Process for the preparation of chiral homopiperazine-5-carboxylic acid and its fluorenylmethoxycarbonyl derivatives

Abstract

The present application relates to a preparation method of chiral homomorpholine-5-methanoic acid and fluorenylmethoxycarbonyl derivatives thereof, and mainly solves the technical problem that there is no industrial synthesis method for chiral homomorpholine-5-methanoic acid at present. The preparation method comprises the following steps: condensing benzyloxyethyloxyethyl bromide and 2-acetylamino malonic acid diethyl ester, hydrolyzing to obtain compound I, and enzymatically separating to obtain compound II and compound III; after Boc protection and methyl ester of compound II, debenzyl, sulfonylation, iodination, obtaining protected compound V, after deprotection, ring formation under alkaline conditions to obtain compound VII, and finally Fmoc protection to obtain 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 flammable and explosive metal organic reagent, and can be mass produced.

Description

Technical Field

[0001] This invention relates to a method for preparing homomorpholine-5-carboxylic acid, specifically to a method for preparing chiral homomorpholine-5-carboxylic acid and fluorenemethyloxycarbonyl (Fmoc) derivatives. Background Technology

[0002] 1,4-oxazepane-5-carboxylic acid is a chiral amino acid containing a 7-membered heteroatom ring and is an important intermediate in organic chemical synthesis. A series of compounds containing the 1,4-oxazepane-5-carboxylic acid structure have been reported in patents US2019 / 119298 and CA2813911, showing potential applications in the treatment of mental illnesses, agricultural pesticides, and other fields.

[0003] The synthetic method of homorpholine-5-carboxylate is reported in patent US2019 / 119298, and the route is as follows:

[0004]

[0005] This route starts with 1,4-oxazolidinyl hepta-5-one, followed by benzyloxycarbonyl (Cbz) protection, phosphorylation, and palladium-catalyzed carbonyl insertion to yield benzyloxycarbonyl-protected methyl holomorpholino-5-carboxylate. Finally, palladium-carbon-catalyzed hydrogenation reduction yields racemic methyl holomorpholino-5-carboxylate. Although the route is relatively short, each step is quite unique, utilizing flammable and explosive organometallic reagents such as n-butyllithium and potassium hexamethyldisilazane (KHMDS), as well as expensive reagents like palladium catalysts and phosphorus ligands, ultimately yielding only racemic amino acids.

[0006] As a special type of chiral amino acid, it has special significance in drug research. However, there is currently a lack of industrial-scale preparation methods for chiral homorpholine-5-carboxylic acid and its fluorene methoxycarbonyl derivatives. Summary of the Invention

[0007] The purpose of this invention is to overcome the limitations of current technology, which can only synthesize racemic holomorpholine-5-carboxylic acid, and to provide a method for synthesizing chiral holomorpholine-5-carboxylic acid and its fluorene methoxycarbonyl derivatives. The technical solution of this invention is as follows: a method for preparing chiral holomorpholine-5-carboxylic acid and its fluorene methoxycarbonyl derivatives, comprising the following steps: condensation of benzyloxyethyloxyethyl bromide and diethyl 2-acetaminomalonate, hydrolysis to obtain acetyl amino acid (compound I), enzymatic separation to obtain L-amino acid (compound II) and D-acetyl amino acid (compound III), L-amino acid (compound II) after Boc protection and methyl esterification, followed by debenzylation, sulfonation, and iodination to obtain protected iodoamino acid (compound V), further deprotection followed by cyclization under alkaline conditions to obtain chiral holomorpholine-5-carboxylic acid (compound VII), and finally Fmoc protection to obtain Fmoc-(S)-holomorpholine-5-carboxylic acid (compound VIII). The entire process involves conventional reactions, requiring no sophisticated operations, no cryogenic reactions, and no expensive palladium coupling reagents or flammable and explosive organometallic reagents, enabling large-scale production. The reaction route of this invention is described below:

[0008]

[0009] The specific reaction steps are as follows:

[0010] (1): Benzyloxyethyloxyethyl bromide and diethyl 2-acetaminomalonic acid were condensed under the action of alcohol and base, and then directly hydrolyzed by heating with sodium hydroxide under reflux to obtain compound I [2-acetamino-4-(2-benzyloxyethoxy)butyric acid].

