Method for synthesizing posaconazole intermediate (2S)-2-benzyloxy-3-pentanone
By using S-methyl lactate and piperidine as starting materials, the synthesis path is simplified and the reaction cycle is shortened, and the problems of high starting materials in the (2S)-2-benzyloxy-3-pentanone synthesis process in the prior art are solved, and low-cost and high-efficiency industrial production is achieved.
Patent Information
- Application Number
- CN202411884851.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-20
- Publication Date
- 2025-03-11
AI Technical Summary
In the existing processes for synthesizing (2S)-2-benzyloxy-3-pentanone, the starting raw materials are priced at a high rate, the reaction time is longer, and the consumption and waste are higher, resulting in low production efficiency and high cost.
Using methyl S-lactate and low-priced piperidine as starting materials, the reaction cycle is shortened and production costs are reduced through simplified synthesis path and mild reaction conditions.
It achieves a shortening of the reaction cycle, reduces production costs, improves production efficiency, and simplifies the post-treatment steps, which is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of synthesis of posaconazole intermediates, and in particular to a method for preparing (2S)-2-benzyloxy-3-pentanone, an intermediate of N'-((2S,3S)-2-(benzyloxy)-3-pentyl-)formylhydrazide. Background Art
[0002] Posaconazole (SCH-56592, saconazole, POS, trade name: Noxafil) was developed by Schering - The new broad-spectrum antifungal drug developed by Plough was approved for marketing by the European Union and the US FDA on October 20, 2005. The Chinese name of posaconazole is 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxa-3-yl]methoxy]phenyl]piperazine-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one, and its structural formula is shown below:
[0003]
[0004] Posaconazole is a structural analogue of itraconazole. It works by inhibiting fungal lanosterol 14α-demethylase, so posaconazole has good activity against Candida, Cryptococcus neoformans, Aspergillus and other fungi. In addition, posaconazole has few adverse reactions, which mainly include thirst, dizziness, headache, fatigue and drowsiness, but these symptoms are mild and can recover on their own. At the same time, in the treatment of invasive fungal infections, posaconazole has low risks, high safety and mild side effects, and can be used as a long-term treatment for such diseases.
[0005] In the prior art, the preparation of posaconazole mainly adopts a partial synthesis method of synthesizing intermediate 1 and intermediate 2 separately. The chemical formulas of intermediate 1 and intermediate 2 are as follows:
[0006]
[0007] Among them, N-((2S, 3S)-2-(benzyloxy)-3-pentyl-)formylhydrazide is an intermediate for synthesizing intermediate 2, and its reaction formula is as follows:
[0008]
[0009] (2S)-2-Benzyloxy-3-pentanone is a key intermediate in the synthesis of N′-((2S,3S)-2-(benzyloxy)-3-pentyl-)formylhydrazide.
[0010] The existing method for synthesizing N′-((2S, 3S)-2-(benzyloxy)-3-pentyl-)formyl hydrazide is mainly to synthesize N-((2S, 3S)-2-(benzyloxy)-3-pentyl-)formyl hydrazide from (2S)-2-benzyloxy-3-pentanone. However, the preparation cycle of (2S)-2-benzyloxy-3-pentanone in the method is too long, which is as long as more than 80 hours, resulting in low production efficiency. Moreover, (2S)-2-benzyloxy-3-pentanone uses S-methyl lactate and tetrahydropyrrole as starting materials. Since the price of the tetrahydropyrrole used is relatively high, the production cost will be too high, which is not conducive to industrial production. In addition, in order to obtain a relatively pure product, the existing method often purifies the material by methods such as recrystallization and chromatography column, which also increases the complexity of the operation steps and leads to a long time consumption. Summary of the invention
[0011] The technical problem to be solved by the present invention is that the existing process for synthesizing (2S)-2-benzyloxy-3-pentanone has a high starting material price, a long reaction time, and high consumption and waste. The purpose of the present invention is to provide a method for synthesizing (2S)-2-benzyloxy-3-pentanone, which has mild reaction conditions, low starting material price, reduces production costs, and realizes industrial production.
