A method for preparing capravirine intermediates based on catalytic oxidation by yeast alcohol dehydrogenase

Abstract

This invention discloses a method for preparing caprepinephrine intermediates based on yeast alcohol dehydrogenase-catalyzed oxidation, comprising the following steps: N-Boc-4-piperidinol is oxidized using yeast alcohol dehydrogenase oxidase to generate intermediate 1; after purification, at least one of aminourea, tert-butyloxycarbonylhydrazine, or methyl hydrazide is added and reacted with a base to generate intermediate 2; DMF-DMA is then added and reacted with a base to generate intermediate 3; benzyl bromide is added and reacted with a basic salt to generate intermediate 4; finally, an acid is added and reacted to generate caprepinephrine intermediates. This invention uses a novel synthetic route. The new process route utilizes inexpensive and readily available aminourea, avoiding the use of hydrated hydrazine, which severely pollutes water bodies, and avoids the use of highly toxic methylhydrazine. Furthermore, the synthetic steps can employ a condensation process and a microchannel continuous flow process, resulting in a simple process, high yield, good safety, and high product quality.

Description

Technical Field

[0001] This invention relates to the field of capreline intermediate synthesis, and particularly to a method for preparing capreline intermediates based on yeast alcohol dehydrogenase-catalyzed oxidation. Background Technology

[0002] Capreline, as an auxin-releasing peptide agonist, can be used to induce hunger and increase appetite. It can be used to treat chronic anorexia and anorexia, and to alleviate long-term weight loss in mammals caused by drug treatment. Most existing methods for preparing capreline intermediates employ methods such as... Figure 1 The existing process route for preparation uses expensive raw materials, and the synthesis step requires the use of methylhydrazine, which is highly toxic and explosive. This results in high costs, environmental pollution, and safety hazards in the production process.

[0003] Based on this, the inventor developed such as Figure 2 The proposed process route, which uses hydrazine hydrate followed by methylation in the synthesis process, avoids the use of methylhydrazine. However, the hydrazine hydrate used in the above steps also pollutes water bodies and results in a low product yield. Based on this, the inventors developed the synthesis method of this invention, such as... Figure 3 The new process route for preparing caprepinephrine intermediates avoids the use of hydrazine hydrate, which severely pollutes water bodies, and avoids the use of highly toxic methylhydrazine. It adopts inexpensive and readily available aminourea, and the intermediate steps can be carried out using cascade technology and microchannel continuous flow technology. The process is simple, has a high yield, good safety, and high product quality. Summary of the Invention

[0004] Based on the above research results, this invention discloses a method for preparing caprelin intermediates based on yeast alcohol dehydrogenase catalytic oxidation, comprising the following steps: N-Boc-4-piperidinol is oxidized using yeast alcohol dehydrogenase catalytic oxidation to generate intermediate 1; after purification, at least one of aminourea, tert-butyloxycarbonylhydrazine, or methyl hydrazine carbamate and a base are added to generate intermediate 2; DMF-DMA and a base are then added to generate intermediate 3; benzyl bromide and a basic salt are added to generate intermediate 4; and finally, an acid is added to generate the caprelin intermediate. This invention uses a novel synthetic route. The new process avoids the use of hydrated hydrazine, which severely pollutes water bodies, and avoids the use of highly toxic methylhydrazine, using inexpensive and readily available aminourea. Furthermore, the intermediate steps can employ a condensation process and a microchannel continuous flow process, resulting in a simple process, high yield, good safety, and high product quality.

[0005] Specifically, this invention provides a method for preparing caprelin intermediates based on yeast alcohol dehydrogenase-catalyzed oxidation, see [link to relevant documentation]. Figure 3 As shown, it includes the following steps:

[0006] S1: N-Boc-4-piperidinol is added to an organic solvent, along with oxidized coenzyme nicotinamide adenine dinucleotide and yeast alcohol dehydrogenase. The reaction is carried out to obtain intermediate product 1. The structural formula of N-Boc-4-piperidinol is shown in a1, and the structural formula of intermediate product 1 is shown in a2.

