Preparation method of (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo [2.2. 1] heptane-5-carboxylic acid tert-butyl ester

Abstract

The invention discloses a preparation method of (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo [2.2. 1] heptane-5-carboxylic acid tert-butyl ester, and belongs to the technical field of synthesis of pharmaceutical and chemical intermediates, a reaction formula is shown as follows: # imgabs0 # compound shown in a formula (I) is subjected to Witting reaction under the action of alkali to obtain a compound shown in a formula (II); performing ester group reduction on the compound shown in the formula (II) to obtain a compound shown in a formula (III); cyclizing and iodinating the compound shown in the formula (III) to obtain a compound shown in a formula (IV); reacting the compound as shown in the formula (IV) with a self-made p-nitrobenzoic acid potassium salt as shown in a formula (V) to obtain a compound as shown in a formula (VI); and hydrolyzing the compound as shown in the formula (VI) to obtain a compound as shown in a formula (VII). The method adopted by the invention is high in yield, short in route and easy to operate, and can be used for amplification.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical intermediate synthesis, and in particular to a method for preparing (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester. Background Art

[0002] Tert-butyl (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate and related derivatives are widely used in pharmaceutical chemistry and organic synthesis and are an important class of chemical and pharmaceutical intermediates. For example, 2-oxa-5-aza compounds and their derivatives are used as raw materials to synthesize inhibitors of protein kinases including JAK kinases, which are used to inhibit Aurora kinases. Kinase inhibitors can be used to treat kinase-related diseases such as immunological diseases and inflammatory diseases including organ transplantation; hyperproliferative diseases including cancer and myeloproliferative diseases, viral diseases, metabolic diseases and vascular diseases. Therefore, a method for preparing tert-butyl (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate with a simple route, convenient operation, high yield and high purity is of great significance.

[0003] According to the document CN 105503891 A7, L-hydroxyproline is used as a raw material, and 5-tert-butyloxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid is obtained through Boc addition, oxidation, reduction, cyclization, and reduction. However, the route is complicated and the yield is low.

[0004] According to the reports in documents CN 104211692 A and CN 104583216 A, L-hydroxyproline is used as a raw material, esterified, Boc or Cbz is added, tert-butyldimethylsilyl trifluoromethanesulfonate is used to protect the hydroxyl group, reduced, TsCl is used to protect the hydroxyl group, and the ring is closed to obtain a 2-oxa-5-aza compound. However, the route is complicated and the yield is low, which limits the development of the industry.

[0005] Based on the above research status, how to provide a high-yield and high-purity (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester to solve the above-mentioned problems of low yield and complicated routes has become a technical problem that the present invention urgently needs to solve. Summary of the invention

[0006] The purpose of the present invention is to provide a method for preparing (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester, which mainly solves the technical problem that there is no suitable industrial synthesis method at present, and has the advantages of high yield, short route and convenience for industrial scale-up production.

[0007] The present invention provides a method for preparing (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester, and the technical scheme adopted is as follows:

[0008] A method for preparing (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester, the reaction formula is as follows:

[0009]

[0010] The following steps are involved:

[0011] 1) dissolving trityl phosphonium bromide in THF, slowly adding potassium tert-butoxide at 0°C, raising the temperature to 25°C and stirring for 1h, then cooling again, dropping the compound of formula (I) dissolved in THF at 0°C, slowly raising the temperature to room temperature and stirring for 3h after dropping; LC detection shows that the reaction is complete, after the reaction is completed, quenching the reaction with saturated NH4Cl solution, extracting with EA, drying with anhydrous sodium sulfate, spin drying, column chromatography, and obtaining the compound of formula (II); wherein, the column chromatography is selected to fill a chromatographic column with 100-200 mesh silica gel, dry loading, washing the silica gel column with a mixed solvent of PE / EA: 3 / 1, and concentrating the solvent to obtain the compound of formula (II);

