A method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline

Abstract

The application discloses a synthesis method of (4S)-N-Boc-4-methoxymethyl-L-proline, which comprises the following steps: taking L-hydroxyproline as a starting material, and obtaining N-Boc-L-hydroxyproline through Boc protection; dissolving N-Boc-L-hydroxyproline in a solvent, and carrying out oxidation reaction with TEMPO (tetramethylpiperidinooxy) to obtain (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid; dissolving (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid and methoxymethyltriphenylphosphonium chloride in a solvent, and carrying out wittig reaction to obtain (2S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid; dissolving (2S)-N-BoC-4-methoxymethylpyrrolidine-2-carboxylic acid and tert-butylamine in water, and carrying out hydrogenation reaction to obtain (4S)-N-Boc-4-methoxymethyl-L-proline; the reaction shortens reaction steps, avoids the use of toxic cyanide, increases safety, reduces environmental pressure, improves atomic economy, reduces waste emission, and greatly reduces raw material cost.

Description

[0001] This application is a divisional application of application number 201410836352.0, filed on December 29, 2014, entitled "A method for synthesizing (4S)-N-Boc-4--methoxymethyl-L-proline". Technical Field

[0002] This invention relates to the field of pharmaceutical technology, and in particular to a method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline. Background Technology

[0003] (4S)-N-Boc-4-methoxymethyl-L-proline is an important intermediate for an anti-hepatitis C drug being researched by Gilead Sciences, currently in Phase II clinical trials. Reported synthetic methods involve multiple steps using L-hydroxyproline as a starting material. However, these methods suffer from drawbacks such as long reaction cycles, high raw material and production costs, and safety and environmental concerns due to the use of highly toxic substances like sodium cyanide and iodomethane. US20130115194 discloses a method for reacting (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid methyl ester with dimethyl 1-diazo-2-oxopropyl)phosphonate to obtain (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid. This method, however, poses certain safety risks due to the use of diazo compounds.

[0004] Therefore, to address the above issues, a novel synthetic route for (4S)-N-Boc-4-methoxymethyl-L-proline should be designed from the perspectives of atom economy, cost, and environmental protection. This route would reduce reaction steps, effectively lower raw material costs, thereby reducing production costs. It would also avoid the use of highly toxic substances, ensuring high safety, while reducing emissions of waste and alleviating environmental pressure. Summary of the Invention

[0005] In view of this, the purpose of this invention is to provide a method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline, which, from the perspectives of atom economy, cost and environmental protection, effectively reduces raw material costs by reducing reaction steps, thereby reducing production costs, while avoiding the use of highly toxic substances, ensuring high safety, and reducing the emission of waste, thus alleviating environmental pressure.

[0006] One compound of the present invention has the structural formula shown in general formula (1):

[0007]

[0008] Where R is an amino protecting group.

[0009] This invention also discloses a method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline, comprising the following steps:

[0010] b. The step of dissolving N-Boc-L-hydroxyproline in a solvent and reacting it with tetramethylpiperidine nitride to give (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid;

[0011] Its synthetic route is as follows:

[0012]

[0013] Furthermore, it also includes the following steps:

[0014] a. The step of obtaining N-Boc-L-hydroxyproline from L-hydroxyproline as a starting material through Boc protection;

[0015] c. The step of preparing (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid by dissolving (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid in a solvent and carrying out a Wittig reaction;

[0016] d. (4S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid and tert-butylamine were dissolved in water and hydrogenated to obtain (4S)-N-Boc-4-methoxymethyl-L-proline;

[0017] Its synthetic route is as follows:

[0018]

[0019] Further, in step a, L-hydroxyproline is dissolved in water to adjust the pH to 8-9 and then heated to 20-25°C. A THF solution of (Boc)2O is added dropwise, and the reaction is maintained at 20-25°C for 16-19 hours. After removing the THF from the system, it is extracted and then cooled to 0-5°C.

