonate, sodium iodide and solvent are mixed and reacted to obtain material C; (2) Mix material C, material D, triethylamine and solvent, and react to obtain material E; (3) Mix material E, ammonia water and solvent, and react to obtain material F; mix material F and material G; extract, separate and column chromatography the mixture of material F and material G to obtain material F; (4) Mix material F, ditert-butyl dicarbonate, palladium on carbon catalyst and solvent, and react to obtain methyl (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylate; In step (1), the chemical formula of material A is: ; In step (1), the chemical formula of material B is: ; In step (2), the chemical formula of material C is: ; In step (2), the chemical formula of material D is: ; In step (3), the chemical formula of material E is: ; In step (4), the chemical formula of material F is: ; In step (3), the chemical formula of material G is: .

[0005] Preferably, in the above-mentioned method for synthesizing (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester, in step (1), the ratio of the amount of material A, material B, potassium carbonate, sodium iodide and solvent is 1 mol: 1 mol~2 mol: 1 mol~2 mol: 0.2 mol~1 mol: 0.3~0.8 L; In step (1), the solvent includes N,N-dimethylformamide; In step (1), the reaction temperature is 80~100℃ and the reaction time is 13~25h.

[0006] Preferably, in the above-mentioned method for synthesizing (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester, step (1) includes the mixing process comprising: Mix material A with solvent, then add potassium carbonate and sodium iodide in sequence to obtain a mixture. Control the internal temperature of the mixture to 25~35℃, and then add material B dropwise. The dripping time for material B is 1 hour.

[0007] In this invention, in step (1), after adding material B, the internal temperature of the resulting mixture may rise to 100°C in 0.5 hours, generating vapor pressure, which requires venting to relieve the pressure.

[0008] In this invention, after the reaction is completed in step (1), post-processing is also included; The post-processing includes: after the reaction, cooling the obtained product to 30-40°C, adding water to dissolve the inorganic salts, then adding ethyl acetate, and then dispersing and allowing it to stand for separation, collecting the upper organic phase and the lower aqueous phase; adding ethyl acetate to the lower aqueous phase, and then dispersing and allowing it to stand for separation, collecting the upper organic phase; then combining all organic phases, adding saturated sodium chloride for dispersion and allowing it to stand for separation, collecting the upper organic phase again; concentrating the upper organic phase under reduced pressure, adding an ethyl acetate solution of 4 mol / L hydrogen chloride cooled to -10 to -5°C, controlling the internal temperature to be less than 30°C, and stirring overnight; finally adding petroleum ether for filtration, collecting the filter cake, washing the filter cake again with petroleum ether, and then filtering and drying to obtain material C.

[0009] Preferably, in the above-mentioned method for synthesizing (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester, in step (2), the ratio of the amount of material C, material D, triethylamine and solvent is 1 mol: 2~2.2 mol: 1~1.3 mol: 0.8~2.2 L; In step (2), the solvent includes toluene; In step (2), the reaction temperature is 55~65℃ and the reaction time is 2~3h.

[0010] Preferably, in the above-mentioned method for synthesizing (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester, step (2) includes the mixing process comprising: Mix material C with solvent, then add triethylamine dropwise while controlling the internal temperature at 20~30℃, and then continue to add material D dropwise while controlling the internal temperature at 20~30℃. The triethylamine is added over a period of 1.5 to 1.6 hours. The dripping time of material D is 1~1.5h.

[0011] In this invention, after the reaction is completed, step (2) further includes post-processing; The post-processing includes: The product obtained after the reaction was further separated to obtain an aqueous phase and an organic phase. The aqueous phase was further extracted with a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:5 to obtain the organic phase. All organic phases were combined and concentrated under reduced pressure, then eluted with silica gel, and finally concentrated under reduced pressure to obtain material E.

[0012] Preferably, in the above-mentioned method for synthesizing (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester, in step (3), the ratio of the amount of material E, ammonia water and solvent is 1mol:0.8~1L:0.8~1L; In step (3), the concentration of the ammonia solution is 20 wt%. In step (3), the solvent includes methanol; In step (3), the reaction temperature is 25~30℃ and the reaction time is 4~5h.

[0013] Preferably, in the above-mentioned method for synthesizing (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester, step (3) includes the mixing process comprising: After mixing and dispersing material E and solvent, ammonia water is added.

[0014] In this invention, step (3) includes the following specific processes: extraction, separation, and column chromatography. Dichloromethane was added to the product obtained after the reaction, and the organic phase was obtained by extraction and separation. The organic phase was washed with saturated sodium chloride solution and then dried with anhydrous sodium sulfate. Silica gel was then added for wet mixing, and the sample was purified by silica gel column chromatography. If the purity of material F is poor after column purification, the purification process using silica gel column also includes: adding a mixture of ethyl acetate and petroleum ether in a volume ratio of 15:85 for pulping and recrystallization.