[0007]

[0008] S2: Add intermediate product 1 to deionized water, add raw material a and base, and react to obtain intermediate product 2. The structural formula of intermediate product 2 is shown in a5. The raw material a is selected from aminourea, tert-butoxycarbonylhydrazine or methyl hydrazine carbamate.

[0009]

[0010] S3: Intermediate product 2, N,N-dimethylformamide dimethyl acetal (DMF-DMA), is mixed with a base and reacted to obtain intermediate product 3, the structural formula of which is shown in a6.

[0011]

[0012] S4: Add intermediate product 3, benzyl bromide and basic salt to an organic solvent and react to obtain intermediate product 4. The structural formula of intermediate product 4 is shown in a7.

[0013]

[0014] S5: Add intermediate product 4 and acid to an organic solvent to react and obtain caprelin intermediate, the structural formula of which is shown in a8;

[0015]

[0016] Further, in step S1, the solvent is selected from dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, and n-heptane; the molar concentration of the oxidized coenzyme nicotinamide adenine dinucleotide in the solution is greater than 10 mM; the mass ratio of yeast alcohol dehydrogenase to N-Boc-4-piperidinol is not less than 0.1:50; the enzyme activity of the yeast alcohol dehydrogenase is 1.8 u / mg; the reaction temperature is 15-40℃; and the reaction time is 8-16 h.

[0017] Furthermore, in step S1, the solvent is dichloromethane, the reaction temperature is 25°C, and the reaction time is 12 hours.

[0018] Furthermore, in step S2, the molar ratio of intermediate product 1, raw material a, and alkali is 1:1.5-3:3-6, the reaction temperature is 55-80℃, and the reaction time is 8-16h.

[0019] Furthermore, in step S2, raw material a is aminourea, the base is sodium hydroxide, the intermediate product 1 has a molar ratio of aminourea to NaOH of 1:2:4, the reaction temperature is 75℃, and the reaction time is 12h.

[0020] Furthermore, in step S3, the molar ratio of intermediate product 2, DMF-DMA and base is 1:2-4:4-8, the reaction temperature is 60-90℃, and the reaction time is 8-16h.

[0021] Furthermore, in step S3, the alkali is sodium hydroxide, the molar ratio of intermediate product 2, DMF-DMA and NaOH is 1:3:6, the reaction temperature is 85℃, and the reaction time is 10h.

[0022] Furthermore, in step S4, the solvent is selected from DMF or tetrahydrofuran, and the basic salt is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, or sodium bicarbonate; the molar ratio of intermediate product 3, benzyl bromo, and base is 1:1.2-1.5:1-1.5; the reaction temperature is 15-40℃, and the reaction time is 16-48h.

[0023] Furthermore, in step S5, the solvent is selected from dichloromethane or ethyl acetate; the acid is selected from hydrochloric acid or trifluoroacetic acid; the molar ratio of intermediate product 4 to acid is 1:3-5; the reaction temperature is 25-40℃; and the reaction time is 2-4h.

[0024] Furthermore, in step S4, the solvent is selected from DMF, the base is selected from potassium carbonate; the molar ratio of intermediate product 3, benzyl bromo and potassium carbonate is 1:1.35:1.25; the reaction temperature is 25℃, and the reaction time is 48h.

[0025] Furthermore, in step S5, the solvent is selected from ethyl acetate; the molar ratio of intermediate product 4 to acid is 1:4, the reaction temperature is 25°C, and the reaction time is 2 hours.

[0026] Beneficial technical effects

[0027] Compared with existing technologies, this invention provides a new process route for preparing caprepinephrine intermediates. The new process route avoids the use of hydrazine hydrate, which severely pollutes water bodies, and avoids the use of highly toxic methylhydrazine. It uses inexpensive and readily available aminourea instead. Furthermore, the intermediate steps can be carried out using a stacking process and a microchannel continuous flow process. The process is simple, has a high yield, good safety, and high product quality. Attached Figure Description

[0028] Figure 1 This is a flowchart of the synthesis process in the existing technology.

[0029] Figure 2This is a flowchart of the intermediate improved synthesis process.