[0020] Further, after adjusting the pH value, the mixture was heated to 23°C, and a (Boc)2O THF solution was added dropwise. The mixture was kept at 23°C for 18 hours. After removing the THF from the system by vacuum distillation, it was extracted with methyl tert-butyl ether. Then, it was cooled to 3°C, and the pH was adjusted to 2-3 with 4N HCl. Solid NaCl was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, separated, and dried with anhydrous sodium sulfate.

[0021] Furthermore, in step b, N-Boc-L-hydroxyproline is dissolved in dichloromethane and TCCA is added, followed by the addition of tetramethylpiperidine nitrogen oxides in batches.

[0022] Further, in step c, (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid, methoxymethyltriphenylphosphonium chloride, and THF are mixed and cooled to -5 to 0°C. Potassium tert-butoxide is added in batches, and the mixture is heated to 10 to 20°C until an orange-red solution is obtained. Then, the mixture is cooled to -5 to 0°C, and THF solution is added dropwise. The mixture is then heated to 10 to 20°C and reacted for 10 to 14 hours.

[0023] Further, after mixing, the mixture was cooled to -3°C, and potassium tert-butoxide was added in batches. The mixture was heated to 15°C until an orange-red solution was obtained, then cooled to -3°C. THF solution was then added dropwise, and the mixture was heated to 15°C and reacted for 12 hours. The reaction was quenched by adding saturated sodium bicarbonate solution. The solvent was removed by vacuum distillation, water was added, the mixture was stirred, and filtered. The mixture was extracted with methyl tert-butyl ether, and 40% citric acid was added to the aqueous phase to adjust the pH to 3-4. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.

[0024] Further, in step d, (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid is dissolved in water and tert-butylamine is added. After being replaced by nitrogen and hydrogen respectively, the mixture is reacted at a temperature of 20-25℃ for 10-15 h.

[0025] Further, the air in the bottle was replaced with nitrogen three times, and the nitrogen in the bottle was replaced with hydrogen three times. After reacting at 23°C for 12 hours, the mixture was filtered and the pH of the filtrate was adjusted to 3-4 with citric acid. The mixture was extracted with ethyl acetate, the extracts were combined and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a white solid, which was recrystallized from ethyl acetate / n-hexane.

[0026] The beneficial effects of the present invention: The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline of the present invention directly shortens the existing multi-step synthetic route to only 4 steps, avoids the use of highly toxic cyanide, increases safety and reduces environmental pressure, improves atom economy, reduces waste liquid discharge, significantly reduces raw material costs, and saves economic costs. Detailed Implementation

[0027] One compound of this embodiment has the structural formula shown in general formula (1):

[0028]

[0029] Where R is an amino protecting group, such as -Boc, -Bz, -Cbz, etc.

[0030] The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline according to this embodiment includes the following steps:

[0031] a. The step of obtaining N-Boc-L-hydroxyproline from L-hydroxyproline as a starting material through Boc protection;

[0032] b. The step of dissolving N-Boc-L-hydroxyproline in a solvent and reacting it with TEMPO (tetramethylpiperidine nitride) to give (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid;

[0033] c. The step of preparing (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid by dissolving (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid in a solvent and carrying out a Wittig reaction;

[0034] d. (4S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid and tert-butylamine were dissolved in water and then hydrogenated to obtain (4S)-N-Boc-4-methoxymethyl-L-proline; the synthetic route is as follows:

[0035]

[0036] In this embodiment, in step a, L-hydroxyproline is dissolved in water to adjust the pH to 8-9 and then heated to 20-25°C. A THF solution of (Boc)2O is added dropwise, and the reaction is maintained at 20-25°C for 16-19 hours. After removing the THF from the system, the mixture is extracted and then cooled to 0-5°C.

[0037] In this embodiment, after adjusting the pH value, the mixture was heated to 23°C, and a (Boc)₂O THF solution was added dropwise. The mixture was kept at 23°C for 18 hours. After removing the THF from the system by vacuum distillation, it was extracted with methyl tert-butyl ether. Then, the mixture was cooled to 3°C, and the pH was adjusted to 2-3 with 4N HCl. Solid NaCl was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, separated, and dried with anhydrous sodium sulfate.