[0015] Preferably, in the above-mentioned method for synthesizing (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester, in step (4), the ratio of the amount of material F, ditert-butyl dicarbonate and solvent is 1 mol: 1~1.3 mol: 2~3 L; In step (4), the mass ratio of material F to palladium on carbon catalyst is 1:0.1~0.3; In step (4), the solvent includes methanol.

[0016] Preferably, in the above-mentioned method for synthesizing (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester, in step (4), the reaction temperature is 25°C and the reaction time is 5.5 h.

[0017] Preferably, in the above-mentioned method for synthesizing (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester, step (4) includes the mixing process as follows: Material F and solvent are mixed and dispersed, then di-tert-butyl dicarbonate is added, followed by palladium on carbon catalyst, and finally hydrogen is introduced to replace it three times.

[0018] In this invention, step (4) also includes post-processing; The post-processing includes: The product obtained after the reaction was filtered, and the filter cake was washed with methanol. Then, ethyl acetate was added to dissolve it completely, followed by the addition of N,N-dimethyl-1,3-propanediamine and stirring for 0.5 hours to remove unreacted di-tert-butyl dicarbonate. After the reaction was completed, 1N HCl was added to remove all N,N-dimethyl-1,3-propanediamine, washing it into the acidic aqueous phase to indirectly remove excess di-tert-butyl dicarbonate. The aqueous phase was then separated and removed. The organic phase was washed successively with a semi-saturated sodium carbonate solution and a saturated brine solution, then dried with anhydrous sodium sulfate, filtered, and dried under reduced pressure using a rotary evaporator. After drying by rotary evaporation, it was further dried by an oil pump.

[0019] The beneficial technical effects of the present invention through the above technical solution are as follows: This invention reveals that the two isomers formed after the third step of ammonolysis exhibit excellent separation. Therefore, column chromatography was used to successfully separate the isomers, providing a method for obtaining chiral compounds with absolute configurations. Furthermore, the addition of di-tert-butyl dicarbonate during the final hydrogenation step lowers the requirements for hydrogenation reaction conditions, allowing it to proceed at room temperature and atmospheric pressure. The process route of this invention is easy to operate and involves no particularly hazardous reactions. The reactants are inexpensive and readily available, resulting in products with high purity. Currently, isomer separation can be achieved using chiral columns or expensive resolving agents, which are inconvenient and costly. The synthetic route of this invention reveals that the two isomers in the third-step intermediate have significantly different polarities, allowing for easy separation using column chromatography to obtain the desired configuration intermediate F. Therefore, the chiral separation of the intermediate can be easily achieved. Attached Figure Description

[0020] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used together with the following detailed description to explain the invention, but do not constitute a limitation thereof.

[0021] Figure 1 The diagram shown is a flowchart of the preparation process of the present invention.

[0022] Figure 2 The image shown is the gas phase (GC) spectrum of methyl (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylate prepared in Example 1.

[0023] Figure 3 The image shows the chiral HPLC spectrum of (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester prepared in Example 1, indicating a chiral purity of 96.5%.

[0024] Figure 4 The image shows the nuclear magnetic resonance (HNMR) spectrum of methyl (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylate prepared in Example 1. Detailed Implementation

[0025] The present invention will be further described in detail below through examples. All raw materials used in the examples are commercially available.

[0026] Example 1 A method for synthesizing methyl (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylate, comprising the following steps: (1) Substitution reaction .

[0027] Material A (10 kg, 82.52 mol, 1.0 eq) and N,N-dimethylformamide (DMF, 30 L) were added to the reactor. While stirring, potassium carbonate (12.5 kg, 90.56 mol, 1.1 eq) and sodium iodide (3.1 kg, 20.66 mol, 0.25 eq) were added sequentially. The internal temperature of the reactor was controlled at 35℃. Material B (12.4 kg, 91.84 mol, 1.1 eq) was then added dropwise. The addition of B was carried out over a period of 1 hour. After the addition was completed, the reaction was carried out at 90°C for 13 hours. After the addition of B was completed, the internal temperature of the reactor was raised to 100°C after 0.5 hours, and vapor pressure was generated in the reactor. It was necessary to release the pressure in the reactor. After the reaction was completed, a sample was taken and the reaction was monitored. Very little raw material remained. The product was cooled to 35°C and water (20L) was added to dissolve the inorganic salt. Then ethyl acetate (20L) was added. The mixture was then dispersed and allowed to stand for separation. The upper organic phase and the lower aqueous phase were collected. Ethyl acetate (20L) was added to the lower aqueous phase. The mixture was then dispersed and allowed to stand for separation. The upper organic phase was collected. All organic phases were then combined and saturated sodium chloride (20L) was added. The mixture was then dispersed and allowed to stand for separation. The upper organic phase was collected again. The upper organic phase was concentrated under reduced pressure to 15L and then added to 4N water cooled to -5°C. HCl / EA, with the internal temperature controlled below 30℃, was stirred overnight; finally, petroleum ether was added for filtration, the filter cake was collected, and the filter cake was washed again with petroleum ether. Then, the filter cake was filtered and dried sequentially to obtain material C.

