WO2016202232A1

WO2016202232A1 - Synthesis method for (4s)-n-boc-4-methoxy methyl-l-proline amine salt

Info

Publication number: WO2016202232A1
Application number: PCT/CN2016/085661
Authority: WO
Inventors: 林文清; 朱剑平; 刘小波; 郑宏杰
Original assignee: 重庆博腾制药科技股份有限公司
Priority date: 2015-06-19
Filing date: 2016-06-14
Publication date: 2016-12-22

Abstract

Disclosed is a synthesis method for (4S)-N-Boc-4-methoxy methyl-L-proline amine salt (TM), comprising the following steps: a. React (2S)-N-Boc-4-methoxy methylene pyrrolidine-2-carboxylic acid with NR1R2R3 amine compound to obtain (2S)-N-Boc-4-methoxy methylene pyrrolidine-2-carboxylic acid amine salt; and b. Obtain (4S)-N-Boc-4-methoxy methyl-L-proline amine salt from (4S)-N-Boc-4-methoxy methyl-L-proline amine salt by palladium carbon hydrogen reduction reaction, R1, R2, and R3 being independently selected from hydrogen and hydroxyl compounds. By using a salt-forming system, the oxidation system is more efficient and the product is easier to separate and purify, thereby the obtained product has a high purity and a good stability. A raw material cost and a production cost are relatively low, and there is no potential safety hazard, which is economic and environment-friendly.

Description

Method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline amine salt

Technical field

The invention relates to the technical field of medicine, in particular to a method for synthesizing a (4S)-N-Boc-4-methoxymethyl-L-proline amine salt.

Background technique

Hepatitis C virus, referred to as hepatitis C and hepatitis C, is a viral disease caused by Hepatitis C Virus (HCV) infection. After HCV infection, 50%-85% will be converted into chronic infection. If reasonable control measures are not taken, the patient will eventually lead to cirrhosis and hepatocellular carcinoma, which is a serious threat to life. HCV is mainly transmitted by blood, acupuncture, and drug use. Some data show that the mortality associated with global hepatitis C virus infection (hepatic failure and death from hepatocellular carcinoma) will continue to increase in the next 20 years, and HCV prevention has become one of the world's major public health problems.

At present, the treatment of hepatitis C is still antiviral. The anti-hepatitis drugs on the market are treated with polydiethanol interferon (PEN-IFN) and ribavirin; HCV NS3-4A protease inhibitors (Telaprevir, Boceprevir, Simeprevir HCV NS5A protease inhibitor (Daclatasvir); nucleoside polymerase inhibitor (sofosbuvir), non-nucleoside polymerase inhibitor, gene therapy, and the like. Newly marketed antiviral drugs are generally more expensive, such as Sofosbuvir for a 12-week course at $84,000 (in the US, 28-piece/bottle Sovaldi wholesaler (WAC) costs are $28,000, per At $1,000, most patients require 12 weeks of treatment and the total cost will be $84,000. This price is unaffordable for most low-income patients. Therefore, the development of drugs with high efficiency, low toxicity, long-lasting efficacy and low price has far-reaching social significance.

(4S)-N-Boc-4-methoxymethyl-L-proline or salt is an important intermediate of anti-hepatitis C drug GS-5816 developed by Gilead Company of the United States. GS-5816 is a class of NS5A protease inhibitors and is currently in Phase 2 clinical trials. The drug has been used in Phase III clinical trials in combination with PSI-7977 (Sofosbuvir) to treat gene type 1-6 and is expected to be available in 2016. Currently, Gilead has announced that it will license the production and distribution rights of GS-5816 and its PSI-7977 (sofosbuvir) compound in 91 underdeveloped countries to eight pharmaceutical companies in India. After the market, HCV patients in these underdeveloped countries will enjoy relatively low-cost anti-HCV medications.

The synthesis method of (4S)-N-Boc-4-methoxymethyl-L-proline reported in the literature mainly uses L-hydroxyproline as a raw material or a multi-step reaction to obtain a product, such as WO2012068234 As shown in the above, the N atom and the carboxyl group of L-hydroxyproline are protected. After the hydroxybenzene is sulfonated, the upper cyano group increases the carbon atom, is oxidized to a carboxyl group and then reduced to a hydroxyl group, and finally the methyl group is obtained to obtain a methoxy group. base. The method has a long reaction route, high raw material cost and production cost, is difficult to purify, and has low yield. And so on. Or as shown in US20130115194, using dimethyl (1-diazo-2-oxopropyl)phosphonate as the reactant, and (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid The methyl ester is reacted to obtain methyl (2S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylate, followed by hydrogenation reduction and esterification to give (4S)-N-Boc-4- Methoxymethyl-L-proline, this method has certain safety hazards due to the use of diazo compounds.