[0012] 2) dissolving the compound represented by formula (II) in a mixed solution of EtOH and THF, then cooling to 0°C, slowly adding NaBH4 in sequence, controlling the temperature of the reaction system to 0-5°C and stirring for 0.5h, then warming to room temperature and stirring for 3 hours; TLC detection shows that the reaction is complete, quenching the reaction with dilute hydrochloric acid, extracting with EA, drying with anhydrous sodium sulfate, spin drying, and column chromatography to obtain the compound represented by formula (III); wherein, the column chromatography is selected to be filled with 100-200 mesh silica gel, dry loading, washing the silica gel column with a mixed solvent of PE / EA: 5 / 1, and concentrating the solvent to obtain the compound represented by formula (III);

[0013] 3) dissolving the compound represented by formula (III) in DMF, adding alkali in batches, then lowering the system temperature to 0°C, adding solid iodine in batches, slowly warming to room temperature and stirring for 12 hours after the addition is complete; after TLC detection, quenching with sodium bisulfite solution, extracting with EA, drying with anhydrous sodium sulfate, spin drying, column chromatography, and obtaining the compound represented by formula (IV); wherein, the column chromatography is selected to be filled with 100-200 mesh silica gel column, dry loading, washing the silica gel column with a mixed solvent of PE / EA: 2 / 1, and concentrating the solvent to obtain the compound represented by formula (IV);

[0014] 4) dissolving the compound represented by formula (IV) in THF, and then sequentially adding the compound represented by formula (V) and 18-crown ether-6; heating to 90° C. and stirring for 2 h; after TLC detection of the reaction being complete, cooling to room temperature, extracting with EA, drying with anhydrous sodium sulfate, spin drying, and column chromatography to obtain the compound represented by formula (VI); wherein, the column chromatography is selected to be filled with 100-200 mesh silica gel, dry loading, washing the silica gel column with a mixed solvent of PE / EA: 10 / 1, and concentrating the solvent to obtain the compound represented by formula (VI);

[0015] 5) dissolving the compound represented by formula (VI) in methanol, slowly adding alkali, stirring at room temperature for 3 hours; TLC detection, after TLC detection, EA extraction, drying over anhydrous sodium sulfate, spin drying, column chromatography, to obtain the compound represented by formula (VII). Wherein, the column chromatography is selected to be filled with 100-200 mesh silica gel, dry loading, washing the silica gel column with a mixed solvent of PE / EA: 3 / 1, and the solvent is concentrated to obtain the compound represented by formula (VII).

[0016] Wherein, in step 1), the molar ratio of trityl phosphonium bromide to the compound represented by formula (I) is (1.1-1.5):1; the molar ratio of potassium tert-butoxide to the compound represented by formula (I) is (1.1-1.5):1.

[0017] Wherein, in step 2), the volume ratio of EtOH and THF in the mixed solution is (1-10):1; the molar ratio of NaBH4 to the compound represented by formula (II) is (1.5-3):1.

[0018] Wherein, in step 3), the molar ratio of iodine to the compound represented by formula (III) is (1.5-3):1; the base is sodium carbonate or potassium carbonate, and the molar ratio of the added base to the compound represented by formula (III) is (2-3):1.

[0019] Wherein, in step 4), the molar ratio of the compound represented by formula (V) to the compound represented by formula (IV) is (1.2-2):1; the molar ratio of the 18-crown ether-6 to the compound represented by formula (IV) is (0.01-0.05):1.

[0020] Wherein, in step 5), the base is one of sodium hydroxide and sodium carbonate, and the molar ratio of the added amount of the base to the compound represented by formula (III) is (1.5-3):1.

[0021] Wherein, the trans form of the compound represented by formula (V) is prepared as follows:

[0022]

[0023] The preparation of the compound represented by formula (V) comprises the following steps: dissolving the compound represented by formula (VIII) in ethanol, lowering the temperature to 0°C, slowly adding solid potassium tert-butoxide, and stirring for 3 hours; after TLC detection shows that the reaction is complete, filtering the reaction solution, washing the solid with ethanol and tert-methyl ether, and drying to obtain the compound represented by formula (V).