[0011] (2): Compound I [2-acetamido-4-(2-benzyloxyethoxy)butyric acid] was dissolved in deionized water, and the pH was adjusted to weakly alkaline with sodium hydroxide aqueous solution. The mixture was heated to about 37°C, and L-acetamidohydrolase was added. The reaction was carried out while maintaining the temperature and stirring. After cooling to room temperature, the mixture was acidified with dilute hydrochloric acid to pH=6, and filtered to obtain compound II [(S)-2-amino-4-(2-benzyloxyethoxy)butyric acid]. The mother liquor was further acidified with dilute hydrochloric acid to pH=2, and filtered to obtain compound III [(R)-2-acetamido-4-(2-benzyloxyethoxy)butyric acid].

[0012] (3): Compound II [(S)-2-amino-4-(2-benzyloxyethoxy)butyric acid] was amino-protected with di-tert-butyl dicarbonate, and then methylated with iodomethane under inorganic alkaline conditions to obtain compound IV [(S)-2-Boc-amino-4-(2-benzyloxyethoxy)butyric acid methyl ester].

[0013] (4): Compound IV [(S)-2-Boc-amino-4-(2-benzyloxyethoxy)butyrate methyl ester] was hydrogenated and debenzylated under palladium on carbon catalysis, esterified with p-toluenesulfonyl chloride, and then reacted with sodium iodide to obtain compound V [(S)-2-Boc-amino-4-(2-iodoethoxy)butyrate methyl ester];

[0014] (5): Compound V [(S)-2-Boc-amino-4-(2-iodoethoxy)butyrate methyl ester] was deprotected with hydrochloric acid aqueous solution to obtain compound VI [(S)-2-amino-4-(2-iodoethoxy)butyrate];

[0015] (6): Compound VI [(S)-2-amino-4-(2-iodoethoxy)butyric acid] was dissolved in the reaction solvent, and after adding alkali, it was heated under reflux to obtain compound VII [(S)-homomorpholino-5-carboxylic acid];

[0016] (7): Compound VII [(S)-homomorpholine-5-carboxylic acid] was reacted with 9-fluorenylmethyl-N-succinimide carbonate (Fmoc-OSu) to give compound VIII [(S)-Fmoc-homomorpholine-5-carboxylic acid].

[0017] In step (1), the molar ratio of benzyloxyethyloxyethyl bromide and diethyl 2-acetaminomalonate used is 1:1 to 1:1.2, preferably 1:1.05; the alcohol base is sodium ethoxide or potassium tert-butoxide. When sodium ethoxide is used, the solvent used is ethanol, and the molar ratio of benzyloxyethyloxyethyl bromide and sodium ethoxide is 1:1 to 1:1.3, preferably 1:1.2; when potassium tert-butoxide is used, the solvent used is N,N-dimethylformamide or N,N-dimethylacetamide, and the molar ratio of benzyloxyethyloxyethyl bromide and potassium tert-butoxide is 1:1 to 1:1.3, preferably 1:1.2; the molar ratio of benzyloxyethyloxyethyl bromide and sodium hydroxide is 1:1.5 to 1:2, preferably 1:1.7.

[0018] In step (2), the amount of deionized water used is (10-15V) of the amount of compound I, the amount of L-acetylaminohydrolase is 3-6% of the weight of compound I, preferably 4%, the reaction temperature is 35-37°C, and the reaction time is 24-48 hours.

[0019] The inorganic base in step (3) is sodium carbonate or potassium carbonate. The molar ratio of ditert-butyl dicarbonate to compound II is 1.0:1 to 1.05:1. The molar ratio of iodomethane to compound II is 1.1:1 to 1.5:1. The molar ratio of inorganic base to compound II is 0.8:1 to 1.2:1.

[0020] The palladium content in the palladium carbon used in step (4) is 5%~10%, and the amount used is 5%~10% of the weight of compound IV. The molar ratio of p-toluenesulfonyl chloride to compound IV is 1.0:1~1.1:1, and the molar ratio of sodium iodide to compound IV is 1.3:1~1.5:1.

[0021] The concentration of the hydrochloric acid aqueous solution used in step (5) is 3~6 mol / L, and the reaction temperature is 60~100℃, preferably 4 mol / L, 80~90℃.