Therefore, in view of the above problems, from the perspective of atomic economy and cost as well as environmental protection, a new (4S)-N-Boc-4--methoxymethyl-L-proline synthesis route is designed. Purification, high yield, low raw material cost and production cost, and good safety.

Summary of the invention

In view of the above, an object of the present invention is to provide a novel synthesis method of (4S)-N-Boc-4-methoxymethyl-L-proline amine salt, which makes the oxidation system more efficient by the salt formation system. High, the product is easier to purify and separate, the obtained product has high quality, good stability, relatively low raw material cost and production cost, and no safety hazard problem, that is, economical and environmentally friendly.

The method for synthesizing the (4S)-N-Boc-4-methoxymethyl-L-proline amine salt (TM) of the present invention comprises the following steps:

a. (2S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid (IM3) is reacted with NR ₁ R ₂ R ₃ amination to obtain (2S)-N-Boc-4 - methoxymethyl pyrrolidine-2-carboxylic acid amine salt (IM4);

b. (2S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid amine salt (IM4) by palladium hydroreduction to obtain (4S)-N-Boc-4-methoxy Methyl-L-proline amine salt (TM);

Wherein R ₁ , R ₂ , R _{3 are} independently selected from the group consisting of hydrogen and a hydrocarbyl compound;

Further, in the step a, R ₁ , R ₂ , and R ₃ in the amination are independently selected from a C ₁ -C ₆ hydrocarbyl compound; or, R ₁ is hydrogen, and R ₂ and R _{3 are} independently selected from C ₁ a hydrocarbyl compound of -C ₈ ; or R ₁ and R ₂ are both hydrogen, and R _{3 is} selected from a C ₁ -C ₁₀ hydrocarbyl compound;

Further, in the step a, the amine compound is one of tert-butylamine, dicyclohexylamine, benzylamine, (S)-phenethylamine, amantadine;

Further, in the step a, the (2S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid (IM3) is obtained by the following method: (2S)-N-Boc-4- Oxopyrrolidine-2-carboxylic acid (IM2) is prepared by Wittig reaction,

Further, the reagent for the Wittig reaction is methoxymethyltriphenylphosphonium chloride, or methoxymethyltriphenylphosphonium chloride with potassium t-butoxide, n-butyllithium, sodium hydride, diiso a mixture of one or more of propylamino lithium;

Further, the ratio of the molar amount of each of the reagent reagents to (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid (IM2) is from 1 to 3:1;

Further, the (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid (IM2) was obtained by the following method:

L-hydroxyproline (RM1) is subjected to Boc protection to obtain N-Boc-L-hydroxyproline (IM1) and then subjected to oxidation reaction;

Further, the reaction reagent for the oxidation reaction is one of sodium dichloroisocyanurate, sodium hypochlorite, tetramethylpiperidine oxynitride or a mixture thereof;

Further, in the step b, the solvent of the palladium hydrocarbon reduction reaction is water.

Advantageous Effects of Invention: A novel synthesis method of a (4S)-N-Boc-4-methoxymethyl-L-proline amine salt of the present invention, which makes the oxidation system more efficient by a salt formation system The product is easier to purify and separate, and the obtained product has high purity and good stability, and the product is directly hydrogenated by the intermediate IM4 (salt of IM3) to reduce the reaction step, the raw material cost and the production cost are relatively low, and there is no safety. The hidden danger problem is economic and environmental protection.

detailed description

Embodiment 1

Synthesis of N-Boc-L-hydroxyproline (IM1):

