CN117700374A

CN117700374A - Preparation method of chiral high morpholine-3-formic acid

Info

Publication number: CN117700374A
Application number: CN202311796544.9A
Authority: CN
Inventors: 徐红岩; 袁伟芳; 王静
Original assignee: Jill Peptide Biopharmaceutical Dalian Co ltd
Current assignee: Jill Peptide Biopharmaceutical Dalian Co ltd
Priority date: 2023-12-25
Filing date: 2023-12-25
Publication date: 2024-03-15

Abstract

The invention relates to a preparation method of chiral homomorpholine-3-formic acid. Mainly solves the technical problem that the chiral high morpholine-3-formic acid lacks an industrialized synthesis method at present. The preparation method of the invention comprises the following steps: condensing benzyloxy ethyl ethoxy bromine and diethyl 2-acetamido malonate, hydrolyzing to obtain a compound I, carrying out enzymolysis separation to obtain a compound II and a compound III, carrying out Boc protection and methyl ester on the compound II, carrying out debenzylation, sulfonylation and iodination to obtain a protected compound V, carrying out deprotection, cyclizing under alkaline conditions to obtain a compound VII, and carrying out Fmoc protection to obtain a compound VIII. The whole process is a conventional reaction, does not need fine operation, does not need deep low-temperature reaction, does not need expensive palladium coupling reagent or inflammable and explosive metal organic reagent, and can be produced in a large scale.

Description

Preparation method of chiral high morpholine-3-formic acid

Technical Field

The invention relates to a preparation method of homomorpholine-3-formic acid, in particular to a preparation method of chiral homomorpholine-3-formic acid.

Background

The homomorpholine-3-carboxylic acid (1, 4-oxazepan-3-carboxilic acid) is a chiral amino acid containing a 7-membered heteroatom ring and is an important intermediate in organic chemical synthesis. In patents US2019/119298 and CA2813911 a series of compounds containing a homomorpholine-3-carboxylic acid structure are reported, which have potential for use in a variety of psychiatric treatments, agricultural pesticides etc.

The synthesis of homomorpholine-3-carboxylic acid esters is reported in patent US2019/119298 as follows:

starting from 1, 4-oxazepan-5-ketone, the route is protected by carbobenzoxy (Cbz), phosphorylated and palladium catalyzed inserting carbonyl reaction to obtain carbobenzoxy-protected high morpholine-3-methyl formate with double bonds, and finally, the racemic high morpholine-3-methyl formate is obtained by palladium-carbon catalytic hydrogenation reduction. Although the route is relatively short, each step of reaction is relatively special, and n-butyllithium and hexamethyldisilazane potassium (KHMDS) inflammable and explosive metal organic reagents, palladium catalysts, phosphorus ligands and other expensive reagents are used, so that the obtained amino acid can be only racemized.

As a special amino acid containing chirality, the chiral high morpholine-3-carboxylic acid has special significance in drug research, but an industrial preparation method for chiral high morpholine-3-carboxylic acid is lacking at present.

Disclosure of Invention

The invention aims to overcome the technical defect that racemized high morpholine-3-formic acid can only be synthesized at present, and provides a method for synthesizing chiral high morpholine-3-formic acid. The technical scheme of the invention is as follows: the preparation method of the chiral homomorpholine-3-formic acid comprises the following steps: condensing benzyloxy ethyl oxyethyl bromide and diethyl 2-acetamido malonate, hydrolyzing to obtain acetamido acid (compound I), performing enzymolysis separation to obtain L-amino acid (compound II) and D-acetamido acid (compound III), performing Boc protection and methyl ester on the L-amino acid (compound II), removing benzyl, sulfonylating and iodizing to obtain protected iodinated amino acid (compound V), performing deprotection, and then performing cyclization under alkaline conditions to obtain chiral homomorpholine-3-carboxylic acid (compound VII), and performing Fmoc protection to obtain Fmoc- (S) -homomorpholine-3-carboxylic acid (compound VIII). The whole process is a conventional reaction, does not need fine operation, does not need deep low-temperature reaction, does not need expensive palladium coupling reagent or inflammable and explosive metal organic reagent, and can be produced in a large scale. The reaction scheme of the invention is described as follows:

。

the specific reaction steps are as follows:

(1): under the action of alcohol base, the benzyl oxyethyl bromide and 2-acetamido diethyl malonate are condensed and then directly heated, refluxed and hydrolyzed by alkaline sodium hydroxide to obtain the compound I [ 2-acetamido-4- (2-benzyl oxyethoxy) butyric acid ].