[0012] The present invention is achieved through the following technical solutions:
[0013] A method for synthesizing a posaconazole intermediate (2S)-2-benzyloxy-3-pentanone, which uses S-methyl lactate and inexpensive piperidine as starting materials, has a short reaction cycle, low preparation cost, simple post-treatment, and easy operation. The synthetic route of the synthetic method is:
[0014]
[0015] Specifically, the method for synthesizing (2S)-2-benzyloxy-3-pentanone of the present invention comprises the following steps:
[0016] (1) adding S-methyl lactate to a reaction system, adding piperidine dropwise, and heating the reaction system to generate (S)-2-hydroxy-1-(1-piperidinyl)-1-propanone;
[0017] (2) Under a nitrogen atmosphere, THF and sodium hydride were added to the reaction system, (S)-2-hydroxy-1-(1-piperidinyl)-1-propanone was added dropwise while cooling, and benzyl chloride was added dropwise after the addition was completed. After the addition was completed, the temperature was raised to react. After the reaction was completed, water was added to dilute, dilute hydrochloric acid was added to adjust the pH value, the organic phase and the aqueous phase were separated, the organic phase was washed with water, dried, and concentrated to obtain (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone;
[0018] (3) Under a nitrogen atmosphere, add (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone dropwise to the Grignard reagent at a controlled temperature, maintain the temperature for reaction, and terminate the reaction. Add a mixture of glacial hydrochloric acid and water to the reaction system and stir, extract with a polar solvent, wash the organic phase with water, dry it, and rotary evaporate to obtain (2S)-2-benzyloxy-3-pentanone.
[0019] In a further embodiment, the molar ratio of (S)-methyl lactate to piperidine in step (1) is 1:1.2-2, preferably 1:1.5. The temperature of the amine transesterification reaction is 20-60°C, preferably 45-60°C.
[0020] In a further embodiment, in step (2), the molar ratio of (S)-2-hydroxy-1-(1-piperidinyl)-1-propanone to benzyl chloride is 1:0.8-1.1, and more preferably 1:0.8-1.02.
[0021] In a further embodiment, the temperature for the reaction in step (3) is -5 to 10°C, and the reaction time is 0.5 to 2 hours.
[0022] In a further embodiment, in step (3), the molar ratio of (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone to the Grignard reagent is 1:2.5-4, and more preferably 1:3.
[0023] In a further embodiment, after quenching the reaction in step (3), extraction is performed with a polar solvent, and the organic phase is separated and then washed, dried, and filtered to obtain (2S)-2-benzyloxy-3-pentanone, wherein the extractant is at least one of dichloromethane, ethyl acetate, chloroform, and toluene.
[0024] The Grignard reagent in step (3) of the present application is ethylmagnesium bromide Grignard reagent, and its preparation process comprises: mixing magnesium, iodine and dry tetrahydrofuran, controlling the temperature at 25-30° C. under nitrogen protection, then dripping a small amount of ethyl bromide to initiate the reaction, and then slowly dripping the remaining ethyl bromide after the dripping is completed, stirring the reaction for 1-2 hours to obtain ethylmagnesium bromide Grignard reagent.
[0025] Advantages and beneficial effects of the present invention:
[0026] 1. Compared with tetrahydropyrrole as a raw material, the present invention uses piperidine as a raw material, and the reaction time required to obtain a product with the same yield and purity is greatly shortened. This is because piperidine is less active than tetrahydropyrrole and the reaction is more stable. If the product with the same yield is obtained, the reaction temperature required for tetrahydropyrrole is lower but the reaction cycle is longer; if the two raw materials are reacted at the same temperature, the reaction cycle is almost equal, but the purity of the product synthesized using tetrahydropyrrole as a raw material is much lower than the purity of the product synthesized using piperidine as a raw material. Therefore, using piperidine as a raw material can reduce the production cycle and improve production efficiency.
[0027] 2. The present invention uses S-methyl lactate and piperidine as raw materials, which are cheaper than tetrahydropyrrole. Therefore, the preparation process of the present invention does not use expensive reagents and can effectively reduce production costs.