In a 2 L reaction flask, 131.13 g (1 mol) of L-hydroxyproline and 500 mL of water were added, stirred to dissolve, and about 240 g of a saturated potassium carbonate solution was added to adjust pH = 8-9. The reaction solution was heated to 20 to 25 ° C, and a solution of 218.25 g (1 mol) of (Boc) 2 O in 500 mL of THF was added dropwise. After the completion of the dropwise addition, the mixture was kept at 20 to 25 ° C for 18 hours, distilled under reduced pressure, and the THF in the system was distilled off. The aqueous phase was extracted with 2 x 250 mL of methyl tert-butyl ether. The aqueous phase was cooled to 0 to 5 ° C with an ice salt bath, pH = 2 to 3 was adjusted with 4N HCl, solid NaCl was added to the aqueous phase, and extracted three times with 1.1 L of ethyl acetate. The organic phase was combined and washed with 300 mL of brine. , liquid separation, the organic phase was dried over anhydrous sodium sulfate for 2 h, filtered, and the filtrate was concentrated to give an oil. White solid, weight 230g, yield 99.0%;

Synthesis of (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid (IM2):

A 3 L reaction flask was charged with 120 g (0.52 mol) of N-Boc-L-hydroxyproline, 2400 mL of dichloromethane, and 114.1 g (0.52 mol) of sodium dichloroisocyanurate (SDIC), stirred and cooled. To the reaction flask, 4.1 g (0.026 mol) of tetramethylpiperidine oxynitride (TEMPO) was added in portions, and the temperature was controlled to be 0 to 10 °C. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to give a white solid (97.6 g, yield: 82.0%;

Synthesis of (2S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylate ammonium salt (IM4):

Under a nitrogen atmosphere, 65.6 g (191 mmol, 1.1 eq) of methoxymethyltriphenylphosphonium chloride and 500 mL of THF were added to a 1 L reaction flask, and the temperature was lowered to -80 to -70 ° C, and 218 mL (348 mmol) was added in portions. 2.0 eq) n-butyllithium solution, after stirring for 2 hours, the mixture was heated to 10 to 20 ° C to obtain a wine red solution, and then cooled to -5 to 0 ° C. 40 g (174 mmol, 1.0 eq) of IM2 in THF was added dropwise, and after completion of the dropwise addition, the mixture was heated to 10 to 20 ° C for 12 hours, and the reaction was quenched by dropwise addition of a saturated sodium hydrogen carbonate solution. Stir for 30 min, filter, and filter cake washed with 3×50 mL water. The aqueous phase was combined, 40% citric acid was added to the aqueous phase, the pH was adjusted to 3-4, and then extracted three times with 800 mL of ethyl acetate. The organic phase of IM3 was combined, and dicyclohexylamine (262 mmol) was added dropwise at 20-30 °C. , 1.5 eq) salt formation, filtration to obtain IM4, yield 77.9%, purity 95%; synthesis of (4S)-N-Boc-4--methoxymethyl-L-proline and its salt (TM) :

To a 250 mL flask was added 7 g of (2S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid dicyclohexylamine salt, 70 mL of water, 0.7 g of 10% palladium carbon. The air in the bottle was replaced with nitrogen three times, and the nitrogen in the bottle was replaced with hydrogen three times, and reacted at 20 to 25 ° C for 12 hours. Filtration, the filtrate was adjusted with acid to pH = 3, extracted with ethyl acetate, concentrated, and then recrystallised from ethyl acetate / n-hexane to yield the free acid, yield 70-80%, purity 99%.

Embodiment 2

Synthesis of N-Boc-L-hydroxyproline (IM1):

In a 2 L reaction flask, 131.13 g (1 mol) of L-hydroxyproline and 500 mL of water were added, stirred to dissolve, and about 240 g of a saturated potassium carbonate solution was added to adjust pH = 8-9. The reaction solution was heated to 20 to 25 ° C, and a solution of 218.25 g (1 mol) of (Boc) 2 O in 500 mL of THF was added dropwise. After the completion of the dropwise addition, the mixture was kept at 20 to 25 ° C for 18 hours, distilled under reduced pressure, and the THF in the system was distilled off. The aqueous phase was extracted with 2 x 250 mL of methyl tert-butyl ether. The aqueous phase was cooled to 0 to 5 ° C with an ice salt bath, pH = 2 to 3 was adjusted with 4N HCl, solid NaCl was added to the aqueous phase, and extracted three times with 1.1 L of ethyl acetate. The organic phase was combined and washed with 300 mL of brine. , the liquid was separated, and the organic phase was dried over anhydrous sodium sulfate for 2h, filtered, and the filtrate was concentrated to give an oily solid, which was white solid, weight 230 g, yield 99.0%;