[0022] The base used in step (6) is an organic base, an inorganic metal hydroxide, or other bases. The organic base is one of triethylamine, diisopropylethylamine, or DBU. The inorganic metal hydroxide is one of lithium hydroxide, sodium hydroxide, or potassium hydroxide, or other bases such as potassium carbonate or cesium carbonate. An organic base is preferred, and triethylamine is even more preferred. The molar ratio of triethylamine to compound VI is 3:1 to 5:1. The reaction solvent is an alcohol with fewer than 5 carbon atoms, preferably one of methanol, ethanol, or isopropanol, and even more preferably methanol. The reaction temperature is 30 to 80°C, preferably 60 to 70°C.

[0023] The molar ratio of 9-fluorenylmethyl-N-succinimide carbonate (Fmoc-OSu) and compound VII used in step (7) is 0.9:1 to 0.95:1.

[0024] The beneficial effects of this invention are as follows: This invention utilizes biological enzymes to synthesize linear amino acids with a single configuration, which are then cyclized to obtain chiral homorpholine-5-carboxylic acid. This fills a gap in existing technologies regarding the synthesis of such compounds. The raw materials used are readily available, the process route is safe, the operation is convenient, the reaction conditions are mild and controllable, the product yield is high, and the use of hazardous organometallic reagents and expensive palladium catalysts is avoided. Attached Figure Description

[0025] Figure 1 Example 1: NMR spectrum of compound VIII [(S)-Fmoc-homomorpholine-5-carboxylic acid].

[0026] Figure 2 Example 1: Chiral HPLC chromatogram of compound VIII [(S)-Fmoc-homomorpholine-5-carboxylic acid]. Detailed Implementation

[0027] Without further detailed explanation, it is believed that those skilled in the art can utilize the present invention to the fullest extent based on the foregoing description. Therefore, the embodiments provided below are merely illustrative of the present invention and are not intended to limit the scope of the invention in any way.

[0028] The raw materials may be obtained commercially, or prepared by methods known in the art, or prepared according to the methods described herein.

[0029] Example 1

[0030] (1): In a 2L three-necked flask, 108.5 g (0.5 mol) of diethyl 2-acetaminomalonate and 500 mL of anhydrous ethanol were added sequentially. After stirring and dissolving, sodium ethoxide-ethanol solution (20%, weight ratio, 200 g, 0.59 mol) was added, and the reaction was stirred at 30~35℃ for 0.5 hours. Benzyloxyethyloxyethyl bromide (129.5 g, 0.5 mol) and sodium iodide (3 g) were added, and the reaction mixture was stirred and refluxed for 16 hours. After cooling, a solution prepared from 30 g (0.75 mol) of sodium hydroxide and 200 mL of water was added, and the mixture was refluxed for another 16 hours. After cooling, the organic solvent was removed by concentration under reduced pressure. The remaining aqueous phase was cooled and washed twice with a mixture of ethyl acetate / petroleum ether (1:3, volume ratio, 200 mL). The aqueous phase was acidified to pH=2 with dilute hydrochloric acid (1N), stirred, and a solid precipitated. The solid was filtered and dried to give compound I [2-acetamido-4-(2-benzyloxyethoxy)butyric acid], 126.8 g, yield 86%.

[0031] (2): Compound I [2-acetamido-4-(2-benzyloxyethoxy)butyric acid, 125.0 g, 0.42 mol] was suspended in 1.2 L of deionized water, and the pH was adjusted to 7.5-8 with 1N sodium hydroxide aqueous solution. The mixture was heated to 36-38℃. 4 g of L-acetamidohydrolase was added, and the mixture was stirred and reacted for 20 hours while maintaining the temperature (36-38℃). Another 1 g of L-acetamidohydrolase was added, and the mixture was stirred and reacted for 20 hours while maintaining the temperature (36-38℃). The pH was adjusted to 6-6.5 with 1N dilute hydrochloric acid, filtered, and dried to obtain compound II [(S)-2-amino-4-(2-benzyloxyethoxy)butyric acid], 42.5 g, yield 40%. The above filtrate was further acidified with 1N dilute hydrochloric acid to pH=3, stirred, filtered, and dried to obtain compound III [(R)-2-acetamido-4-(2-benzyloxyethoxy)butyric acid], 53.1 g, yield 42.5%.