[0028] 3. The preparation process of the present invention is easy to operate and the post-processing is relatively simple. Compared with the traditional preparation method which requires purification by methods such as recrystallization and chromatography, the process only requires filtration, solvent removal and drying to obtain the target product with high purity, which is easy to realize industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0029] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of (S)-2-hydroxy-1-(1-piperidinyl)-1-propanone prepared in Example 1.
[0030] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone prepared in Example 1.
[0031] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of (2S)-2-benzyloxy-3-pentanone prepared in Example 1. DETAILED DESCRIPTION
[0032] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with embodiments. The illustrative embodiments of the present invention and their description are only used to explain the present invention and are not intended to limit the present invention.
[0033] Embodiment 1:
[0034] A method for synthesizing (2S)-2-benzyloxy-3-pentanone, comprising the following steps:
[0035] (1) 20.8 g (0.2 mol) of S-methyl lactate was added to a flask at room temperature, and 25.25 g (0.3 mol) of piperidine was slowly added dropwise. After the addition was completed, the temperature was raised to 60° C. and the reaction was allowed to proceed for 30 hours. The reaction was monitored to be complete by TLC. The mixture was concentrated under reduced pressure to obtain 31.16 g of (S)-2-hydroxy-1-(1-piperidinyl)-1-propanone (dark yellow oil) with a yield of 99.1% and an ee of 99.7%.
[0036] The H NMR spectrum of (S)-2-hydroxy-1-(1-piperidinyl)-1-propanone is as follows Figure 1, wherein: 1H NMR (400MHz,) δ4.68 (s, 1H), 4.42 (q, J = 6.6 Hz, 1H), 3.63-3.47 (m, 2H), 3.30 (t, J = 5.5 Hz, 2H), 1.67-1.52 (m, 6H), 1.28 (d, J = 6.6 Hz, 3H).
[0037] (2) Under nitrogen protection, 300 ml of THF and 8.64 g (0.36 mol) of sodium hydride were added to a flask to obtain a mixed solution, which was cooled to below 0° C. 31.44 g (0.2 mol) of (S)-2-hydroxy-1-(1-piperidinyl)-1-propanone was slowly added dropwise to the mixed solution. After the addition was completed, the mixture was stirred for 10 min. 25.82 g (0.204 mol) of benzyl chloride was continuously added dropwise to obtain a reaction solution. The reaction solution was slowly heated to 30° C. and stirred for 20 hours. The reaction was completed after TLC monitoring, and the reaction solution was cooled to T≤10°C. Dilute HCl was added to the reaction solution to terminate the reaction, and the pH was adjusted to 3. Water was added to the reaction solution, stirred to dissolve, and the liquid was separated to obtain an aqueous layer and a THF layer. The aqueous layer was discarded, and a saturated NaCl solution was added to the THF layer for washing, and then anhydrous sodium sulfate was added for drying. After filtering, the brown oil obtained by concentrating under reduced pressure was 47.73 g of (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone, with a yield of 96.5%.
[0038] The H NMR spectrum of (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone is as follows Figure 2 As shown, wherein: 1HNMR (400MHz, Chloroform-d) δ7.76-6.90 (m, 5H), 4.53 (dd, J = 74.4, 11.6Hz, 2H), 4.36 (q, J = 6.8Hz, 1H), 3.83-3.33 (m, 4H), 1.70-1.47 (m, 6H), 1.45 (d, J = 6.8Hz, 3H).
[0039] (3) Under N2 protection, 6 g (0.25 mol) of magnesium, iodine and 400 ml of dry THF were added to a flask and mixed to obtain a reaction solution, which was controlled at 25°C under nitrogen protection, and then 28 g (0.25 mol) of ethyl bromide was added dropwise to the reaction solution. After the addition was completed, the reaction was carried out at 25°C for two hours to obtain a Grignard reagent. The Grignard reagent was cooled to 5°C, and 20.53 g (0.083 mol) of (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone was slowly added dropwise to the Grignard reagent. After the addition was completed, the temperature was controlled at 0°C for one hour, and the reaction was completed by monitoring by TLC to obtain a mixed solution. The mixed solution was slowly added into glacial hydrochloric acid to quench the reaction, stirred for 2 hours, extracted with dichloromethane, and the dichloromethane layer was separated. The dichloromethane layer was washed with water and saturated NaCl in sequence, and then dried over anhydrous sodium sulfate. Finally, it was filtered and concentrated under reduced pressure to obtain a yellow oily substance of 15.24 g of (2S)-2-benzyloxy-3-pentanone, with a yield of 95.5% and ee of 96.2%.