[0030] Figure 3 This is a flowchart of the synthesis process of the present invention.

[0031] Figure 4 The NMR spectrum of intermediate product 4 of this invention. Detailed Implementation

[0032] The technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings and specific embodiments. However, those skilled in the art will understand that the embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, and should not be regarded as limiting the scope of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall be followed. Where the manufacturers of reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0033] See Figure 3 As shown in Figure a1, the structural formula of N-Boc-4-piperidinol in this invention is shown in Figure a2; the structural formula of intermediate product 1 is shown in Figure a5; the structural formula of intermediate product 3 is shown in Figure a6; the structural formula of intermediate product 4 is shown in Figure a7; and the structural formula of caprelin intermediate is shown in Figure a8.

[0034] Example 1:

[0035] S1: 50g of N-Boc-4-piperidinol was added to 75g of dichloromethane, and oxidized coenzyme nicotinamide adenine dinucleotide was added until the molar concentration in the solution reached 10mM. The mixture was stirred at 15℃ for 10min, and 0.1g of yeast alcohol dehydrogenase with an enzyme activity of 1.8u / mg was added. The mixture was kept at 15℃ for 16h. After the reaction was completed, water was added to remove the solvent, and a white solid precipitated out. The filter cake was washed with an appropriate amount of water and dried to obtain intermediate product 1. Yield: 94.5%, purity: 98.5%.

[0036] S2: Add 50g of intermediate product 1 to 100g of deionized water, then add 28.26g of aminourea and 30.11g of NaOH. The molar ratio of aminourea to NaOH in intermediate product 1 is 1:1.5:3. Stir and heat to 55℃ for 16h. After the reaction is complete, cool to room temperature. A white solid precipitates. Wash the filter cake with an appropriate amount of water and dry to obtain intermediate product 2. Yield: 90.3%, purity: 98.7%.

[0037] S3: Mix 50g of intermediate product 2, 49.83g of N,N-dimethylformamide dimethyl acetal (DMF-DMA), and 33.43g of NaOH. The molar ratio of intermediate product 2, DMF-DMA, and NaOH is 1:2:4. Stir and heat to 60℃ for 16h. After the reaction is complete, intermediate product 3 is obtained. Yield: 85.3%, purity: 99.5%.

[0038] S4: Add 50g of intermediate product 3 to 100g of DMF, add 66.94g of benzyl bromine and 27.27g of potassium carbonate, wherein the molar ratio of intermediate product 3, benzyl bromine and potassium carbonate is 1:1.2:1; keep the mixture at 15℃ for 48h; after the reaction is complete, wash with water, filter, recrystallize with ethyl acetate, and dry to obtain intermediate product 4; yield: 96.3%, purity: 98.5%;

[0039] S5: Add 50g of intermediate product 4 to 100g of ethyl acetate, add 45.50g of 36wt% hydrochloric acid, the molar ratio of intermediate product 4 to hydrochloric acid is 1:3, stir the reaction at 25℃ for 4h, after the reaction is completed, remove the solvent, adjust the pH to 7, wash the filter cake with an appropriate amount of water to obtain caprelin intermediate, yield: 98.0%, purity: 99.0%.

[0040] Example 2:

[0041] S1: 50g of N-Boc-4-piperidinol was added to 75g of dichloromethane, and oxidized coenzyme nicotinamide adenine dinucleotide was added until the molar concentration in the solution reached 10mM. The mixture was stirred at 40℃ for 10min, and 0.1g of yeast alcohol dehydrogenase with an enzyme activity of 1.8u / mg was added. The mixture was kept at 40℃ for 8h. After the reaction was completed, water was added to remove the solvent, and a white solid precipitated out. The filter cake was washed with an appropriate amount of water and dried to obtain intermediate product 1. Yield: 95.0%, purity: 97.5%.