[0032] (3): Compound II ([(S)-2-amino-4-(2-benzyloxyethoxy)butyric acid], 40.0 g, 0.158 mol), acetone (160 mL), and water (160 mL) were added to a 2-liter three-necked flask. The mixture was stirred, and the pH was adjusted to 7.5-8 with 1N sodium hydroxide aqueous solution. Di-tert-butyl dicarbonate (38.0 g, 0.18 mol) was added, and the mixture was stirred for 5 hours. 1N sodium hydroxide aqueous solution was slowly added dropwise to maintain the pH at 7.5-8. The reaction solution was diluted with water (200 mL) and washed twice with a mixture of ethyl acetate / petroleum ether (1:3, volume ratio, 200 mL). The aqueous phase was acidified with dilute hydrochloric acid (1N) to pH=3, extracted three times with ethyl acetate (200 mL each time), and the organic phases were combined. The mixture was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The concentrated solution was dissolved in acetonitrile (300 mL), and iodomethane (33.6 g, 0.237 mol) and anhydrous sodium carbonate (21.8 g, 0.158 mol) were added. The mixture was stirred and heated to 50–60 °C for 6 hours. After cooling, the mixture was filtered and concentrated to give compound IV [(S)-2-Boc-amino-4-(2-benzyloxyethoxy)butyrate methyl ester] 60.0 g, yield ~100%. This crude product was directly used in the next reaction without further purification.

[0033] (4): In a 1-liter single-necked flask, IV ([(S)-2-Boc-amino-4-(2-benzyloxyethoxy)butyrate methyl ester], 60.0 g, 0.158 mol) and methanol (300 mL) were added. After purging with nitrogen, palladium on carbon (10%, 5 g) was added, followed by another nitrogen purging. Hydrogen was then introduced, and the mixture was stirred for 3 hours. The palladium on carbon was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The concentrate was dissolved in dichloromethane (300 mL), cooled to 0 °C, and triethylamine (24.0 g, 0.237 mol) was added. The mixture was stirred, and then p-toluenesulfonyl chloride (30.0 g, 0.158 mol) was added. The reaction mixture was stirred at 0 °C for 4 hours. The reaction mixture was washed twice with water, saturated potassium thioate aqueous solution, and saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated to dryness. The concentrated solution was dissolved in acetone (200 mL), and sodium iodide (35.5 g, 0.237 mol) was added. The mixture was heated under reflux for 3 hours. A solid precipitated during the reaction. After cooling, the mixture was filtered, and the filtrate was concentrated to dryness to give compound V [(S)-2-Boc-amino-4-(2-iodoethoxy)butyrate methyl ester], 46.5 g, yield 76%, crude product, which was directly proceeded to the next step without further purification.

[0034] (5): Compound V ([(S)-2-Boc-amino-4-(2-iodoethoxy)butyrate methyl ester], 46.5 g, 0.12 mol), hydrochloric acid aqueous solution (4 mol / L, 200 mL), and dioxane (100 mL) were added to a 1-liter single-necked flask. The reaction solution was heated to 90 °C and stirred for 6 hours. After cooling, the mixture was concentrated to dryness under reduced pressure. The residue was washed with acetone and dried to give compound VI [(S)-2-amino-4-(2-iodoethoxy)butyrate] hydrochloride, 27.8 g, yield 75%.

[0035] (6): Compound VI [(S)-2-amino-4-(2-iodoethoxy)butyrate salt, 27.8 g, 90 mmol], methanol (200 mL), and triethylamine (27.3 g, 0.27 mol) were added to a 1-liter single-necked flask. The reaction mixture was heated under reflux for 16 hours. After cooling, the mixture was concentrated to dryness under reduced pressure to give compound VII [(S)-homomorpholino-5-carboxylic acid], about 50 g, with a yield of ~100%. The crude product contained triethylamine salt and was not further purified before proceeding to the next step.