(2): dissolving compound I [ 2-acetamido-4- (2-benzyloxy ethoxy) butyric acid ] in deionized water, adjusting pH to alkalescence with sodium hydroxide aqueous solution, heating to about 37 ℃, adding L-acetamido hydrolase, and keeping temperature and stirring for reaction. After cooling to room temperature, acidifying with dilute hydrochloric acid to ph=6 and filtering to give compound II [ (S) -2-amino-4- (2-benzyloxy ethoxy) butanoic acid ]. The mother liquor was further acidified with dilute hydrochloric acid to ph=2 and filtered to give compound III [ (R) -2-acetamido-4- (2-benzyloxy ethoxy) butanoic acid ].

(3): performing amino protection on a compound II [ (S) -2-amino-4- (2-benzyloxy ethoxy) butyric acid ] and di-tert-butyl dicarbonate, and then performing methyl ester with methyl iodide under the inorganic base condition to obtain a compound IV [ (S) -2-Boc-amino-4- (2-benzyloxy ethoxy) butyric acid methyl ester ];

(4): hydrogenation debenzylation of compound IV [ (S) -2-Boc-amino-4- (2-benzyloxy ethoxy) butyric acid methyl ester ] under palladium-charcoal catalysis, esterification of p-toluenesulfonyl chloride, and reaction with sodium iodide to obtain compound V [ (S) -2-Boc-amino-4- (2-iodoethoxy) butyric acid methyl ester ];

(5): deprotection of compound V [ (S) -2-Boc-amino-4- (2-iodoethoxy) butanoic acid ] with aqueous hydrochloric acid affords compound VI [ (S) -2-amino-4- (2-iodoethoxy) butanoic acid ];

(6): compound VI [ (S) -2-amino-4- (2-iodoethoxy) butyric acid ] is dissolved in a reaction solvent, and then heated and refluxed after adding alkali to obtain compound VII [ (S) -homomorpholine-2-carboxylic acid ].

(7): compound VII [ (S) -homomorpholine-2-carboxylic acid ] is reacted with 9-fluorenylmethyl-N-succinimidyl carbonate (Fmoc-OSu) to give compound VIII [ (S) -Fmoc-homomorpholine-2-carboxylic acid ].

The molar ratio of the benzyloxy ethyl oxyethyl bromide to the acetamido diethyl malonate used in the step (1) is 1:1-1:1.2, preferably 1:1.05; the alcohol alkali is sodium ethoxide or potassium tert-butoxide, and when sodium ethoxide is used, the solvent is ethanol, and the molar ratio of the benzyloxy ethyl oxyethyl bromide to the sodium ethoxide is 1:1-1:1.3, preferably 1:1.2; when the potassium tert-butoxide is used, the solvent is N, N-dimethylformamide, N-dimethylacetamide, and the molar ratio of the benzyloxy ethyl oxyethyl bromide to the potassium tert-butoxide is 1:1-1:1.3, preferably 1:1.2; the molar ratio of the benzyloxy ethyl oxyethyl bromide to the sodium hydroxide is 1:1.5-1:2, preferably 1:1.7.

The amount of deionized water used in the step (2) is (10-15V) of the compound I, the amount of the L-acetamido hydrolase is 3-6% of the weight of the compound I, preferably 4%, the reaction temperature is 35-37 ℃, and the reaction time is 24-48 hours.

The inorganic base in the step (3) is sodium carbonate or potassium carbonate, and the molar ratio of the di-tert-butyl dicarbonate to the compound II is 1.0: 1-1.05: 1, the molar ratio of methyl iodide to compound II used was 1.1: 1-1.5: 1, the molar ratio of inorganic base to compound II used is 0.8: 1-1.2: 1.

the palladium content in the palladium-carbon used in the step (4) is 5% -10%, the dosage is 5% -10% of the weight of the compound IV, and the molar ratio of the p-toluenesulfonic acid chloride to the compound IV is 1.0: 1-1.1: 1, the molar ratio of sodium iodide to compound IV used was 1.3: 1-1.5: 1.

the concentration of the hydrochloric acid aqueous solution used in the step (5) is 3-6 mol/L, the reaction temperature is 60-100 ℃, preferably 4mol/L, and 80-90 ℃.