[0042] S2: Add 50g of intermediate product 1 to 100g of deionized water, then add 56.52g of aminourea and 60.23g of NaOH. The molar ratio of aminourea to NaOH in intermediate product 1 is 1:3:6. Stir and heat to 80℃ for 8h. After the reaction is complete, cool to room temperature. A white solid precipitates. Wash the filter cake with an appropriate amount of water and dry to obtain intermediate product 2. Yield: 90.5%, purity: 98.0%.

[0043] S3: Mix 50g of intermediate product 2, 99.65g of N,N-dimethylformamide dimethyl acetal (DMF-DMA), and 66.87g of NaOH. The molar ratio of intermediate product 2, DMF-DMA, and NaOH is 1:4:8. Stir and heat to 90℃ for 8 hours. After the reaction is complete, intermediate product 3 is obtained. Yield: 85.5%, purity: 99.0%.

[0044] S4: Add 50g of intermediate product 3 to 100g of DMF, add 83.68g of benzyl bromide and 40.91g of potassium carbonate, wherein the molar ratio of intermediate product 3, benzyl bromide and potassium carbonate is 1:1.5:1.5; keep the reaction at 40℃ for 16h, after the reaction is completed, wash with water, filter, recrystallize with ethyl acetate, and dry to obtain intermediate product 4; yield: 96.5%, purity: 98.2%;

[0045] S5: Add 50g of intermediate product 4 to 100g of ethyl acetate, add 75.83g of 36wt% hydrochloric acid, the molar ratio of intermediate product 4 to hydrochloric acid is 1:5, stir the reaction at 40℃ for 2h, after the reaction is completed, remove the solvent, adjust the pH to 7, wash the filter cake with an appropriate amount of water to obtain caprelin intermediate, yield: 97.8%, purity: 99.2%.

[0046] Example 3:

[0047] S1: 50g of N-Boc-4-piperidinol was added to 75g of dichloromethane, and oxidized coenzyme nicotinamide adenine dinucleotide was added until the molar concentration in the solution reached 10mM. The mixture was stirred at 25℃ for 10min, and 0.1g of yeast alcohol dehydrogenase with an enzyme activity of 1.8u / mg was added. The mixture was kept at 25℃ for 12h. After the reaction was completed, water was added to remove the solvent, and a white solid precipitated out. The filter cake was washed with an appropriate amount of water and dried to obtain intermediate product 1. Yield: 97.3%, purity: 98.5%.

[0048] S2: Add 50g of intermediate product 1 to 100g of deionized water, then add 37.68g of aminourea and 40.15g of NaOH. The molar ratio of aminourea to NaOH in intermediate product 1 is 1:2:4. Stir and heat to 75℃ for 12h. After the reaction is complete, cool to room temperature. A white solid precipitates. Wash the filter cake with an appropriate amount of water and dry to obtain intermediate product 2. Yield: 92.5%, purity: 98.7%.

[0049] S3: Mix 50g of intermediate product 2, 74.74g of N,N-dimethylformamide dimethyl acetal (DMF-DMA), and 50.15g of NaOH. The molar ratio of intermediate product 2, DMF-DMA, and NaOH is 1:3:6. Stir and heat to 85℃ for 10h. After the reaction is complete, intermediate product 3 is obtained. Yield: 87.3%, purity: 99.5%.

[0050] S4: Add 50g of intermediate product 3 to 100g of DMF, add 75.31g of benzyl bromo and 34.09g of potassium carbonate, wherein the molar ratio of intermediate product 3, benzyl bromo, and potassium carbonate is 1:1.35:1.25; keep the mixture at 25℃ for 48h; after the reaction is complete, wash with water, filter, recrystallize with ethyl acetate, and dry to obtain intermediate product 4; yield: 97.3%, purity: 98.5%;

[0051] S5: Add 50g of intermediate product 4 to 100g of ethyl acetate, add 60.66g of 36wt% hydrochloric acid, the molar ratio of intermediate product 4 to hydrochloric acid is 1:4, stir the reaction at 25℃ for 2h, after the reaction is completed, remove the solvent, adjust the pH to 7, wash the filter cake with an appropriate amount of water to obtain caprelin intermediate, yield: 98.5%, purity: 99.5%.