Synthesis of (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid (IM2):

Add 176.4 g (0.43 mol) of N-Boc-L-hydroxyproline, 500 mL of dichloromethane and 6 g to a 2 L reaction vial. (0.038 mol) tetramethylpiperidine oxynitride (TEMPO), stirred and cooled to 0 °C. Sodium hypochlorite solution (0.86 mol, 2.0e) was added dropwise to the reaction flask. After the reaction was completed, a saturated KHSO4 solution was added to adjust the pH to about 2, and the mixture was filtered, and the filter cake was collected to obtain a white solid 130 g, yield 74%;

Under a nitrogen atmosphere, 77.5 g (226 mmol, 1.3 eq) of methoxymethyltriphenylphosphonium chloride, 500 mL of THF were added to a 1 L reaction flask, and the temperature was lowered to -5 to 0 ° C, and 16.8 g (421 mmol) was added in portions. 2.2 eq) sodium hydride. The temperature was raised to 10 to 20 ° C to obtain an orange-red solution, and the temperature was lowered to -5 to 0 °C. A solution of 40 g (174 mmol, 1.0 eq) of IM2 in 150 mL of THF was added dropwise, and after the dropwise addition was completed, the mixture was heated to 10 to 20 ° C for 24 hours, and the reaction was quenched by dropwise addition of a saturated sodium hydrogen carbonate solution. Stir for 30 min, filter, and filter cake washed with 3×50 mL water. The aqueous phase was combined, 40% citric acid was added to the aqueous phase, the pH was adjusted to 3 to 4, and then extracted with 800 mL of ethyl acetate in three portions. The organic phase of IM3 was combined, and dicyclohexylamine (262 mmol) was added dropwise at 20 to 30 °C. 1.5 eq) salt formation, filtration to obtain IM4, yield 81.6%, purity 96%.

Synthesis of (4S)-N-Boc-4--methoxymethyl-L-proline and its salt (TM):

To a 250 mL flask was added 7 g of (2S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid tert-butylamine salt, 70 mL of methanol, and 0.7 g of 10% palladium carbon. The air in the bottle was replaced with nitrogen three times, and the nitrogen in the bottle was replaced with hydrogen three times, and reacted at 0 to 5 ° C for 24 hours. After filtration and concentration of the filtrate, ethyl acetate was added thereto, and the pH was adjusted to 3 with an acid. The organic layer was dried, filtered, concentrated, and then recrystallized from ethyl acetate / n-hexane to give the free acid. ~75%, purity 99%.

Embodiment 3

Synthesis of N-Boc-L-hydroxyproline (IM1):

Synthesis of (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid (IM2):

A 3 L reaction flask was charged with 120 g (0.52 mol) of N-Boc-L-hydroxyproline, 2400 mL of dichloromethane, and 114.1 g (0.52 mol) of SDIC (sodium dichloroisocyanurate), stirred and cooled. To the reaction flask, 4.1 g (0.026 mol) of tetramethylpiperidine oxynitride (TEMPO) was added in portions, and the temperature was controlled to be 0 to 10 °C. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated to give a white solid (97.6 g).

Under a nitrogen atmosphere, 65.6 g (191 mmol, 1.1 eq) of methoxymethyltriphenylphosphonium chloride, 800 mL of THF was added to a 2 L reaction flask, and the temperature was lowered to -80 to -70 ° C, and 218 mL (435 mmol, 2.5) was added dropwise. Eq) lithium diisopropylamide obtained an orange-red solution. 40 g (174 mmol, 1.0 eq) of IM2 in 250 mL of THF was added dropwise, and after the addition was completed, the mixture was heated to 10 to 20 ° C for 12 hours, and the reaction was quenched by dropwise addition of a saturated sodium hydrogen carbonate solution. Stir for 30 min, filter, and filter cake washed with 3×50 mL water. The aqueous phase was combined, 40% citric acid was added to the aqueous phase, the pH was adjusted to 3-4, and then extracted three times with 800 mL of methyl tert-butyl ether. The organic phase of IM3 was combined, and t-butylamine (262 mmol) was added dropwise at 20-30 °C. , 1.5 eq) salt formation, filtration to obtain IM4, yield 77.0%, purity 97%;

Synthesis of (4S)-N-Boc-4--methoxymethyl-L-proline and its salt (TM):

To a 250 mL flask was added 7 g of (2S)-N-Boc-4-methoxymethylidene pyrrolidine-2-carboxylic acid (S) phenethylamine salt, 70 mL of ethanol, 0.7 g of 10% palladium carbon. The air in the bottle was replaced with nitrogen three times, and the nitrogen in the bottle was replaced with hydrogen three times, and reacted at 20 to 25 ° C for 12 hours. Filtration, the filtrate of TM was obtained, concentrated, and recrystallized from ethanol / n-hexane to obtain 5.5 g of ammonium salt, yield 75%, purity 99%.