[0028] (2) Addition reaction Material C (10 kg, 47.2 mol, 1 eq) and 40 L of toluene were added to the reactor, and the internal temperature of the reactor was controlled at 25 °C. Triethylamine (5.24 kg, 1.1 eq) was added dropwise while stirring over a period of 1.5 h. Stirring became difficult as the triethylamine was added. Then, material D (13 kg, 94.5 mol, 2.0 L) was added dropwise. The internal temperature of the reactor was controlled at 25℃, and the dropping time of material D was 1h. As material D was added, the reaction solution gradually changed from a paste to a clear two-phase mixture. After the addition of material D was completed, the temperature was raised to 60℃ for 2h and the reaction continued for 3h. After the reaction was completed, the temperature was lowered to 20℃. The aqueous phase and organic phase were sampled separately for TLC to separate the organic and aqueous phases. The aqueous phase was further extracted with a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:5. The organic phase was collected, and all organic phases were combined and concentrated under reduced pressure to 2V. The concentrated product was subjected to gradient elution with silica gel (2kg) using a mixed solution of ethyl acetate and petroleum ether, and concentrated under reduced pressure to obtain 5.4kg of oily material E. (3) Ammonolysis reaction Dissolve 0.6 kg of material E (2.6 mol) in 2.4 L of methanol, and slowly add 2.4 L of ammonia (20 wt%) at room temperature. After the addition is complete, stir the reaction at room temperature (25 °C) for 4 h (to reduce side reactions) and then stop the reaction. Add 2.5 L of dichloromethane (DCM) to the product obtained after the reaction, extract and separate until the extraction is clear by TLC. Combine the organic phases, wash three times with saturated brine to remove ammonia, dry with anhydrous sodium sulfate, and remove most of the solvent by vacuum distillation in a rotary evaporator. Add 800 g of 100 mesh silica gel and mix the sample by wet mixing. Pack an 8 kg column with 100 mesh silica gel and purify by column chromatography to separate material G and material F as much as possible. 425 g of pure material F (containing 10% EA) was obtained by column chromatography.

[0029] (4) Hydrogenation reaction Add 2 L of methanol and 200 g (0.76 mol, 1 eq) of material F to a single-necked flask. While stirring, add 182 g of di-tert-butyl dicarbonate (0.83 mol, 1.1 eq), and finally add 20 g of palladium on carbon catalyst (Pd / C). Then, purge with hydrogen three times. React at room temperature (25 °C) for 5.5 h (with evacuation every 1.5 hours to remove CO2, followed by purging and hydrogen purging). Filter the product, wash the filter cake with methanol, and then dissolve it completely in 1000 mL of ethyl acetate. Add N,N-dimethyl-1,3-propanediamine (0.3 eq, 0.23 mol, 23 g) and stir for 0.5 h to remove unreacted di-tert-butyl dicarbonate. After the reaction is complete, add 500 mL of 1N... HCl was used to remove all N,N-dimethyl-1,3-propanediamine into the acidic aqueous phase, indirectly removing excess di-tert-butyl dicarbonate. The aqueous phase was then separated, and the organic phase was washed sequentially with 200 mL of semi-saturated sodium carbonate solution and 200 mL of saturated brine. After drying with anhydrous sodium sulfate, the mixture was filtered, evaporated under reduced pressure using a rotary evaporator, and then further dried using an oil pump to obtain a white solid, H, which is methyl (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylate, with a yield of 93.6%.

[0030] Figure 2 The image shown is the gas phase (GC) spectrum of methyl (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylate prepared in Example 1. According to... Figure 2 It can be seen that the chemical purity of the (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester prepared in Example 1 is 98.6%.

[0031] Figure 3The image shows the chiral HPLC spectrum of (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester prepared in Example 1, indicating a chiral purity of 96.5%. According to... Figure 3 It can be seen that the chiral purity of (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester prepared in Example 1 is 96.5%.

[0032] Figure 4 The image shown is the nuclear magnetic resonance (HNMR) spectrum of methyl (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylate prepared in Example 1. According to... Figure 4 It can be seen that the structure of (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester prepared in Example 1 is correct.

[0033] That is, the HNMR of the (2R,4S)-N-BOC-4-hydroxypiperidine-2-carboxylic acid methyl ester prepared above is qualified, with an EE of 96.5% and a GC of 98.6%.