[0052] Example 4:

[0053] S1: 50g of N-Boc-4-piperidinol was added to 75g of toluene, and oxidized coenzyme nicotinamide adenine dinucleotide was added until the molar concentration in the solution reached 10mM. The mixture was stirred at 25℃ for 10min, and 0.1g of yeast alcohol dehydrogenase with an enzyme activity of 1.8u / mg was added. The mixture was kept at 25℃ for 12h. After the reaction was completed, water was added to remove the solvent, and a white solid precipitated out. The filter cake was washed with an appropriate amount of water and dried to obtain intermediate product 1. Yield: 97.0%, purity: 98.2%.

[0054] S2: Add 50g of intermediate product 1 to 100g of deionized water, then add 37.68g of aminourea and 40.15g of NaOH. The molar ratio of aminourea to NaOH in intermediate product 1 is 1:2:4. Stir and heat to 75℃ for 12h. After the reaction is complete, cool to room temperature. A white solid precipitates. Wash the filter cake with an appropriate amount of water and dry to obtain intermediate product 2. Yield: 92.5%, purity: 98.7%.

[0055] S3: Mix 50g of intermediate product 2, 74.74g of N,N-dimethylformamide dimethyl acetal (DMF-DMA), and 50.15g of NaOH. The molar ratio of intermediate product 2, DMF-DMA, and NaOH is 1:3:6. Stir and heat to 85℃ for 10h. After the reaction is complete, intermediate product 3 is obtained. Yield: 87.3%, purity: 99.5%.

[0056] S4: 50g of intermediate product 3 was added to 100g of tetrahydrofuran, along with 75.31g of benzyl bromide and 34.09g of potassium carbonate. The molar ratio of intermediate product 3, benzyl bromide, and potassium carbonate was 1:1.35:1.25. The reaction was maintained at 25℃ for 48h. After the reaction was completed, the mixture was washed with water, filtered, recrystallized from ethyl acetate, and dried to obtain intermediate product 4. Yield: 97.2%, purity: 98.2%.

[0057] S5: Add 50g of intermediate product 4 to 100g of dichloromethane, add 60.66g of 36wt% hydrochloric acid, the molar ratio of intermediate product 4 to hydrochloric acid is 1:4, stir and react at 25℃ for 2h. After the reaction is completed, remove the solvent, adjust the pH to 7, and wash the filter cake with an appropriate amount of water to obtain caprelin intermediate. Yield: 98.4%, purity: 99.3%.

[0058] Example 5:

[0059] S1: 50g of N-Boc-4-piperidinol was added to 75g of dichloromethane, and oxidized coenzyme nicotinamide adenine dinucleotide was added until the molar concentration in the solution reached 10mM. The mixture was stirred at 20℃ for 10min, and 0.1g of yeast alcohol dehydrogenase with an enzyme activity of 1.8u / mg was added. The mixture was kept at 20℃ for 12h. After the reaction was completed, water was added to remove the solvent, and a white solid precipitated out. The filter cake was washed with an appropriate amount of water and dried to obtain intermediate product 1. Yield: 96.0%, purity: 97.8%.

[0060] S2: Add 50g of intermediate product 1 to 100g of deionized water, then add 47.1g of aminourea and 50.19g of NaOH. The molar ratio of aminourea to NaOH in intermediate product 1 is 1:2.5:5. Stir and heat to 60℃ for 10h. After the reaction is complete, cool to room temperature. A white solid precipitates. Wash the filter cake with an appropriate amount of water and dry to obtain intermediate product 2. Yield: 92.2%, purity: 98.0%.

[0061] S3: Mix 50g of intermediate product 2, 74.74g of N,N-dimethylformamide dimethyl acetal (DMF-DMA), and 41.79g of NaOH. The molar ratio of intermediate product 2, DMF-DMA, and NaOH is 1:3:5. Stir and heat to 70℃ for 15h. After the reaction is complete, intermediate product 3 is obtained. Yield: 86.2%, purity: 98.8%.