[0038] In this embodiment, in step b, N-Boc-L-hydroxyproline is dissolved in dichloromethane and TCCA is added, followed by the addition of tetramethylpiperidine nitride (TEMPO) in batches.

[0039] In this embodiment, in step c, (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid, methoxymethyltriphenylphosphonium chloride, and THF are mixed and cooled to -5 to 0°C. Potassium tert-butoxide is added in batches, and the mixture is heated to 10 to 20°C until an orange-red solution is obtained. Then, the mixture is cooled to -5 to 0°C, and THF solution is added dropwise. The mixture is then heated to 10 to 20°C and reacted for 10 to 14 hours.

[0040] In this embodiment, after mixing, the mixture was cooled to -3°C, potassium tert-butoxide was added in batches, the temperature was raised to 15°C until an orange-red solution was obtained, then the temperature was lowered to -3°C, THF solution was added dropwise, the temperature was raised to 15°C and the reaction was carried out for 12 hours, saturated sodium bicarbonate solution was added dropwise to quench the reaction, the solvent was removed by vacuum distillation, water was added, the mixture was stirred and filtered, extracted with methyl tert-butyl ether, 40% citric acid was added to the aqueous phase to adjust the pH to 3-4, and then extracted three times with ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated.

[0041] In this embodiment, in step d, (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid is dissolved in water and tert-butylamine is added. After being replaced by nitrogen and hydrogen, the mixture is reacted at a temperature of 20-25°C for 10-15 hours.

[0042] In this embodiment, the air in the bottle was replaced with nitrogen three times, and the nitrogen in the bottle was replaced with hydrogen three times. After reacting at 23°C for 12 hours, the mixture was filtered and the pH of the filtrate was adjusted to 3-4 with citric acid. The mixture was then extracted with ethyl acetate, the extracts were combined and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a white solid, which was recrystallized with ethyl acetate / n-hexane.

[0043] The present invention will be further illustrated below through specific embodiments.

[0044] compound R in the figure represents the Boc group.

[0045] 1. Synthesis of N-Boc-L-hydroxyproline (IM1):

[0046] Example 1

[0047] In a 2L reaction flask, 131.13g (1mol) L-hydroxyproline and 500mL of water were added and stirred until dissolved. Approximately 240g of saturated potassium carbonate solution was then added to adjust the pH to 8-9. The reaction solution was heated to 23℃, and 218.25g (1mol) (Boc)₂O in 500mL of THF solution was added dropwise. After the addition was complete, the reaction was maintained at 23℃ for 18h. After the reaction was complete, the THF in the system was removed by vacuum distillation. The aqueous phase was extracted with 2×250mL of methyl tert-butyl ether, then cooled to 3℃, and the pH was adjusted to 2-3 with 4N HCl. Solid NaCl was added, and the mixture was extracted three times with 1.1L of ethyl acetate. The organic phases were combined, washed with 300mL of saturated brine, separated, and dried over anhydrous sodium sulfate for 2h. The mixture was filtered, and the filtrate was concentrated to obtain an oily substance, which, after standing, became a white solid weighing 230.0g, with a yield of 99%.

[0048] Example 2

[0049] In a 2L reaction flask, 131.24 g (1 mol) of L-hydroxyproline and 500 mL of water were added and stirred until dissolved. Approximately 240 g of saturated potassium carbonate solution was then added to adjust the pH to 8–9. The reaction solution was heated to 20°C, and 218.18 g (1 mol) of (Boc)₂O in 500 mL of THF solution was added dropwise. After the addition was complete, the reaction was maintained at 20°C for 16 h. After the reaction was complete, the THF in the system was removed by vacuum distillation. The aqueous phase was extracted with 2 × 250 mL of methyl tert-butyl ether, then cooled to 0°C, and adjusted to pH 2–3 with 4N HCl. Solid NaCl was added, and the mixture was extracted three times with 1.1 L of ethyl acetate. The organic phases were combined, washed with 300 mL of saturated brine, separated, and dried over anhydrous sodium sulfate for 2 h. The mixture was filtered, and the filtrate was concentrated to obtain an oily substance, which, after standing, became a white solid weighing 223.1 g, with a yield of 96%.