[0036] (7): In a 500 mL beaker, add the above compound VII [(S)-homomorpholine-5-carboxylic acid, 50 g, based on 90 mmol], acetone (200 mL), and water (200 mL), stir, adjust the pH to 7.5-8 with 1N sodium hydroxide aqueous solution, add 9-fluorenylmethyl-N-succinimide carbonate (Fmoc-OSu, 28.6 g, 85 mmol), stir for 5 hours, and slowly add 1N sodium hydroxide aqueous solution dropwise to maintain the pH at 7.5-8. After diluting the reaction solution with water (200 mL), wash twice with a mixed solvent of ethyl acetate / petroleum ether (1:3, volume ratio, 200 mL). Acidify the aqueous phase with dilute hydrochloric acid (1N) to pH=3, extract three times with ethyl acetate (200 mL each time), combine the organic phases, wash once with water and once with saturated brine, dry with anhydrous sodium sulfate, and concentrate to dryness. The residue was slurried in a 1:2 volumetric ethyl acetate / petroleum ether mixture (1:2), filtered, and dried to give compound VIII [(S)-Fmoc-homomorpholine-5-carboxylic acid], 18.4 g, yield 55.5% (calculated from compound VII), white solid, with a chiral HPLC purity of 99.67%. NMR spectrum is shown below. Figure 1 The chiral HPLC chromatogram is shown below. Figure 2. 1H-NMR (DMSO-d6, 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).

[0037] Example 2:

[0038] Step (1) In a 2L three-necked flask, add 108.5 g (0.5 mol) of diethyl 2-acetaminomalonate and 500 mL of N,N-dimethylformamide sequentially. Cool to 0°C, and add potassium tert-butoxide (61.6 g, 0.55 mol) in portions. Maintain the reaction solution at 0-5°C and stir for 0.5 hours. Add benzyloxyethyloxyethyl bromide (129.5 g, 0.5 mol) and sodium iodide (3 g). Heat the reaction solution to 60-70°C and react for 16 hours. After cooling, dilute the reaction solution with 2L of water, extract three times with ethyl acetate (500 mL each time), combine the organic phases, wash twice sequentially with water, saturated potassium thioate aqueous solution, and saturated sodium bicarbonate aqueous solution, dry with anhydrous sodium sulfate, concentrate to dryness, add a solution of 34 g (0.85 mol) sodium hydroxide and 200 mL of water to the concentrate, and continue heating under reflux for 16 hours. After cooling, the organic solvent was removed by concentration under reduced pressure. The remaining aqueous phase was cooled and washed twice with a mixture of ethyl acetate and petroleum ether (1:3, volume ratio, 200 mL). The aqueous phase was acidified to pH 2 with dilute hydrochloric acid (1N), stirred, and a solid precipitated. The solid was filtered and dried to give compound I [2-acetamido-4-(2-benzyloxyethoxy)butyric acid], 130.5 g, yield 88%.

[0039] The remaining steps (2), (3), (4), (5) and (6) are the same as in Example 1, with a combined yield of 18%.

[0040] Example 3:

[0041] Steps (1), (2), (3), (4) and (5) are the same as in Example 1;

[0042] Step (6): Compound VI [(S)-2-amino-4-(2-iodoethoxy)butyrate salt, 5.0 g, 16 mmol], methanol (50 mL), and diisopropylethylamine (6.25 g, 48 mmol) were added to a 250 mL single-necked flask. The reaction mixture was heated under reflux for 16 hours. After cooling, the mixture was concentrated to dryness under reduced pressure to obtain compound VII [(S)-homomorpholino-5-carboxylic acid], approximately 10 g, with a yield of ~100%. The crude product contained diisopropylethylamine salt and was not further purified before proceeding to the next step.

[0043] The remaining steps (7) are the same as in Example 1, with a yield of 50%.

[0044] Example 4:

[0045] Steps (1), (2), (3), (4) and (5) are the same as in Example 1;

[0046] Step (6): Compound VI [(S)-2-amino-4-(2-iodoethoxy)butyrate, 5.0 g, 16 mmol], methanol (50 mL), and potassium carbonate (6.6 g, 48 mmol) were added to a 1 mL single-necked flask. The reaction mixture was heated under reflux for 16 hours. After cooling, the mixture was concentrated to dryness under reduced pressure to obtain compound VII [(S)-homomorpholino-5-carboxylic acid], approximately 10 g, with a yield of ~100%. The crude product contained inorganic salts and was not further purified before proceeding to the next step.

[0047] The remaining steps (7) are the same as in Example 1, with a yield of 43%.