Embodiment 4

Synthesis of N-Boc-L-hydroxyproline (IM1): same as in Example 1;

Synthesis of (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid (IM2): same as Example 2;

Under a nitrogen atmosphere, 89.5 g (261 mmol, 1.5 eq) of methoxymethyltriphenylphosphonium chloride, 400 mL of THF were added to a 1 L reaction flask, and the temperature was lowered to -5 to 0 ° C, and 48.7 g (435 mmol) was added in portions. 2.5 eq) potassium t-butoxide. The mixture was heated to 10 to 20 ° C to obtain an orange solution, and the temperature was lowered to -5 to 0 ° C. 40 g (174 mmol, 1.0 eq) of IM2 in THF was added dropwise. After the addition was completed, the temperature was raised to 10 to 20 ° C for 12 hours. The reaction was quenched by dropwise addition of a saturated sodium hydrogen carbonate solution. Stir for 30 min, filter, and filter cake washed with 3×50 mL water. The aqueous phase was combined, 40% citric acid was added to the aqueous phase, the pH was adjusted to 3-4, and then extracted three times with 800 mL of ethyl acetate. The organic phase of IM3 was combined, and (S)-phenylethyl was added dropwise at 20-30 °C. The amine (262 mmol) was salted and filtered to obtain IM4, the yield was 62.1%, and the purity was 96%;

Synthesis of (4S)-N-Boc-4--methoxymethyl-L-proline and its salt (TM): same as in Example 3.

Embodiment 5

Synthesis of N-Boc-L-hydroxyproline (IM1):

Synthesis of (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid (IM2): same as in Example 1

Under a nitrogen atmosphere, 131 g (348 mmol, 2.0 eq) of methoxymethyltriphenylphosphonium chloride, 400 mL of THF was added to a 1 L reaction flask, and the temperature was lowered to -5 to 0 ° C, and 39.0 g (348 mmol, 2.0) was added in portions. Eq) potassium t-butoxide. The mixture was heated to 10 to 20 ° C to obtain an orange solution, and the temperature was lowered to -5 to 0 ° C. 40 g (174 mmol, 1.0 eq) of IM2 in THF was added dropwise. After the addition was completed, the temperature was raised to 10 to 20 ° C for 12 hours. The reaction was quenched by dropwise addition of a saturated sodium hydrogen carbonate solution. Stir for 30 min, filter, and filter cake washed with 3×50 mL water. The aqueous phase was combined, 40% citric acid was added to the aqueous phase, the pH was adjusted to 3-4, and then extracted three times with 800 mL of ethyl acetate. The organic phase of IM3 was combined, and benzylamine (262 mmol) was added dropwise at 20-30 °C. Salt, filtered to obtain IM4, yield 41.1%, purity 99%;

Synthesis of (4S)-N-Boc-4--methoxymethyl-L-proline and its salt (TM):

Embodiment 6

Synthesis of N-Boc-L-hydroxyproline (IM1): same as in Example 1;

Under a nitrogen atmosphere, 65.6 g (191 mmol, 1.1 eq) of methoxymethyltriphenylphosphonium chloride, 400 mL of THF were added to a 1 L reaction flask, and the temperature was lowered to -5 to 0 ° C, and 39.0 g (348 mmol) was added in portions. 2.0 eq) potassium t-butoxide. The mixture was heated to 20-30 ° C to obtain an orange-red solution, and the temperature was lowered to -5 to 0 ° C. 40 g (174 mmol, 1.0 eq) of IM2 in THF was added dropwise, and after the addition was completed, the temperature was raised to 10 to 20 ° C for 12 hours. The reaction was quenched by dropwise addition of a saturated sodium hydrogen carbonate solution. Stir for 30 min, filter, and filter cake washed with 3×50 mL water. The aqueous phase was combined, 40% citric acid was added to the aqueous phase, the pH was adjusted to 3-4, and then extracted three times with 800 mL of ethyl acetate. The organic phase of IM3 was combined, and amantadine (262 mmol) was added dropwise at 20-30 °C. Salt formation, filtration to obtain IM4, yield 65%, purity 97%;

Synthesis of (4S)-N-Boc-4--methoxymethyl-L-proline and its salt (TM): same as in Example 2.