[0062] S4: Add 50g of intermediate product 3 to 100g of DMF, add 78.10g of benzyl bromine and 32.73g of potassium carbonate. The molar ratio of intermediate product 3, benzyl bromine and potassium carbonate is 1:1.4:1.2. Keep the mixture at 30℃ for 32h. After the reaction is complete, wash with water, filter, recrystallize with ethyl acetate, and dry to obtain intermediate product 4. Yield: 98.2%, purity: 98.3%.

[0063] S5: Add 50g of intermediate product 4 to 100g of ethyl acetate, add 53.08g of 36wt% hydrochloric acid, the molar ratio of intermediate product 4 to hydrochloric acid is 1:3.5, stir the reaction at 40℃ for 3h, after the reaction is completed, remove the solvent, adjust the pH to 7, wash the filter cake with an appropriate amount of water to obtain caprelin intermediate, yield: 98.3%, purity: 99.4%.

[0064] Example 6:

[0065] S1: 50g of N-Boc-4-piperidinol was added to 75g of dichloromethane, and oxidized coenzyme nicotinamide adenine dinucleotide was added until the molar concentration in the solution reached 10mM. The mixture was stirred at 35℃ for 10min, and 0.1g of yeast alcohol dehydrogenase with an enzyme activity of 1.8u / mg was added. The mixture was kept at 35℃ for 10h. After the reaction was completed, water was added to remove the solvent, and a white solid precipitated out. The filter cake was washed with an appropriate amount of water and dried to obtain intermediate product 1. Yield: 96.5%, purity: 98.1%.

[0066] S2: Add 50g of intermediate product 1 to 100g of deionized water, then add 47.1g of aminourea and 40.15g of NaOH. The molar ratio of aminourea to NaOH in intermediate product 1 is 1:2.5:4. Stir and heat to 65℃ for 12h. After the reaction is complete, cool to room temperature. A white solid precipitates. Wash the filter cake with an appropriate amount of water and dry to obtain intermediate product 2. Yield: 91.5%, purity: 98.2%.

[0067] S3: Mix 50g of intermediate product 2, 99.65g of N,N-dimethylformamide dimethyl acetal (DMF-DMA), and 50.15g of NaOH. The molar ratio of intermediate product 2, DMF-DMA, and NaOH is 1:4:6. Stir and heat to 75℃ for 12h. After the reaction is complete, intermediate product 3 is obtained. Yield: 87.0%, purity: 99.2%.

[0068] S4: Add 50g of intermediate product 3 to 100g of DMF, add 83.68g of benzyl bromide and 34.09g of potassium carbonate, wherein the molar ratio of intermediate product 3, benzyl bromide and potassium carbonate is 1:1.5:1.25; keep the mixture at 20℃ for 36h; after the reaction is complete, wash with water, filter, recrystallize with ethyl acetate, and dry to obtain intermediate product 4; yield: 98.2%, purity: 98.3%;

[0069] S5: Add 50g of intermediate product 4 to 100g of ethyl acetate, add 60.66g of 36wt% hydrochloric acid, the molar ratio of intermediate product 4 to hydrochloric acid is 1:4, stir and react at 40℃ for 2h. After the reaction is completed, remove the solvent, adjust the pH to 7, and wash the filter cake with an appropriate amount of water to obtain caprelin intermediate. Yield: 98.5%, purity: 99.2%.

[0070] like Figure 4 As can be seen, the synthesis process of the present invention has successfully synthesized intermediate product 4. As can be seen from Examples 1-6 of the present invention, the caprerelin intermediate was successfully prepared through the new process route. The new process route avoids the use of hydrazine hydrate, which seriously pollutes water bodies, and avoids the use of highly toxic methylhydrazine, using inexpensive and readily available aminourea. Moreover, the yield and purity of the intermediate steps are relatively high. Except for the yield of step 3, which is over 85%, the yields of other steps all reach over 94%, and the purity all reach over 97%. Example 3 of the present invention is the optimal example, and its yield and purity have basically reached the highest values. Because the yield and purity of the process steps of the present invention are high, the intermediate steps can adopt the stacking process and the microchannel continuous flow process, which can be used for continuous production and simplify the process.

[0071] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the claimed invention.