Claims

1. A method for preparing chiral homomorpholine-5-carboxylic acid and its fluorene methoxycarbonyl derivatives, characterized in that, Includes the following steps: (1): Compound I was obtained by condensing benzyloxyethyloxyethyl bromide and diethyl 2-acetaminomalonic acid under the action of alcohol and base and then directly hydrolyzing it under reflux with sodium hydroxide. (2): Compound I was dissolved in deionized water and resolved by L-acetylaminohydrolase to obtain compounds II and III; (3): Compound II was protected with di-tert-butyl dicarbonate and then methylated with iodomethane under inorganic base conditions to obtain compound IV; (4): Compound IV was hydrogenated and debenzylated under palladium on carbon catalysis, then esterified with p-toluenesulfonyl chloride and reacted with sodium iodide to give compound V; (5): Compound V was deprotected with aqueous hydrochloric acid to give compound VI; (6): Compound VI dissolves in the reaction solvent and cyclizes under the action of a base to give compound VII; (7): Compound VII reacts with Fmoc-OSu to give compound VIII; the synthetic route is shown below:

2. The method for preparing chiral homorpholine-5-carboxylic acid and its fluorenemethoxycarbonyl derivatives according to claim 1, characterized in that: In step (1), the molar ratio of benzyloxyethyloxyethyl bromide and diethyl 2-acetaminomalonic acid used is 1:1 to 1:1.2; the molar ratio of benzyloxyethyloxyethyl bromide and sodium hydroxide is 1:1.5 to 1:

2.

3. The method for preparing chiral homorpholine-5-carboxylic acid and its fluorenemethoxycarbonyl derivatives according to claim 1, characterized in that: Step (1) The alcohol base is sodium ethoxide or potassium tert-butoxide.

4. The method for preparing chiral homorpholine-5-carboxylic acid and its fluorenemethoxycarbonyl derivatives according to claim 1, characterized in that: When the alcohol base is sodium ethoxide, the solvent used is ethanol, and the molar ratio of benzyloxyethyloxyethyl bromide to sodium ethoxide is 1:1 to 1:1.

3.

5. The method for preparing chiral homorpholine-5-carboxylic acid and its fluorenemethoxycarbonyl derivatives according to claim 1, characterized in that: When the alcohol base is potassium tert-butoxide, the solvent used is N,N-dimethylformamide or N,N-dimethylacetamide, and the molar ratio of benzyloxyethyloxyethyl bromide and potassium tert-butoxide is 1:1 to 1:1.

3.

6. The method for preparing chiral homorpholine-5-carboxylic acid and its fluorene methoxycarbonyl derivatives according to claim 1, characterized in that: In step (2), the amount of deionized water used is 10V~15V of the amount of compound I, the amount of L-acetylaminohydrolase is 3~6% of the weight of compound I, the reaction temperature is 35~37℃, and the reaction time is 24~48 hours.

7. The method for preparing chiral homorpholine-5-carboxylic acid and its fluorenemethoxycarbonyl derivatives according to claim 1, characterized in that: The inorganic base in step (3) is sodium carbonate or potassium carbonate. The molar ratio of ditert-butyl dicarbonate to compound II is 1.0:1 to 1.05:

1. The molar ratio of iodomethane to compound II is 1.1:1 to 1.5:

1. The molar ratio of inorganic base to compound II is 0.8:1 to 1.2:

1.

8. The method for preparing chiral homorpholine-5-carboxylic acid and its fluorenemethoxycarbonyl derivatives according to claim 1, characterized in that: The palladium content in the palladium carbon used in step (4) is 5%~10%, the amount used is 5%~10% of the weight of compound IV, the molar ratio of p-toluenesulfonyl chloride to compound IV is 1.0:1~1.1:1, and the molar ratio of sodium iodide to compound IV is 1.3:1~1.5:

1.

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

10. The method for preparing chiral homorpholine-5-carboxylic acid and its fluorenemethoxycarbonyl derivatives according to claim 1, characterized in that: The reaction solvent used in step (6) is an alcohol with less than 5 carbon atoms, and the base is an organic base or an inorganic metal hydroxide.

11. The method for preparing chiral homorpholine-5-carboxylic acid and its fluorene methoxycarbonyl derivatives according to claim 10, characterized in that: The organic base is one of triethylamine, diisopropylethylamine, or DBU.

12. The method for preparing chiral homorpholine-5-carboxylic acid and its fluorenemethoxycarbonyl derivatives according to claim 10, characterized in that: Inorganic metal hydroxides include lithium hydroxide, sodium hydroxide, and potassium hydroxide.

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

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