[0040] The H NMR spectrum of (2S)-2-benzyloxy-3-pentanone is as follows Figure 3 As shown, wherein: 1H NMR (400 MHz, Chloroform-d) δ 7.60-7.08 (m, 5H), 4.71-4.36 (m, 2H), 3.97 (q, J = 6.8 Hz, 1H), 2.62 (qd, J = 7.3, 6.1 Hz, 2H), 1.37 (d, J = 6.9 Hz, 3H), 1.08 (t, J = 7.3 Hz, 3H).
[0041] Embodiment 2:
[0042] A method for synthesizing (2S)-2-benzyloxy-3-pentanone, comprising the following steps:
[0043] (1) 20.8 g (0.2 mol) of S-methyl lactate was added to a flask at room temperature, and 30.65 g (0.36 mol) of piperidine was slowly added dropwise. After the addition was completed, the temperature was raised to 45° C. and the reaction was allowed to proceed for 25 hours. The reaction was completed under the control of TLC. The mixture was concentrated under reduced pressure to obtain 30.97 g of (S)-2-hydroxy-1-(1-piperidinyl)-1-propanone (dark yellow oil) with a yield of 98.5% and an ee of 99.5%.
[0044] (2) Under nitrogen protection, 300 ml of THF and 7.2 g (0.3 mol) of sodium hydride were added to a flask to obtain a mixed solution, which was cooled to below 0° C. 31.44 g (0.2 mol) of (S)-2-hydroxy-1-(1-piperidinyl)-1-propanone was slowly added dropwise to the above reaction solution. After the addition was completed, the mixture was stirred for 10 min. 25.82 g (0.21 mol) of benzyl chloride was continuously added dropwise to obtain a reaction solution. The reaction solution was slowly heated to 25° C. and stirred for 18 hours. The reaction was completed by TLC monitoring, and the reaction solution was cooled to T≤10°C. Dilute HCl was added to the reaction solution to terminate the reaction, and the pH was adjusted to 2. Water was added to the reaction solution and stirred to dissolve. The solution was separated to obtain an aqueous layer and a THF layer. The aqueous layer was discarded, and a saturated NaCl solution was added to the THF layer for washing. The layer was then dried over anhydrous sodium sulfate. The brown oil obtained by filtration and concentration under reduced pressure was 47.14 g of (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone in a yield of 95.3%.
[0045] (3) Under N2 protection, 5.04 g (0.21 mol) of magnesium, iodine and 400 ml of dry THF were added to the flask and mixed to obtain a reaction solution. The temperature was controlled at 30°C under nitrogen protection, and then 22.89 g (0.21 mol) of ethyl bromide was added dropwise to the reaction solution. After the addition was completed, the reaction was carried out at 25°C for two hours to complete the preparation of the Grignard reagent. The Grignard reagent was cooled to 0°C, and 20.53 g (0.083 mol) of (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone was slowly added dropwise to the Grignard reagent. After the addition was completed, the temperature was controlled at 0°C for one hour to obtain a mixed solution after monitoring the reaction. The mixed solution was slowly added into glacial hydrochloric acid to quench the reaction, stirred for 2 hours, extracted with chloroform, and the chloroform layer was separated. The chloroform layer was washed with water and saturated NaCl in sequence, and then dried over anhydrous sodium sulfate. Finally, it was filtered and concentrated under reduced pressure to obtain a yellow oily substance, which was 15.1 g of the intermediate (2S)-2-benzyloxy-3-pentanone, with a yield of 94.6% and ee: 95.8%.