Claims

1. A method for preparing caprelin intermediates based on yeast alcohol dehydrogenase-catalyzed oxidation, characterized in that: Includes the following steps: S1: N-Boc-4-piperidinol is added to an organic solvent, along with oxidized coenzyme nicotinamide adenine dinucleotide and yeast alcohol dehydrogenase. The reaction is carried out to obtain intermediate product 1. The structural formula of N-Boc-4-piperidinol is shown in a1, and the structural formula of intermediate product 1 is shown in a2. S2: Add intermediate product 1 to deionized water, add raw material a and base, and react to obtain intermediate product 2. The structural formula of intermediate product 2 is shown in a5. The raw material a is selected from aminourea, tert-butoxycarbonylhydrazine or methyl hydrazine carbamate. S3: Intermediate product 2, N,N-dimethylformamide dimethyl acetal (DMF-DMA), is mixed with a base and reacted to obtain intermediate product 3, the structural formula of which is shown in a6. S4: Add intermediate product 3, benzyl bromide and basic salt to an organic solvent and react to obtain intermediate product 4. The structural formula of intermediate product 4 is shown in a7. S5: Add intermediate product 4 and acid to an organic solvent to react and obtain caprelin intermediate, the structural formula of which is shown in a8; 2. The preparation method according to claim 1, characterized in that: In step S1, the solvent is selected from dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, and n-heptane; the molar concentration of the oxidized coenzyme nicotinamide adenine dinucleotide in the solution is greater than 10 mM; the mass ratio of yeast alcohol dehydrogenase to N-Boc-4-piperidinol is not less than 0.1:50; the enzyme activity of the yeast alcohol dehydrogenase is 1.8 u / mg; the reaction temperature is 15-40℃; and the reaction time is 8-16 h.

3. The preparation method according to claim 2, characterized in that: In step S1, the solvent is dichloromethane, the reaction temperature is 25°C, and the reaction time is 12 hours.

4. The preparation method according to claim 1, characterized in that: In step S2, the intermediate product 1 has a molar ratio of raw material a to alkali of 1:1.5-3:3-6, a reaction temperature of 55-80℃, and a reaction time of 8-16h.

5. The preparation method according to claim 4, characterized in that: In step S2, raw material a is aminourea, the base is sodium hydroxide, the intermediate product 1 has a molar ratio of aminourea to NaOH of 1:2:4, the reaction temperature is 75℃, and the reaction time is 12h.

6. The preparation method according to claim 1, characterized in that: In step S3, the molar ratio of intermediate product 2, DMF-DMA and base is 1:2-4:4-8, the reaction temperature is 60-90℃, and the reaction time is 8-16h.

7. The preparation method according to claim 1, characterized in that: In step S3, the alkali is sodium hydroxide, the molar ratio of intermediate product 2, DMF-DMA and NaOH is 1:3:6, the reaction temperature is 85℃, and the reaction time is 10h.

8. The preparation method according to claim 1, characterized in that: In step S4, the solvent is selected from DMF or tetrahydrofuran, and the basic salt is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, or sodium bicarbonate; the molar ratio of intermediate product 3, benzyl bromo, and base is 1:1.2-1.5:1-1.5; the reaction temperature is 15-40℃, and the reaction time is 16-48h.

9. The preparation method according to claim 1, characterized in that: In step S5, the solvent is selected from dichloromethane or ethyl acetate; the acid is selected from hydrochloric acid or trifluoroacetic acid; the molar ratio of intermediate product 4 to acid is 1:3-5; the reaction temperature is 25-40℃; and the reaction time is 2-4h.

10. The preparation method according to claim 8 or 9, characterized in that: In step S4, the solvent is selected from DMF, and the base is selected from potassium carbonate; the molar ratio of intermediate product 3, benzyl bromo, and potassium carbonate is 1:1.35:1.25; the reaction temperature is 25℃, and the reaction time is 48h; in step S5, the solvent is selected from ethyl acetate; the molar ratio of intermediate product 4 to acid is 1:4, the reaction temperature is 25℃, and the reaction time is 2h.

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