[0024] Wherein, the molar ratio of the potassium tert-butoxide to the compound represented by formula (III) is (1.1-1.5):1.

[0025] The present invention provides a method for preparing tert-butyl 1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate, which has the following beneficial technical effects compared with the prior art:

[0026] 1. The compound represented by formula (I) of the present invention undergoes Witting reaction under the action of a base to obtain a compound represented by formula (II); the compound represented by formula (II) is reduced by ester group to obtain a compound represented by formula (III); the compound represented by formula (III) is cyclized and iodinated to obtain a compound represented by formula (IV); the compound represented by formula (IV) reacts with a self-made potassium salt of p-nitrobenzoic acid of a compound represented by formula (V) to obtain a compound represented by formula (VI); the compound represented by formula (VI) is hydrolyzed to obtain a compound represented by formula (VII). Wherein, the compound represented by formula (V) is obtained by neutralizing the compound represented by (VIII) with potassium tert-butoxide.

[0027] 2. The present invention uses the compound represented by formula (I) and the compound represented by formula (VIII) and other reagents as raw materials, which are cheap and easy to obtain and have low production cost.

[0028] 3. The synthesis route of the present invention is short, the operation is simple and reliable, the yield is high, and it is easy to scale up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The compound represented by formula (II) 1 HNMR spectrum;

[0030] Figure 2 is the 1HNMR spectrum of the compound represented by formula (III);

[0031] Figure 3 is the 1HNMR spectrum of the compound represented by formula (IV);

[0032] Figure 4 is the 1HNMR spectrum of the compound represented by formula (V);

[0033] Figure 5 The compound represented by formula (VII) 1 HNMR spectrum. DETAILED DESCRIPTION

[0034] The following embodiments are provided for a better understanding of the present invention, but are not limited to the best mode of implementation, and do not limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0035] Example 1: Synthesis of the compound represented by formula (V)

[0036] 200 g of the compound represented by formula (VIII) was dissolved in 2 L of methanol, and 186.8 g of potassium tert-butoxide was slowly added at 0°C and stirred for 3 h. After the reaction was completed as detected by TLC, the reaction solution was filtered, and the solid was washed with ethanol and tert-methyl ether and dried to obtain 232.9 g of the compound represented by formula (V), with a yield of 95%. Figure 4 1HNMR spectrum of the compound represented by formula (V);

[0037] Example 2

[0038] This embodiment provides a method for preparing (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester, comprising the following steps:

[0039] (1) Synthesis of the compound represented by formula (II):

[0040] Dissolve 155g of tritylphosphonium bromide in 1L of THF, slowly add 39.6g of potassium tert-butoxide at 0°C, heat to 25°C and stir for 1h after addition, then cool again, drop 100g of the compound of formula (I) dissolved in 500mL of THF at 0°C, slowly heat to room temperature and stir for 3h after addition, and detect the reaction is complete by LC. After the reaction is completed, quench the reaction with saturated NH4Cl solution, extract with EA, dry over anhydrous sodium sulfate, spin dry, and column chromatography to obtain 68.4g of the compound of formula (II), with a yield of 73%. Figure 1 The compound represented by formula (II) 1 HNMR spectrum.

[0041] (2) Synthesis of the compound represented by formula (III)

[0042] 68.4 g of the compound represented by formula (II) was dissolved in a mixed solution of 342 mL of MeOH and 342 mL of THF, and then 17 g of NaBH4 was slowly added at 0°C, the temperature of the reaction system was controlled at 0-5°C and stirred for 0.5 h, then the temperature was raised to room temperature and stirred for 3 h. The reaction was detected to be complete by TLC. The reaction was quenched with dilute hydrochloric acid, extracted with EA, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 54.5 g of the compound represented by formula (III), with a yield of 90%. Figure 2It is the 1HNMR spectrum of the compound represented by formula (III).