Example 7

Synthesis of N-Boc-L-hydroxyproline (IM1): same as in Example 2;

Under a nitrogen atmosphere, 65.6 g (191 mmol, 1.1 eq) of methoxymethyltriphenylphosphonium chloride and 400 mL of THF were added to a 1 L reaction flask, and the temperature was lowered to -5 to 0 ° C, and 47.2 g (421 mmol) was added in portions. 2.2 eq) potassium t-butoxide. The mixture was heated to 30-40 ° C to obtain an orange solution, and the temperature was lowered to -5 to 0 ° C. 40 g (174 mmol, 1.0 eq) of IM2 in THF was added dropwise. After the addition was completed, the temperature was raised to 10 to 20 ° C for 12 hours. The reaction was quenched by dropwise addition of a saturated sodium hydrogen carbonate solution. Stir for 30 min, filter, and filter cake washed with 3×50 mL water. The aqueous phase was combined, 40% citric acid was added to the aqueous phase, the pH was adjusted to 3-4, and then extracted three times with 800 mL of ethyl acetate. The organic phase of IM3 was combined, and triethylenediamine DABCO was added dropwise at 20-30 °C. (262 mmol) salt formation, filtration to obtain IM4, yield 60%, purity 97%;

Synthesis of (4S)-N-Boc-4--methoxymethyl-L-proline and its salt (TM):

The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to be limiting. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art Modifications or equivalents are intended to be included within the scope of the appended claims.

Claims

A method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline amine salt, comprising the steps of:

a. (2S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid is reacted with NR 1 R 2 R 3 amination to obtain (2S)-N-Boc-4-methoxy Alkyl pyrrolidine-2-carboxylic acid amine salt;

b. (2S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid amine salt by palladium hydroreduction to obtain (4S)-N-Boc-4-methoxymethyl -L-proline amine salt;

Wherein R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen and a hydrocarbyl compound.
The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline amine salt according to claim 1, wherein in the step a, R 1 in the amine compound, R 2 , R 3 are independently selected from C 1 -C 6 hydrocarbyl compounds; alternatively, R 1 is hydrogen, R 2 and R 3 are independently selected from C 1 -C 8 hydrocarbyl compounds; or R 1 and R 2 are both Is hydrogen, and R 3 is selected from a C 1 -C 10 hydrocarbyl compound.
The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline amine salt according to claim 2, wherein in the step a, the amine compound is tert-butylamine, two One of cyclohexylamine, benzylamine, (S)-phenethylamine, amantadine.
The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline amine salt according to claim 1, wherein in step a, said (2S)-N- Boc-4-methoxymethylpyrrolidine-2-carboxylic acid was obtained by the following method: (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid was obtained by Wittig reaction.
The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline amine salt according to claim 4, wherein the reaction reagent of the Wittig reaction is methoxymethyl A mixture of one or more of triphenylphosphonium chloride or methoxymethyltriphenylphosphonium chloride with potassium t-butoxide, n-butyllithium, sodium hydride, lithium diisopropylamide.
The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline amine salt according to claim 5, characterized in that each reaction reagent is (2S)-N- The molar ratio of Boc-4-oxopyrrolidine-2-carboxylic acid is from 1 to 3:1.
A method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline amine salt according to claim 4, wherein: (2S)-N-Boc-4- Oxopyrrolidine-2-carboxylic acid is obtained by the following method:

L-hydroxyproline is subjected to Boc protection to obtain N-Boc-L-hydroxyproline and then subjected to oxidation reaction;
The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline amine salt according to claim 7, wherein the reaction reagent for the oxidation reaction is dichloroisocyanide One of sodium urate, sodium hypochlorite, tetramethylpiperidine oxynitride or a mixture thereof.
The method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline amine salt according to claim 1, wherein in the step b, the palladium hydroreduction reaction The solvent is water.