[0046] Embodiment 3:
[0047] A method for synthesizing (2S)-2-benzyloxy-3-pentanone, comprising the following steps:
[0048] (1) 20.8 g (0.2 mol) of S-methyl lactate was added to a flask at room temperature, and 34.06 g (0.4 mol) of piperidine was slowly added dropwise. After the addition was completed, the temperature was raised to 50° C. and the reaction was allowed to proceed for 22 hours. The reaction was completed after monitoring by TLC. The mixture was concentrated under reduced pressure to obtain 30.75 g of (S)-2-hydroxy-1-(1-piperidinyl)-1-propanone (dark yellow oil) with a yield of 97.8% and an ee of 99.1%.
[0049] (2) Under nitrogen protection, 300 ml of THF and 9.6 g (0.4 mol) of sodium hydride were added to a flask to obtain a mixed solution, which was cooled to below 0° C. 31.44 g (0.2 mol) of (S)-2-hydroxy-1-(1-piperidinyl)-1-propanone was slowly added dropwise to the mixed solution. After the addition was completed, the mixture was stirred for 10 min. 20.25 g (0.16 mol) of benzyl chloride was continuously added dropwise to obtain a reaction solution. The reaction solution was slowly heated to 25° C. and stirred for 20 hours. The reaction was completed by TLC monitoring, and the reaction solution was cooled to T≤10°C. Dilute HCl was added to the reaction solution to terminate the reaction, and the pH was adjusted to 2. Water was added to the reaction solution and stirred to dissolve. The solution was separated to obtain an aqueous layer and a THF layer. The aqueous layer was discarded, and a saturated NaCl solution was added to the THF layer for washing. The layer was then dried over anhydrous sodium sulfate. The brown oil obtained by filtration and concentration under reduced pressure was 46.13 g of (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone in a yield of 93.2%.
[0050] (3) Under N2 protection, 6.970 g (0.29 mol) of magnesium, iodine and 400 ml of dry THF were added to the flask and mixed to obtain a reaction solution, which was controlled at 25°C under nitrogen protection. Then 31.61 g (0.29 mol) of ethyl bromide was added dropwise to the reaction solution. After the addition was completed, the reaction was carried out at 25°C for two hours to complete the preparation of the Grignard reagent. The Grignard reagent was cooled to -5°C, and 20.53 g (0.083 mol) of (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone was slowly added dropwise to the Grignard reagent. After the addition was completed, the reaction was carried out at 0°C for 1 hour. The reaction was completed by monitoring by TLC to obtain a mixed solution. The mixed solution was slowly added into glacial hydrochloric acid to quench the reaction, stirred for 2 hours, extracted with ethyl acetate, and the ethyl acetate layer was separated. The ethyl acetate layer was washed with water and saturated NaCl in sequence, and then dried over anhydrous sodium sulfate. Finally, the yellow oil obtained by filtration and concentration under reduced pressure was 14.92 g of the intermediate (2S)-2-benzyloxy-3-pentanone, with a yield of 93.5% and ee: 94.3%.
[0051] Comparative Example 1:
[0052] A method for synthesizing (2S)-2-benzyloxy-3-pentanone, comprising the following steps:
[0053] (1) 20.8 g (0.2 mol) of S-methyl lactate was added to a flask at room temperature, and 21.3 g (0.3 mol) of tetrahydropyrrole was slowly added dropwise. After the addition was completed, the temperature was raised to 25° C. and the reaction was allowed to proceed for 48 hours. The reaction was completed after monitoring by TLC. The mixture was concentrated under reduced pressure to obtain 28.43 g of (S)-2-hydroxy-(pyrrolidin-1-yl)acetone (dark yellow oil). The yield was 99.3%, and the ee was 99.1%.