The alkali used in the step (6) is organic alkali, inorganic metal hydroxide or other alkali, wherein the organic alkali is one of triethylamine, diisopropylethylamine or DBU, and the inorganic metal hydroxide is lithium hydroxide, sodium hydroxide, potassium hydroxide or other alkali such as potassium carbonate, cesium carbonate and the like; preferably an organic base, and more preferably triethylamine. The molar ratio of triethylamine to compound VII used was 3: 1-5:1, wherein the reaction solvent is alcohol with carbon number less than 5, preferably one of methanol, ethanol and isopropanol, and more preferably methanol. The reaction temperature is 30 to 80 ℃, preferably 60 to 70 ℃.

The molar ratio of 9-fluorenylmethyl-N-succinimidyl carbonate (Fmoc-OSu) to compound VII used in step (7) was 0.9: 1-0.95: 1.

the beneficial effects of the invention are as follows: the invention synthesizes linear amino acid with single configuration by using biological enzyme, and then cyclizes to obtain chiral homomorpholine-3-formic acid. The method makes up the blank of the prior art about the synthesis method of the compound, has the advantages of easily available raw materials, safe process route, convenient operation process, mild and controllable reaction conditions, high product yield and avoidance of dangerous metal organic reagents and expensive palladium catalysts.

Drawings

Fig. 1: example 1 nuclear magnetic pattern of compound VIII [ (S) -Fmoc-homomorpholine-2-carboxylic acid ].

Fig. 2: example 1 chiral HPLC profile of compound VIII [ (S) -Fmoc-homomorpholine-2-carboxylic acid ].

Detailed Description

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the examples provided below are merely to further illustrate the invention and are not intended to limit the scope of the invention in any way.

The starting materials may be obtained commercially, or prepared by methods known in the art, or prepared according to the methods described herein.

Example 1

(1): 108.5 g (0.5 mol) of diethyl N-acetamido malonate and 500mL of absolute ethyl alcohol are sequentially added into a 2L three-necked flask, sodium ethoxide-ethanol solution (20% by weight, 200g, 0.59 mol) is added after stirring and dissolving, and stirring reaction is carried out for 0.5 hour at the temperature of 30-35 ℃. Benzyloxy ethyl oxyethyl bromide (129.5 g, 0.5 mol) and sodium iodide (3 g) were added, and the reaction solution was stirred and heated under reflux for 16 hours. After cooling, a solution of 30g (0.75 mol) sodium hydroxide and 200mL water was added and the heating reflux was continued for 16 hours. After cooling, the organic solvent was removed by concentrating under reduced pressure, and after cooling the remaining aqueous phase, the aqueous phase was washed twice with ethyl acetate/petroleum ether mixed solvent (1:3, volume ratio, 200 mL). The aqueous phase was acidified to ph=2 with dilute hydrochloric acid (1N), stirred, solid precipitated, filtered and dried to give compound I [ 2-acetamido-4- (2-benzyloxy ethoxy) butanoic acid ], 126.8g, 86% yield.

(2): the compound I [ 2-acetamido-4- (2-benzyloxy-ethoxy) butyric acid, 125.0 g, 0.42 mol) is suspended in 1.2L deionized water, the pH is adjusted to 7.5-8 with 1N sodium hydroxide aqueous solution, and heated to 36-38 ℃.4g of L-acetamido transferase is added, and the reaction is carried out for 20 hours with stirring at a temperature of 36-38 ℃. Then 1g L-acetamido transferase is added, and the temperature (36-38 ℃) is kept, and the stirring reaction is carried out for 20 hours. And (3) regulating the pH value to be 6-6.5 by using 1N dilute hydrochloric acid, filtering, and drying to obtain the compound II [ (S) -2 amino-4- (2-benzyloxy ethoxy) butyric acid ], wherein the yield is 42.5 g and 40%. The filtrate was further acidified to ph=3 with 1N diluted hydrochloric acid, stirred, filtered and dried to give compound III [ (R) -2-acetamido-4- (2-benzyloxy ethoxy) butanoic acid ], 53.1g, yield 42.5%.