[0050] Example 3

[0051] In a 2L reaction flask, 130.89 g (1 mol) of L-hydroxyproline and 500 mL of water were added and stirred until dissolved. Approximately 240 g of saturated potassium carbonate solution was then added to adjust the pH to 8-9. The reaction solution was heated to 25°C, and 218.15 g (1 mol) of (Boc)₂O in 500 mL of THF solution was added dropwise. After the addition was complete, the reaction was maintained at 25°C for 19 h. After the reaction was complete, the THF in the system was removed by vacuum distillation. The aqueous phase was extracted with 2 × 250 mL of methyl tert-butyl ether, then cooled to 5°C, and adjusted to pH 2-3 with 4N HCl. Solid NaCl was added, and the mixture was extracted three times with 1.1 L of ethyl acetate. The organic phases were combined, washed with 300 mL of saturated brine, separated, and dried over anhydrous sodium sulfate for 2 h. The mixture was filtered, and the filtrate was concentrated to obtain an oily substance, which, after standing, became a white solid weighing 219.2 g, with a yield of 94.3%.

[0052] 2. Synthesis of (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid (IM2):

[0053] Example 4

[0054] Add 60.0 g (0.26 mol) N-Boc-L-hydroxyproline, 600 mL dichloromethane, and 60.30 g (0.26 mol) TCCA to a 1 L reaction flask, stir, and cool to room temperature. Add 2.02 g (0.012 mol) TEMPO (exothermic reaction) to the reaction flask in batches, controlling the addition rate and operating at a temperature within -3 °C. Filter, and concentrate the filtrate to obtain 40.12 g of white solid, yield 67%.

[0055] Example 5

[0056] Add 60.08 g (0.26 mol) N-Boc-L-hydroxyproline, 600 mL dichloromethane, and 60.28 g (0.26 mol) TCCA to a 1 L reaction flask. Stir and cool to room temperature. Add 2.01 g (0.012 mol) TEMPO (exothermic reaction) in portions to the reaction flask, controlling the addition rate and operating at -5 °C. Filter, concentrate the filtrate to obtain 38.51 g of white solid, yield 64.5%.

[0057] Example 6

[0058] Add 60.05 g (0.26 mol) N-Boc-L-hydroxyproline, 600 mL dichloromethane, and 60.25 g (0.26 mol) TCCA to a 1 L reaction flask. Stir and cool to room temperature. Add 2.05 g (0.012 mol) TEMPO (exothermic reaction) in portions to the reaction flask, controlling the addition rate and operating at 0 °C. Filter, concentrate the filtrate to obtain 35.02 g of white solid, yield 58.6%.

[0059] 3. Synthesis of (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid (IM3):

[0060] Example 7

[0061] Under nitrogen protection, 38.94 g (0.169 mol) of (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid, 77.8 g (0.227 mol) of methoxymethyltriphenylphosphonium chloride, and 500 mL of THF were added to a 1 L reaction flask. The mixture was cooled to -3 °C, and 47.0 g (0.137 mol) of potassium tert-butoxide was added in portions. The mixture was heated to 15 °C to give an orange-red solution. The mixture was then cooled to -3 °C, and 40 g (0.17 mol, 1 eq) of 150 mL of THF solution was added dropwise. After the addition was complete, the mixture was heated to 15 °C and reacted for 12 h. The reaction was quenched by adding saturated sodium bicarbonate solution. The solvent was removed by vacuum distillation, 500 mL of water was added, and the mixture was stirred for 30 min. The mixture was filtered, and the filter cake was washed with 3 × 50 mL of water. The aqueous phases were combined and extracted with 250 mL × 2 methyl tert-butyl ethers. The aqueous phase was retained. 40% citric acid was added to the aqueous phase to adjust the pH to 3-4. Then, the mixture was extracted three times with 800 mL of ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 33.3 g of oil, with a yield of 76.2%.