[0043] (3) Synthesis of the compound represented by formula (IV)

[0044] 54.5 g of the compound represented by formula (III) was dissolved in 544 mL of DCM, and 90.3 g of sodium carbonate was added in batches. Then the system temperature was lowered to 0°C, and 103.6 g of solid iodine was added in batches. After the addition was complete, the temperature was slowly raised to room temperature and stirred for 12 hours. After TLC detection, the reaction was completed, quenched with sodium bisulfite solution, extracted with EA, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 83.3 g of the compound represented by formula (IV), with a yield of 99%. Figure 3 It is the 1HNMR spectrum of the compound represented by formula (IV).

[0045] (4) Synthesis of the compound represented by formula (VI)

[0046] 83.3g of the compound represented by formula (IV) was dissolved in 857mL THF, and then 88.9g of the compound represented by formula (V) and 2.14g of 18-crown ether-6 were added in sequence; the temperature was raised to 90°C and stirred for 2h. After TLC detection of the reaction was complete, the temperature was lowered to room temperature, extracted with EA, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 89.9g of the compound represented by formula (VI), with a yield of 95%.

[0047] (5) Synthesis of the compound represented by formula (VII)

[0048] 89.9 g of the compound represented by formula (VI) was dissolved in methanol, and 30.8 g of sodium hydroxide was slowly added, and stirred at room temperature for 3 hours. After TLC detection, the reaction was complete, and EA was extracted, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 53.5 g of the compound represented by formula (VII), with a yield of 91%. Figure 5 The compound represented by formula (VII) 1 HNMR spectrum.

[0049] Example 3

[0050] This embodiment provides a method for preparing (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester, comprising the following steps:

[0051] (1) Synthesis of the compound represented by formula (II):

[0052] 165.88g of tritylphosphonium bromide was dissolved in 1L of THF, and 41.93g of potassium tert-butoxide was slowly added at 0°C. After the addition, the temperature was raised to 25°C and stirred for 1h, then the temperature was lowered again, and 100g of the compound represented by formula (I) dissolved in 500mL of THF was added dropwise at 0°C. After the addition, the temperature was slowly raised to room temperature and stirred for 3h. The reaction was detected to be complete by LC. After the reaction was completed, the reaction was quenched with a saturated NH4Cl solution, extracted with EA, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 72.4g of the compound represented by formula (II), with a yield of 77%.

[0053] (2) Synthesis of the compound represented by formula (III)

[0054] 72.4 g of the compound represented by formula (II) was dissolved in a mixed solution of 72 mL of MeOH and 724 mL of THF, and then 18.01 g of NaBH4 was slowly added in sequence at 0°C. The temperature of the reaction system was controlled at 0-5°C and stirred for 0.5 h, and then the temperature was raised to room temperature and stirred for 3 h. The reaction was detected to be complete by TLC. The reaction was quenched with dilute hydrochloric acid, extracted with EA, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 58.9 g of the compound represented by formula (III), with a yield of 92%.

[0055] (3) Synthesis of the compound represented by formula (IV)

[0056] 58.9 g of the compound represented by formula (III) was dissolved in 589 mL of DCM, and 121.9 g of potassium carbonate was added in batches. Then the system temperature was lowered to 0°C, and 223.9 g of solid iodine was added in batches. After the addition was complete, the temperature was slowly raised to room temperature and stirred for 12 hours. After TLC detection, the reaction was completed, quenched with sodium bisulfite solution, extracted with EA, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 89.2 g of the compound represented by formula (IV) with a yield of 98%.