[0054] (2) Under nitrogen protection, 300 ml of THF and 9.1 g (0.38 mol) of sodium hydride were added to a flask to obtain a mixed solution, which was cooled to below 0° C. 30 g (0.21 mol) of (S)-2-hydroxy-(pyrrolidin-1-yl)acetone was slowly added dropwise to the mixed solution. After the addition was completed, the mixture was stirred for 10 min. 27.9 g (0.22 mol) of benzyl chloride was continuously added dropwise to obtain a reaction solution. The reaction solution was slowly heated to 25° C. and stirred for reaction for 30 hours. The reaction was completed under LC monitoring, and the mixture was cooled to T≤10°C. Diluted HCl was added to the reaction solution to terminate the reaction, and the pH was adjusted to 2. Water was added to the reaction solution, stirred to dissolve, and the solution was separated to obtain an aqueous layer and a THF layer. The aqueous layer was discarded, and a saturated NaCl solution was added to the THF layer for washing, followed by drying with anhydrous sodium sulfate. Finally, the yellow oil obtained by filtration and concentration under reduced pressure was 46.64 g of (S)-2-benzyloxy-1-(pyrrolidin-1-yl)acetone, with a yield of 95.2%.
[0055] (3) Under N2 protection, 6 g (0.25 mol) of magnesium, iodine and 400 ml of dry THF were added to the flask and mixed to obtain a reaction solution. The temperature was controlled to 25°C under nitrogen protection, and then 28 g (0.25 mol) of ethyl bromide was added dropwise to the reaction solution. After the addition was completed, the reaction was carried out at 25°C for two hours to complete the preparation of the Grignard reagent. The Grignard reagent was cooled to -5°C, and 19.36 g (0.083 mol) of (S)-2-benzyloxy-1-(pyrrolidin-1-yl)acetone was slowly added dropwise to the Grignard reagent. After the addition was completed, the temperature was controlled to 0°C for one hour. The reaction was completed by monitoring by TLC to obtain a mixed solution. The mixed solution was slowly added into glacial hydrochloric acid, stirred for 2 hours, extracted with dichloromethane, and the dichloromethane layer was separated. The dichloromethane layer was washed with water and saturated NaCl in sequence, and then dried over anhydrous sodium sulfate. Finally, it was filtered and concentrated under reduced pressure to obtain a yellow oily substance of 14.92 g of (2S)-2-benzyloxy-3-pentanone, with a yield of 93.5% and ee: 94.3%.
[0056] By comparing Example 3 with the comparative example, it is found that when preparing (2S)-2-benzyloxy-3-pentanone with the same yield and purity, the total reaction time of Example 3 is about 47 hours and 10 minutes, while the total reaction time of the comparative example is about 83 hours and 10 minutes. Therefore, the reaction time of Example 3 is greatly shortened, that is, the preparation method of the present application can reduce the production cycle, the production efficiency is higher, and due to the reduction of raw material costs and the commission of production efficiency, the overall production cost is greatly reduced.
[0057] Comparative Example 2
[0058] (1) 20.8 g (0.2 mol) of S-methyl lactate was added to a flask at room temperature, and 21.3 g (0.3 mol) of tetrahydropyrrole was slowly added dropwise. After the addition was completed, the temperature was raised to 60° C. and the reaction was allowed to proceed for 28 hours. The reaction was completed under TLC monitoring, and the mixture was concentrated under reduced pressure to obtain (S)-2-hydroxy-(pyrrolidin-1-yl)acetone (dark yellow oil) with a yield of 96.5% and an ee of 95.8%.
[0059] (2) Under nitrogen protection, 300 ml of THF and 8.64 g (0.36 mol) of sodium hydride were added to a flask to obtain a mixed solution, which was cooled to below 0° C., (S)-2-hydroxy-(pyrrolidin-1-yl)acetone (0.2 mol) was slowly added dropwise to the mixed solution, and after the addition was completed, the mixture was stirred for 10 min, and benzyl chloride (0.204 mol) was continuously added dropwise to obtain a reaction solution. The reaction solution was slowly heated to 30° C. and stirred for reaction for 20 hours. The reaction was completed under TLC monitoring, and the mixture was cooled to T≤10° C., and dilute HCl was added to the reaction solution to terminate the reaction. The pH was adjusted to 3, and water was added to the reaction solution to stir and dissolve. The mixture was separated, and a saturated NaCl solution was added to the organic phase for washing. The mixture was then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oily substance, which was (S)-2-benzyloxy-1-(pyrrolidin-1-yl)acetone. The yield was 94.6%.