(3): compound II [ (S) -2 amino-4- (2-benzyloxy ethoxy) butyric acid ],40.0 g,0.158 mol), acetone (160 mL) and water (160 mL) were added to a2 liter three-necked flask, stirred, pH was adjusted to 7.5-8 with 1N aqueous sodium hydroxide solution, di-tert-butyl dicarbonate (38.0 g, 0.18 mol) was added, stirred for 5 hours, and 1N aqueous sodium hydroxide solution was slowly added dropwise to maintain pH at 7.5-8. The reaction mixture was diluted with water (200. 200 mL), and washed twice with a mixed solvent of ethyl acetate and petroleum ether (1:3, volume ratio, 200. 200 mL). The aqueous phase was acidified to ph=3 with dilute hydrochloric acid (1N), extracted three times with ethyl acetate (200 mL each time), the organic phases were combined, washed once with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated to dryness. The concentrate was dissolved in acetonitrile (300 mL), methyl iodide (33.6 g,0.237 mol) and anhydrous sodium carbonate (21.8 g,0.158 mol) were added, and the mixture was stirred and heated to 50 to 60℃for reaction for 6 hours. After cooling, filtering and concentrating to obtain 60.0g of compound IV [ (S) -2-Boc-amino-4- (2-benzyloxy ethoxy) butyric acid methyl ester ], the yield is 100%, and the crude product is directly subjected to the next reaction without further purification.

(4): in a 1 liter single flask were added IV [ (S) -2-Boc-amino-4- (2-benzyloxy-ethoxy) butanoic acid methyl ester, 60.0g, 0.158 mol) and methanol (300 mL), after nitrogen substitution palladium on charcoal (10%, 5 g) was added, after nitrogen substitution, hydrogen was introduced and the reaction was stirred for 3 hours. The palladium on charcoal was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The concentrate was dissolved in methylene chloride (300 mL), cooled to 0℃and triethylamine (24.0. 24.0 g,0.237 mol) was added thereto, followed by stirring, p-toluenesulfonyl chloride (30.0 g,0.158 mol) was further added thereto, and the reaction mixture was stirred at 0℃for 4 hours. The reaction solution was washed twice with water, a saturated aqueous potassium thiosulfate solution and a saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, and concentrated to dryness. The concentrate was dissolved in acetone (200 mL), and sodium iodide (35.5 g,0.237 mol) was added thereto, followed by heating and refluxing for 3 hours. Solid is separated out in the reaction process. After cooling, filtration and concentration of the filtrate to dryness, compound V [ (S) -2-Boc-amino-4- (2-benzyloxy ethoxy) butanoic acid methyl ester ],46.5, g, yield 76%, crude product, were obtained for the next reaction without further purification.

(5): in a 1 liter single flask, compound V [ (S) -2-Boc-amino-4- (2-benzyloxy-ethoxy) butanoic acid methyl ester, 46.5 g, 0.12 mol), aqueous hydrochloric acid (4 mol/L, 200 mL) and dioxane (100 mL) were added, and the reaction solution was heated to 90℃and stirred for 6 hours. After cooling, concentrating under reduced pressure to dryness, washing the residue with acetone, and drying to obtain compound VI [ (S) -2-amino-4- (2-iodoethoxy) butyric acid ] hydrochloride ],27.8 g, with a yield of 75%.

(6): in a 1 liter single vial was added compound VI [ (S) -2-amino-4- (2-iodoethoxy) butanoic acid ] hydrochloride, 27.8 g, 90 mmol ], methanol (200 mL) and triethylamine (27.3 g, 0.27 mol). The reaction solution was heated under reflux for 16 hours. After cooling, concentrating under reduced pressure to dryness, the compound VII [ (S) -homomorpholine-2-carboxylic acid ] is obtained, the yield is about 50 g, the crude product contains triethylamine salt, and the crude product is directly subjected to the next reaction without further purification.

(7): in a 500mL beaker, the above compound VII [ (S) -homomorpholine-2-carboxylic acid, 50 g in 90 mmol ] and acetone (200 mL) and water (200 mL) were added, stirred, pH was adjusted to 7.5-8 with 1N aqueous sodium hydroxide solution, 9-fluorenylmethyl-N-succinimidyl carbonate (Fmoc-OSu, 28.6 g, 85 mmol) was added, stirred for 5 hours, and 1N aqueous sodium hydroxide solution was slowly added dropwise to maintain pH at 7.5-8. The reaction mixture was diluted with water (200. 200 mL), and washed twice with a mixed solvent of ethyl acetate and petroleum ether (1:3, volume ratio, 200. 200 mL). The aqueous phase was acidified to ph=3 with dilute hydrochloric acid (1N), extracted three times with ethyl acetate (200 mL each time), the organic phases were combined, washed once with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was slurried with ethyl acetate/petroleum ether mixed solvent (1:2, volume ratio, 100 mL), filtered, and dried to give compound VIII [ (S) -Fmoc-homomorpholine-2-carboxylic acid ], 18.4g, 55.5% yield (calculated from compound VII), white solid, chiral HPLC purity 99.67%. The nuclear magnetic pattern is shown in figure 1, and the chiral HPLC pattern is shown in figure 2.1H-NMR (DMSO-d 6, 400 MHz) 12.80 (bs, 1H), 7.90 (m, 2H), 7.88 (m, 2H), 7.20-7.50 (m, 4H), 4.20-4.6 (m, 4H), 3.70-3.90 (m, 2H), 3.65 (m, 1H), 2.90-3.30 (m, 3H), 2.20 (m, 1H), 1.90 (m, 1H).