[0057] (4) Synthesis of the compound represented by formula (VI)

[0058] 91.8 g of the compound represented by formula (IV) was dissolved in 918 mL of THF, and then 73.5 g of the compound represented by formula (V) and 0.78 g of 18-crown ether-6 were added in sequence; the temperature was raised to 90° C. and stirred for 2 h. After TLC detection of the reaction was complete, the temperature was lowered to room temperature, extracted with EA, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 102.5 g of the compound represented by formula (VI), with a yield of 98.5%.

[0059] (5) Synthesis of the compound represented by formula (VII)

[0060] 102.5 g of the compound represented by formula (VI) was dissolved in methanol, and 46.5 g of sodium carbonate was slowly added, and stirred at room temperature for 3 hours. After TLC detection, the reaction was complete, and EA was extracted, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 59.0 g of the compound represented by formula (VII), with a yield of 88%.

[0061] Example 4

[0062] This embodiment provides a method for preparing (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester, comprising the following steps:

[0063] (1) Synthesis of the compound represented by formula (II):

[0064] 121.05g of tritylphosphonium bromide was dissolved in 1L of THF, and 30.75g of potassium tert-butoxide was slowly added at 0°C. After the addition, the temperature was raised to 25°C and stirred for 1h, then the temperature was lowered again, and 100g of the compound represented by formula (I) dissolved in 500mL of THF was added dropwise at 0°C. After the addition, the temperature was slowly raised to room temperature and stirred for 3h. The reaction was detected to be complete by LC. After the reaction was completed, the reaction was quenched with saturated NH4Cl solution, extracted with EA, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 67.4g of the compound represented by formula (II), with a yield of 72%.

[0065] (2) Synthesis of the compound represented by formula (III)

[0066] 67.4 g of the compound represented by formula (II) was dissolved in a mixed solution of 67 mL of MeOH and 335 mL of THF, and then 22.4 g of NaBH4 was slowly added in sequence at 0°C. The temperature of the reaction system was controlled at 0-5°C and stirred for 0.5 h, and then the temperature was raised to room temperature and stirred for 3 h. The reaction was completed by TLC detection. The reaction was quenched with dilute hydrochloric acid, extracted with EA, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 57.6 g of the compound represented by formula (III), with a yield of 94%.

[0067] (3) Synthesis of the compound represented by formula (IV)

[0068] 57.6 g of the compound represented by formula (III) was dissolved in 589 mL of DCM, and 59.4 g of potassium carbonate was added in batches. Then the system temperature was lowered to 0°C, and 138.7 g of solid iodine was added in batches. After the addition was complete, the temperature was slowly raised to room temperature and stirred for 12 hours. After TLC detection, the reaction was completed, quenched with sodium bisulfite solution, extracted with EA, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 87.2 g of the compound represented by formula (IV), with a yield of 98%.

[0069] (4) Synthesis of the compound represented by formula (VI)

[0070] 87.2g of the compound represented by formula (IV) was dissolved in 918mL THF, and then 116.3g of the compound represented by formula (V) and 3.73g of 18-crown ether-6 were added in sequence; the temperature was raised to 90°C and stirred for 2h. After TLC detection of the reaction was complete, the temperature was lowered to room temperature, extracted with EA, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 97.1g of the compound represented by formula (VI), with a yield of 98.2%.

[0071] (5) Synthesis of the compound represented by formula (VII)

[0072] 97.1 g of the compound represented by formula (VI) was dissolved in methanol, and 70.4 g of sodium carbonate was slowly added, and stirred at room temperature for 3 hours. After TLC detection, the reaction was complete, and EA was extracted, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 56.5 g of the compound represented by formula (VII), with a yield of 89%.

[0073] The above descriptions are only preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Other embodiments obtained by those skilled in the art without creative work should all fall within the protection scope of the present invention.