[0034] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A process for the synthesis of (2R,4S)-methyl-N-BOC-4-hydroxypiperidine-2-carboxylate, characterized in that, The method comprises the following steps: (1) mixing material A, material B, potassium carbonate, sodium iodide and a solvent to perform a reaction to obtain material C; (2) mixing material C, material D, triethylamine and a solvent to perform a reaction to obtain material E; (3) mixing material E, ammonia water and a solvent to perform a reaction to obtain a mixture of material F and material G; and performing extraction, separation and column chromatography on the mixture of material F and material G to obtain material F and material G; (4) mixing material F, di-tert-butyl dicarbonate, a palladium-carbon catalyst and a solvent to perform a reaction to obtain (2R, 4S)-N-BOC-4-hydroxypiperidine-2-carboxylate methyl ester; In step (1), the chemical formula of the material A is ; In step (1), the chemical formula of the material B is ; In step (2), the chemical formula of the material C is ; In step (2), the chemical formula of the material D is ; In step (3), the chemical formula of the material E is ; In step (4), the chemical formula of the material F is ; In step (3), the chemical formula of the material G is .

2. The process for the synthesis of (2R,4S)-methyl-N-BOC-4-hydroxypiperidine-2-carboxylate according to claim 1, characterized in that, In step (1), the amount ratio of material A, material B, potassium carbonate, sodium iodide and the solvent is 1 mol: 1 mol~2 mol: 1 mol~2 mol: 0.2 mol~1 mol: 0.3~0.8L; In step (1), the solvent comprises N,N-dimethylformamide; In step (1), the reaction temperature is 80~100℃, and the reaction time is 13~25h.

3. The process for synthesis of (2R, 4S)-methyl-N-BOC-4-hydroxypiperidine-2-carboxylate as claimed in claim 1, wherein, In step (1), the mixing process comprises: Mixing material A and a solvent, adding potassium carbonate and sodium iodide to obtain a mixture, controlling the internal temperature of the mixture to be 25~35℃, and dropping material B; The dropping time of material B is 1h.

4. The process for synthesis of (2R, 4S)-methyl-N-BOC-4-hydroxypiperidine-2-carboxylate as claimed in claim 1, wherein, In step (2), the amount ratio of material C, material D, triethylamine and the solvent is 1 mol: 2~2.2 mol: 1~1.3mol: 0.8~2.2L; In step (2), the solvent comprises toluene; In step (2), the reaction temperature is 55~65℃, and the reaction time is 2~3h.

5. The process for synthesis of (2R,4S)-methyl-N-BOC-4-hydroxypiperidine-2-carboxylate as claimed in claim 1, wherein, In step (2), the mixing process comprises: Mixing material C and a solvent, then controlling the internal temperature to be 20~30℃ to drop triethylamine, and then continuing to control the internal temperature to be 20~30℃ to drop material D; The dropping time of triethylamine is 1.5h~1.6h; The dropping time of material D is 1h~1.5h.

6. The process for synthesis of (2R, 4S)-methyl-N-BOC-4-hydroxypiperidine-2-carboxylate as claimed in claim 1, wherein, In step (3), the amount ratio of material E, ammonia water and the solvent is 1 mol: 0.8~1L: 0.8~1L; In step (3), the concentration of ammonia water is 20wt%; In step (3), the solvent comprises methanol; In step (3), the reaction temperature is 25~30℃, and the reaction time is 4~5h.

7. The process for synthesis of (2R, 4S)-methyl-N-BOC-4-hydroxypiperidine-2-carboxylate as claimed in claim 1, wherein, In step (3), the mixing process comprises: Mixing and dispersing material E and a solvent, and then adding ammonia water.

8. The process for synthesis of (2R, 4S)-methyl-N-BOC-4-hydroxypiperidine-2-carboxylate as claimed in claim 1, wherein, In step (4), the amount ratio of material F, di-tert-butyl dicarbonate and the solvent is 1 mol: 1~1.3 mol: 2~3L; In step (4), the mass ratio of material F and a palladium-carbon catalyst is 1: 0.1~0.3; In step (4), the solvent comprises methanol.

9. The process for synthesis of (2R,4S)-methyl-N-BOC-4-hydroxypiperidine-2-carboxylate as claimed in claim 1, wherein, In step (4), the reaction temperature is 25℃, and the reaction time is 5.5h.

10. The process for synthesis of (2R, 4S)-methyl-N-BOC-4-hydroxypiperidine-2-carboxylate as claimed in claim 1, wherein, In step (4), the mixing process comprises: Mixing and dispersing material F and a solvent, then adding di-tert-butyl dicarbonate, then adding a palladium-carbon catalyst, and finally replacing three times with hydrogen.

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