[0060] (3) Under N2 protection, 6 g (0.25 mol) of magnesium, iodine and 400 ml of dry THF were added to a flask and mixed to obtain a reaction solution, which was controlled at 25°C under nitrogen protection. Then, 28 g (0.25 mol) of ethyl bromide was added dropwise to the reaction solution. After the addition was completed, the reaction was carried out at 25°C for two hours to obtain a Grignard reagent. The Grignard reagent was cooled to 5°C, (S)-2-benzyloxy-1-(pyrrolidin-1-yl)acetone (0.083 mol) was slowly added dropwise to the Grignard reagent. After the addition was completed, the temperature was controlled at 0°C for reaction for 1 hour. The reaction was completed by monitoring by TLC to obtain a mixed solution. The mixed solution was slowly added into glacial hydrochloric acid to quench the reaction, stirred for 2 hours, extracted with dichloromethane, and the dichloromethane layer was separated. The dichloromethane layer was washed with water and saturated NaCl in sequence, and then dried over anhydrous sodium sulfate. Finally, it was filtered and concentrated under reduced pressure to obtain a yellow oily substance, which was (2S)-2-benzyloxy-3-pentanone with a yield of 92.8% and ee of 93.6%.
[0061] By comparing Comparative Example 2 with Example 1, it can be seen that under the same reaction temperature, the reaction cycles required for using tetrahydropyrrole as a raw material and using piperidine as a raw material are almost equal, but the purity of the product synthesized using tetrahydropyrrole as a raw material is much lower than the purity of the product synthesized using piperidine as a raw material. Therefore, the synthesis method using piperidine as a raw material of the present invention has better economic benefits.
[0062] The above description of the embodiments is to facilitate the understanding and application of the present invention by those skilled in the art. It is obvious that those familiar with the art can easily make various modifications to the implementation cases and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the implementation cases here, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.
Claims
1. A method for synthesizing (2S)-2-benzyloxy-3-pentanone, characterized in that: The following steps are involved: Features: (1) adding S-methyl lactate to a reaction system, adding piperidine dropwise, and heating the reaction system to generate (S)-2-hydroxy-1-(1-piperidinyl)-1-propanone; (2) Under a nitrogen atmosphere, THF and sodium hydride were added to the reaction system, (S)-2-hydroxy-1-(1-piperidinyl)-1-propanone was added dropwise while cooling, and benzyl chloride was added dropwise after the addition was completed. After the addition was completed, the temperature was raised to react. After the reaction was completed, water was added to dilute, dilute hydrochloric acid was added to adjust the pH value, the organic phase and the aqueous phase were separated, the organic phase was washed with water, dried, and concentrated to obtain (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone; (3) Under a nitrogen atmosphere, add (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone dropwise to the Grignard reagent at a controlled temperature, maintain the temperature for reaction, and terminate the reaction. Add a mixture of glacial hydrochloric acid and water to the reaction system and stir, extract with a polar solvent, wash the organic phase with water, dry it, and rotary evaporate to obtain (2S)-2-benzyloxy-3-pentanone.
2. The preparation method according to claim 1, characterized in that In the step (1), the molar ratio of (S)-methyl lactate to piperidine is 1:1.2-2; and the temperature of the temperature-raising reaction is 20-60°C.
3. The preparation method according to claim 1, characterized in that In the step (2), the temperature of the cooling dropwise addition is 0°C to 5°C; the temperature of the heating reaction is 20 to 30°C; and the pH value is adjusted to 2-3 with dilute hydrochloric acid.
4. The preparation method according to claim 1, characterized in that The temperature of the temperature-controlled dropwise addition in the step (3) is -5 to 10°C.
5. The preparation method according to claim 1, characterized in that In the step (3), the molar ratio of (2S)-2-(benzyloxy)-1-(1-piperidinyl)-1-propanone to the Grignard reagent is 1:2.5-4.
6. The preparation method according to claim 1, characterized in that The polar solvent in step (3) is at least one of dichloromethane, ethyl acetate, chloroform and toluene.
7. The preparation method according to claim 1, characterized in that The Grignard reagent in step (3) is ethylmagnesium bromide Grignard reagent.