[0062] Example 8

[0063] Under nitrogen protection, 38.96 g (0.169 mol) of (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid, 78.11 g (0.227 mol) of methoxymethyltriphenylphosphonium chloride, and 500 mL of THF were added to a 1 L reaction flask. The mixture was cooled to -5 °C, and 47.05 g (0.137 mol) of potassium tert-butoxide was added in portions. The mixture was heated to 10 °C to give an orange-red solution. The mixture was then cooled to -5 °C, and 39.97 g (0.17 mol, 1 eq) of 150 mL of THF solution was added dropwise. After the addition was complete, the mixture was heated to 10 °C and reacted for 10 h. The reaction was quenched by adding saturated sodium bicarbonate solution. The solvent was removed by vacuum distillation, 500 mL of water was added, and the mixture was stirred for 30 min. The mixture was filtered, and the filter cake was washed with 3 × 50 mL of water. The aqueous phases were combined and extracted with 250 mL × 2 methyl tert-butyl ether. The aqueous phase was retained. 40% citric acid was added to the aqueous phase to adjust the pH to 3-4. Then, the mixture was extracted three times with 800 mL of ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 29.8 g of oil, with a yield of 68.2%.

[0064] Example 9

[0065] Under nitrogen protection, 39.05 g (0.169 mol) of (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid, 77.9 g (0.227 mol) of methoxymethyltriphenylphosphonium chloride, and 500 mL of THF were added to a 1 L reaction flask. The mixture was cooled to 0 °C, and 49.98 g (0.137 mol) of potassium tert-butoxide was added in portions. The mixture was heated to 20 °C to obtain an orange-red solution. The mixture was cooled to 0 °C, and 40.05 g (0.17 mol, 1 eq) of 150 mL of THF solution was added dropwise. After the addition was complete, the mixture was heated to 20 °C and reacted for 14 h. The reaction was quenched by adding saturated sodium bicarbonate solution. The solvent was removed by vacuum distillation, 500 mL of water was added, and the mixture was stirred for 32 min. The mixture was filtered, and the filter cake was washed with 3 × 50 mL of water. The aqueous phases were combined and extracted with 250 mL × 2 methyl tert-butyl ether. The aqueous phase was retained. 40% citric acid was added to the aqueous phase to adjust the pH to 3-4. Then, the mixture was extracted three times with 800 mL of ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 30.9 g of oil, with a yield of 70.7%.

[0066] 4. Synthesis of (4S)-N-Boc-4-methoxymethyl-L-proline (TM):

[0067] Example 10

[0068] 10.2 g (0.04 mol) of (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid, 100 mL of water, and 29.2 g (0.04 mol) of tert-butylamine were added to a 250 mL flask. The air in the flask was replaced with nitrogen three times, and then the nitrogen in the flask was replaced with hydrogen three times. The reaction was carried out at 23 °C for 12 h. The mixture was filtered, and the pH of the filtrate was adjusted to 3-4 with citric acid. The filtrate was extracted with 2 × 100 mL of ethyl acetate. The extracts were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give a white solid. The product was recrystallized from ethyl acetate / n-hexane to give 4.01 g, with a yield of 33.9%.

[0069] Example 11

[0070] 10.18 g (0.04 mol) of (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid, 100 mL of water, and 29.22 g (0.04 mol) of tert-butylamine were added to a 250 mL flask. The air in the flask was replaced with nitrogen three times, and then the nitrogen in the flask was replaced with hydrogen three times. The reaction was carried out at 20 °C for 10 h. The mixture was filtered, and the pH of the filtrate was adjusted to 3-4 with citric acid. The filtrate was extracted with 2 × 100 mL of ethyl acetate. The extracts were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give a white solid. The product was recrystallized from ethyl acetate / n-hexane to give 3.81 g, with a yield of 32.2%.