Claims

1. A method for preparing (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester, characterized in that The reaction formula is as follows: The following steps are involved: 1) dissolving trityl phosphonium bromide in THF, slowly adding potassium tert-butoxide at 0°C, heating to 25°C and stirring for 1h after the addition, then cooling again, dropping the compound of formula (I) dissolved in THF at 0°C, slowly heating to room temperature and stirring for 3h after the addition; LC detection shows that the reaction is complete, after the reaction is completed, quenching the reaction with saturated NH4Cl solution, extracting with EA, drying over anhydrous sodium sulfate, spin drying, and column chromatography to obtain a compound of formula (II); 2) dissolving the compound represented by formula (II) in a mixed solution of EtOH and THF, then cooling to 0°C, slowly adding NaBH4 in sequence, controlling the temperature of the reaction system to 0-5°C and stirring for 0.5h, then warming to room temperature and stirring for 3 hours; TLC detection shows that the reaction is complete, quenching the reaction with dilute hydrochloric acid, extracting with EA, drying over anhydrous sodium sulfate, spin drying, and column chromatography to obtain the compound represented by formula (III); 3) dissolving the compound represented by formula (III) in DMF, adding alkali in batches, then lowering the system temperature to 0°C, adding solid iodine in batches, slowly warming to room temperature and stirring for 12 hours after the addition is complete; after TLC detection, quenching with sodium bisulfite solution, extracting with EA, drying over anhydrous sodium sulfate, spin drying, and column chromatography to obtain the compound represented by formula (IV); 4) dissolving the compound represented by formula (IV) in THF, and then sequentially adding the compound represented by formula (V) and 18-crown ether-6; heating to 90° C. and stirring for 2 h; after TLC detection of the reaction being complete, cooling to room temperature, extracting with EA, drying over anhydrous sodium sulfate, spin drying, and column chromatography to obtain the compound represented by formula (VI); 5) The compound represented by formula (VI) was dissolved in methanol, and then a base was slowly added and stirred at room temperature for 3 hours; TLC detection was performed. After the reaction was complete, EA extraction was performed, the mixture was dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain the compound represented by formula (VII).

2. The method for preparing (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester according to claim 1, characterized in that: In step 1), the molar ratio of trityl phosphonium bromide to the compound represented by formula (I) is (1.1-1.5):1; the molar ratio of potassium tert-butoxide to the compound represented by formula (I) is (1.1-1.5):

1.

3. The method for preparing (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester according to claim 1, characterized in that: In step 2), the volume ratio of EtOH and THF in the mixed solution is (1-10):1; the molar ratio of NaBH4 to the compound represented by formula (II) is (1.5-3):

1.

4. The method for preparing (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester according to claim 1, characterized in that: In step 3), the molar ratio of iodine to the compound represented by formula (III) is (1.5-3):1; the base is sodium carbonate or potassium carbonate, and the molar ratio of the added base to the compound represented by formula (III) is (2-3):

1.

5. The method for preparing (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester according to claim 1, characterized in that: In step 4), the molar ratio of the compound represented by formula (V) to the compound represented by formula (IV) is (1.2-2):1; the molar ratio of the 18-crown ether-6 to the compound represented by formula (IV) is (0.01-0.05):

1.

6. The method for preparing tert-butyl (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate according to claim 1, characterized in that: In step 5), the base is one of sodium hydroxide and sodium carbonate, and the molar ratio of the added base to the compound represented by formula (III) is (1.5-3):

1.

7. The method for preparing tert-butyl (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate according to claim 1, characterized in that The preparation method of the compound represented by formula (V) is as follows: The compound represented by formula (V) comprises the following steps: The compound represented by formula (VIII) was dissolved in ethanol, the temperature was lowered to 0°C, solid potassium tert-butoxide was slowly added, and the mixture was stirred for 3 hours. After the reaction was completed as detected by TLC, the reaction solution was filtered, the solid was washed with ethanol and tert-methyl ether, and dried to obtain the compound represented by formula (V).

8. The method for preparing (1S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester according to claim 7, characterized in that: The molar ratio of the potassium tert-butoxide to the compound represented by formula (III) is (1.1-1.5):1.

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