Example 2:

108.5 g (0.5 mol) of diethyl N-acetamidomalonate and 500mLN, N-dimethylformamide are sequentially added into a 2L three-necked flask, the mixture is cooled to 0 ℃, potassium tert-butoxide (61.6 g, 0.55 mol) is added in batches, and the reaction solution is stirred and reacted for 0.5 hour at the temperature of 0-5 ℃. Benzyloxy ethyl oxyethyl bromide (129.5 g, 0.5 mol) and sodium iodide (3 g) were added, and the reaction solution was heated to 60-70 ℃ to react for 16 hours. After cooling, the reaction solution was diluted with 2L of water, extracted three times with ethyl acetate (500 mL each time), and the organic phases were combined, washed twice with water, saturated aqueous potassium thiosulfate solution and saturated aqueous sodium bicarbonate solution in this order, dried over anhydrous sodium sulfate, concentrated to dryness, and a solution composed of 34g (0.85 mol) of sodium hydroxide and 200mL of water was added to the concentrated solution, followed by further heating and refluxing for 16 hours. After cooling, the organic solvent was removed by concentrating under reduced pressure, and after cooling the remaining aqueous phase, the aqueous phase was washed twice with ethyl acetate/petroleum ether mixed solvent (1:3, volume ratio, 200 mL). The aqueous phase was acidified to ph=2 with dilute hydrochloric acid (1N), stirred, solid precipitated, filtered and dried to give compound I [ 2-acetamido-4- (2-benzyloxy ethoxy) butanoic acid ], 130.5g, 88% yield.

The remaining steps (2), (3), (4), (5) and (6) were combined in 18% yield as in example 1.

Example 3:

steps (1), (2), (3), (4) and (5) are the same as in example 1;

step (6): in a single vial of 250 mL was added compound VI [ (S) -2-amino-4- (2-iodoethoxy) butanoic acid ] hydrochloride, 5.0 g, 16 mmol ], methanol (50 mL) and diisopropylethylamine (6.25 g, 48 mmol). The reaction solution was heated under reflux for 16 hours. After cooling, concentrating under reduced pressure to dryness, the compound VII [ (S) -homomorpholine-2-carboxylic acid ] is obtained, the yield is about 10 g, the yield is 100%, the crude product contains diisopropylethylamine salt, and the next reaction is directly carried out without further purification.

The other steps (7) were carried out in the same manner as in example 1, and the yield was 50%.

Example 4:

steps (1), (2), (3), (4) and (5) are the same as in example 1;

step (6): in a 1mL single vial was added compound VI [ (S) -2-amino-4- (2-iodoethoxy) butanoic acid ] hydrochloride, 5.0 g, 16 mmol), methanol (50 mL) and potassium carbonate (6.6 g, 48 mmol). The reaction solution was heated under reflux for 16 hours. After cooling, concentrating under reduced pressure to dryness to obtain a compound VII [ (S) -homomorpholine-2-carboxylic acid ], wherein the yield is about 10-g, and the crude product contains inorganic salt and is directly subjected to the next reaction without further purification.

The remainder of step (7) was carried out in the same manner as in example 1, with a yield of 43%.