[0071] Example 12

[0072] 10.21 g (0.04 mol) of (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid, 100 mL of water, and 29.18 g (0.04 mol) of tert-butylamine were added to a 250 mL flask. The air in the flask was purged with nitrogen three times, followed by purging the nitrogen with hydrogen three times. The reaction was carried out at 25 °C for 15 h. The mixture was filtered, and the pH of the filtrate was adjusted to 3–4 with citric acid. The filtrate was extracted with 2 × 100 mL of ethyl acetate. The extracts were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give a white solid. Recrystallization from ethyl acetate / n-hexane gave 3.90 g of the product, with a yield of 24.6%.

[0073] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline, characterized in that: Includes the following steps: a. The step of obtaining N-Boc-L-hydroxyproline from L-hydroxyproline as a starting material through Boc protection; b. The step of dissolving N-Boc-L-hydroxyproline in a solvent and reacting it with tetramethylpiperidine nitride to give (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid; c. The step of preparing (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid by mixing (2S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid with methoxymethyltriphenylphosphonium chloride and THF and cooling to -5 to 0℃ and performing a Wittig reaction; d. (4S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid and tert-butylamine were dissolved in water and hydrogenated to obtain (4S)-N-Boc-4-methoxymethyl-L-proline; ， In step c, (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid, methoxymethyltriphenylphosphonium chloride, and THF are mixed and cooled to -5 to 0°C. Potassium tert-butoxide is added in batches, and the mixture is heated to 10 to 20°C until an orange-red solution is obtained. The mixture is then cooled to -5 to 0°C, and THF solution is added dropwise. The mixture is then heated to 10 to 20°C and reacted for 10–14 hours. In step d, (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid is dissolved in water and tert-butylamine is added. After being replaced with nitrogen and hydrogen respectively, the mixture is reacted at a temperature of 20-25℃ for 10-15 h.

2. The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline according to claim 1, characterized in that: In step a, L-hydroxyproline is dissolved in water to adjust the pH to 8-9, then heated to 20-25°C. A THF solution of (Boc)2O is added dropwise, and the reaction is maintained at 20-25°C for 16-19 hours. After removing the THF from the system, the mixture is extracted and then cooled to 0-5°C.

3. The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline according to claim 2, characterized in that: After adjusting the pH value in step a, heat to 23°C, add (Boc)2O THF solution dropwise, and keep the reaction at 23°C for 18 hours. Remove THF from the system by vacuum distillation, extract with methyl tert-butyl ether, then cool to 3°C, adjust the pH to 2-3 with 4N HCl, add solid NaCl, and extract three times with ethyl acetate. Combine the organic phases, wash with saturated brine, separate the liquid and dry the organic phase with anhydrous sodium sulfate.

4. The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline according to claim 3, characterized in that: In step b, N-Boc-L-hydroxyproline is dissolved in dichloromethane and TCCA is added, followed by the addition of tetramethylpiperidine nitrogen oxides in batches.

5. The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline according to claim 4, characterized in that: In step c, after mixing, the mixture is cooled to -3°C, potassium tert-butoxide is added in batches, the temperature is raised to 15°C until an orange-red solution is obtained, then the temperature is lowered to -3°C, THF solution is added dropwise, the temperature is raised to 15°C and the reaction is carried out for 12 hours, saturated sodium bicarbonate solution is added dropwise to quench the reaction, the solvent is removed by vacuum distillation, water is added, the mixture is stirred and filtered, extracted with methyl tert-butyl ether, 40% citric acid is added to the aqueous phase to adjust the pH to 3-4, and then the mixture is extracted three times with ethyl acetate. The combined organic phases are dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated.

6. The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline according to claim 5, characterized in that: In step d, the air in the bottle was replaced with nitrogen three times, and the nitrogen in the bottle was replaced with hydrogen three times. After reacting at 23℃ for 12 hours, the mixture was filtered and the pH of the filtrate was adjusted to 3-4 with citric acid. The mixture was extracted with ethyl acetate, the extracts were combined and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a white solid, which was recrystallized with ethyl acetate / n-hexane.

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