Claims

1. The preparation method of the chiral homomorpholine-3-carboxylic acid is characterized by comprising the following steps:

(1): condensing benzyloxy ethyl oxy ethyl bromide and 2-acetamido diethyl malonate under the action of alcohol alkali, and then directly heating, refluxing and hydrolyzing with sodium hydroxide to obtain a compound I;

(2): dissolving the compound I in deionized water, and resolving by using L-acetamido hydrolase to obtain a compound II and a compound III;

(3): the compound II is protected with di-tert-butyl dicarbonate and then is subjected to methyl esterification with methyl iodide under the condition of inorganic alkali to obtain a compound IV;

(4): the compound IV is hydrogenated and debenzylated under the catalysis of palladium-charcoal, and then reacts with sodium iodide after being esterified with tosyl chloride to obtain a compound V;

(5): deprotection of compound V with aqueous hydrochloric acid to give compound VI;

(6): dissolving the compound VI in a reaction solvent, and cyclizing under the action of alkali to obtain a compound VII;

(7): reacting the compound VII with Fmoc-OSu to obtain a compound VIII; the synthetic route is illustrated as follows:

。

2. the preparation method of chiral homomorpholine-3-carboxylic acid according to claim 1, which is characterized in that: the molar ratio of the benzyloxy ethyl oxyethyl bromide to the acetamido diethyl malonate used in the step (1) is 1:1-1:1.2; the molar ratio of the benzyloxy ethyl oxyethyl bromide to the sodium hydroxide is 1:1.5-1:2.

3. The process for preparing chiral homomorpholine-3-carboxylic acid according to claim 1, characterized in that: the alcohol base in the step (1) is sodium ethoxide or potassium tert-butoxide.

4. The process for preparing chiral homomorpholine-3-carboxylic acid according to claim 1, characterized in that: when the alcohol base is sodium ethoxide, the solvent is ethanol, and the molar ratio of the benzyloxy ethyl oxyethyl bromide to the sodium ethoxide is 1:1-1:1.3.

5. The process for preparing chiral homomorpholine-3-carboxylic acid according to claim 1, characterized in that: when the alcohol base is potassium tert-butoxide, the solvent is N, N-dimethylformamide or N, N-dimethylacetamide, and the molar ratio of the benzyloxy ethyl oxyethyl bromide to the potassium tert-butoxide is 1:1-1:1.3.

6. The process for preparing chiral homomorpholine-3-carboxylic acid according to claim 1, characterized in that: the amount of deionized water used in the step (2) is 10-15V of the amount of the compound I, the amount of the L-acetamido hydrolase is 3-6% of the weight of the compound I, the reaction temperature is 35-37 ℃, and the reaction time is 24-48 hours.

7. The process for preparing chiral homomorpholine-3-carboxylic acid according to claim 1, characterized in that: the inorganic base in the step (3) is sodium carbonate or potassium carbonate, and the molar ratio of the di-tert-butyl dicarbonate to the compound II is 1.0: 1-1.05: 1, the molar ratio of methyl iodide to compound II used was 1.1: 1-1.5: 1, the molar ratio of inorganic base to compound II used is 0.8: 1-1.2: 1.

8. the process for preparing chiral homomorpholine-3-carboxylic acid according to claim 1, characterized in that: the palladium content in the palladium-carbon used in the step (4) is 5% -10%, the dosage is 5% -10% of the weight of the compound IV, and the molar ratio of the p-toluenesulfonic acid chloride to the compound IV is 1.0: 1-1.1: 1, the molar ratio of sodium iodide to compound IV used was 1.3: 1-1.5: 1.

9. the process for preparing chiral homomorpholine-3-carboxylic acid according to claim 1, characterized in that: the concentration of the hydrochloric acid aqueous solution used in the step (5) is 3-6 mol/L, and the reaction temperature is 60-100 ℃.

10. The process for preparing chiral homomorpholine-3-carboxylic acid according to claim 1, characterized in that: the reaction solvent used in the step (6) is alcohol with the carbon number less than 5, and the alkali is organic alkali or inorganic metal hydroxide.

11. The process for preparing chiral homomorpholine-3-carboxylic acid according to claim 10, characterized in that: the organic base is one of triethylamine, diisopropylethylamine or DBU.

12. The process for preparing chiral homomorpholine-3-carboxylic acid according to claim 10, characterized in that: the inorganic metal hydroxide is one of lithium hydroxide, sodium hydroxide, potassium carbonate or cesium carbonate.

13. The process for preparing chiral homomorpholine-3-carboxylic acid according to claim 10, characterized in that: the reaction solvent is methanol, the base is triethylamine, and the molar ratio of the triethylamine to the compound VII is 3: 1-5:1, and the reaction temperature is 30-80 ℃.

14. The process for preparing chiral homomorpholine-3-carboxylic acid according to claim 1, characterized in that: the molar ratio of Fmoc-OSu to compound VII used in step (7) was 0.9: 1-0.95: 1.